Allergic Bronchopulmonary Aspergillosis
Conditions
Keywords
ABPA, Asthma, Voriconazole, Allergic Bronchopulmonary Aspergillosis
Brief summary
The primary safety objectives were: * Part 1: To determine the safety and tolerability of single doses of ZP-059 in healthy subjects * Part 2: To determine the safety and tolerability of multiple doses of ZP-059 in subjects with mild stable asthma * Part 3: To determine the safety and tolerability of single doses of ZP-059 in subjects with mild to moderate stable asthma. The primary PK objectives were: * Part 1: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 in healthy subjects * Part 2: To characterize systemic PK of voriconazole and N-oxide voriconazole after multiple doses of ZP-059 in subjects with mild stable asthma * Part 3: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 and single doses of oral voriconazole in subjects with mild to moderate stable asthma.
Detailed description
This was an integrated Phase 1, single centre, multi-part, open-label study in both healthy subjects (Part 1), subjects with mild stable asthma (Part 2) and subjects with mild to moderate stable asthma (Part 3). In all three parts of the study every effort was made to include as close as possible an equal balance between male and female subjects. This study assessed safety, tolerability and PK of single and multiple ascending doses of ZP-059 capsules administered as dry powder for inhalation in Part 1 to healthy volunteers (single ascending dose; SAD) and in Part 2 to subjects with mild asthma (multiple ascending dose; MAD), respectively. In Part 3, the bioavailability of ZP-059 in subjects with mild to moderate stable asthma were compared to that of oral voriconazole. Part 3 started only after review of safety data from cohorts 1 to 4 of Part 1 (SAD) have been completed. Parts 2 and 3 of the study also explored voriconazole concentrations in induced sputum samples in asthmatic subjects. As part of the safety and tolerability assessment, this study investigated the effects of ZP-059 on airway function in both mild and mild to moderate stable asthma subjects.
Interventions
DRUGVoriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a 4 \[20mg BID\] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
DRUGoral voriconazole
Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study.
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Intervention model description
Safety, tolerability and PK will be assessed following either single ascending (SAD) or multiple ascending (MAD) dosing of ZP-059; Part 1 and Part 2, respectively. Part 1 will comprise 4 separate cohorts planned to receive single doses of ZP-059; part 2 will comprise 3 separate cohorts planned to receive daily doses of ZP-059 on Day 1 to 10; part 3 is a 2-period, randomised crossover study in subjects with mild to moderate stable asthma to assess the safety, tolerability and PK of single doses of ZP-059 and single doses of oral voriconazole.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
(part 1): * Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method * Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s) * Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP. * BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening. * Are willing and able to comply with all aspects of the protocol. * FEV1 ≥80% of the predicted value and FEV1/FVC ratio \> 0.70; at screening. * Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1. Inclusion Criteria (part 2): * Subjects with mild stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening. * Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to Day 1. * Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method * Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s). * Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP. * Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening. * Are willing and able to comply with all aspects of the protocol. * Subject is being treated with short acting beta-agonists alone or in conjunction with low to medium doses of ICS. * Pre-bronchodilator FEV1 ≥70% of the predicted value at screening. * Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1. Inclusion Criteria (part 3): * Subjects with mild to moderate stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening. * Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to randomisation. * Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method . * Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s) * Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP. * BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening. * Are willing and able to comply with all aspects of the protocol. * Subject is being treated with low to medium doses of ICS with or without long-acting beta-agonists. * Pre-bronchodilator FEV1 ≥70% of the predicted value at screening. * Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1, Treatment Period 1. * Able to produce a sputum sample with a minimum weight of 50 mg at screening.
Exclusion criteria
(part 1): * Subjects who are Chinese or Japanese. * Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1. * Participation in other interventional studies for the duration of the study. * Subjects who are study site employees or immediate family members of a study site or sponsor employee. * History of any drug or alcohol abuse in the past 2 years prior to screening. * Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type). * Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1. * A confirmed positive urine cotinine test at screening or Day -1. * Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1. * Smoking history of \>5 pack years at screening. * Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause). * Female subject with a positive pregnancy test at screening or pre-dose on Day 1. * Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening. * Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required. * Positive urine drugs of abuse test or alcohol breath test result at screening or Day -1. * History of or currently infected with/carrier of human immunodeficiency virus (HIV). * Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative. * Evidence or history of clinically significant cardiovascular, renal, hepatic, endocrine, immunological or autoimmune, dermatological, ophthalmological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator. * Subjects with congestive heart failure or a history of congestive heart failure. * 12-lead ECGs demonstrating a mean QTcF interval \>450 msec for males or QTcF interval \>470 msec for females at screening or pre-dose Day 1. * History of severe cough or bronchospasm upon inhalation of any inhalation product. * Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients. * Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles. * Presence or history of clinically significant allergy, including drug allergies, but excluding untreated, mild seasonal allergies, as judged by the investigator. Hay fever is allowed unless it is active. * Major trauma or surgery within the last 3 months prior to screening or prior to Day 1. * Planned or elective surgery or hospitalisations for the duration of the study that may interfere with study logistics or safety. * Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening. * Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than ≤4 g per day of paracetamol, hormonal contraception or hormone replacement therapy), dietary supplements or CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the Principal Investigator and sponsor's medical monitor. * Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1. * Any use of voriconazole in the 3 months prior to Day 1. * Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1. * Upper respiratory tract infection (excluding otitis media), fever, acute or chronic cough within 14 days of Day 1, or lower respiratory tract infection within the last 4 weeks prior to Day 1. * Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed. * Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the investigator would make the subject inappropriate for entry into the study. * Failure to satisfy the investigator of fitness to participate for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Part 1: screening (Day -28 to -1) to follow-up (8 to 12 days after last dose); part 2: screening (Day -28 to -1) to follow-up (11-17 days after last dose); Part 3: screening (Day -28 to -1) to follow-up (8-12 days after last dose of study drug). | An AE is any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of IMP, whether or not considered related to the study IMP. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given; |
| Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value. |
| Kel for Voriconazole and N-oxide Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h. |
| CL/F for Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. |
| Vz/F for Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | Vz/F=Apparent volume of distribution during terminal phase. |
| MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) |
| MR Cmax for N-oxide Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. |
| AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-24 for Part 2) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity |
| Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given; |
| Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value. |
| Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h. |
| CL/F for Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. |
| Swing for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Swing for voriconazole and N-oxide voriconazole = \[(Cmax - Cmin) / Cmin\]\*100% |
| AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Area under the serum concentration time curve for the dosing interval |
| Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Css,av or Css(ave): Average drug concentration at steady state; Steady-state concentration (Css) occurs when the amount of a drug being absorbed is the same amount that's being cleared from the body when the drug is given continuously or repeatedly |
| AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). | AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-12 for Part 1) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity |
| Rac for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Accumulation ratio. The drug accumulation ratio (Rac) is the ratio of accumulation of a drug under steady state conditions as compared to a single dose. The higher the value, the more the drug accumulates in the body. An Rac of 1 means no accumulation. |
| Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Rlinear means linearity ratio for Area Under the Serum Concentration-Time Curve from time zero to infinity. |
| MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) |
| MR Cmax N-oxide Voriconazole - Part 2 | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. |
| Cmax for Voriconazole and N-oxide Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 | Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given; |
| Vz/F for Voriconazole - Part 3 | Only at Day 10 | Vz/F=Apparent volume of distribution during terminal phase. |
| AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 | AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-96 for Part 3) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity |
| Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 (Pre-dose, 0.25h, 0.75h 1.5h, 2h ,3h ,4h ,6h ,8h ,12h ,16h , 24h ,48h after dosing) | Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value. |
| CL/F for Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 | Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. |
| Kel for Voriconazole and N-oxide Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 | Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h. |
| MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) |
| MR Cmax for N-oxide Voriconazole - Part 3 | Day 1 of the respective treatment period 1 or 2 | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. |
| Bioavailability of Voriconazole - Cmax | On Day 1 in Parts 1-3 and on Day 10 in Part 2 | The Cmax estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The Cmax was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, Cmax was estimated only on Day1. In Part 2, Cmax was estimated on Day 10. |
| Bioavailability of Voriconazole - AUC-inf | On Day 1 in Parts 1-3 and on Day 10 in Part 2 | The AUC0-inf estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The AUC0-inf was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, AUC0-inf was estimated on Day 1. In part 2, AUC0-in f was estimated on Day 10. |
| Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) | Peak trough fluctuation in serum concentrations within one dosing interval at steady state. Fluctuation - Over the Dosing Interval - is expressed as percentage concentration. |
Countries
United Kingdom
Participant flow
Recruitment details
The investigator or his/her representative explained the nature of the study to the subject and answered all questions regarding the study. Subjects had to be informed that their participation was voluntary. Subjects were required to sign a statement of informed consent that met the requirements of UK regulations, ICH E6 GCP guidelines, General Data Protection Regulation, and the IEC or study site requirements. The authorized person who obtained the informed consent had to also sign the ICF.
Pre-assignment details
Subjects were screened for eligibility to participate in the study within 28 days before dosing (Day 1). Part 2 and Part 3 subjects who had completed the initial screening visit attended the study site on Day -4 or Day -3, for Covid-19 reverse transcriptase - polymerase chain reaction (RT-PCR) test, together with additional daily tympanic temperature measurements, and other tests as applicable. Subjects were then be admitted to the study site on the evening of Day -1.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - ZP-059 5mg Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 1 - ZP-059 10mg Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 1 - ZP-059 20mg Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 1 - ZP-059 40mg Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 2 - ZP-059 10mg Bid Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10.
Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 2 - ZP-059 20mg Bid Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10.
Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 2 - ZP-059 40mg qd Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10.
Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) administered via DPI (RS01 monodose device) on Days 1 to 10.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | 6 |
| Part 3 - ZP-059 / Oral Voriconazole Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | 8 |
| Part 3 - Oral Voriconazole / ZP-059 Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours.
Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily \[BID\]) or 4 \[20mg BID\]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily \[QD\]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | 8 |
| Total | 58 |
Baseline characteristics
| Characteristic | Total | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 3 - ZP-059 / Oral Voriconazole | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - Oral Voriconazole / ZP-059 |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 58 Participants | 6 Participants | 6 Participants | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 6 Participants | 7 Participants |
| Region of Enrollment United Kingdom | 58 participants | 6 participants | 6 participants | 8 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 8 participants |
| Sex: Female, Male Female | 21 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 37 Participants | 3 Participants | 3 Participants | 7 Participants | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 0 / 6 | 3 / 6 | 2 / 6 | 2 / 6 | 5 / 6 | 4 / 6 | 4 / 6 | 9 / 16 | 7 / 16 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAE)
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of IMP, whether or not considered related to the study IMP.
Time frame: Part 1: screening (Day -28 to -1) to follow-up (8 to 12 days after last dose); part 2: screening (Day -28 to -1) to follow-up (11-17 days after last dose); Part 3: screening (Day -28 to -1) to follow-up (8-12 days after last dose of study drug).
Population: Safety Analysis Set (SAF): subjects who received at least 1 IMP dose, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 0 participants |
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 0 participants |
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 0 participants |
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 0 participants |
| Part 1 - ZP-059 5mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 0 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 3 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 3 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 1 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 0 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 2 participants |
| Part 1 - ZP-059 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 2 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 2 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 0 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 0 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 2 participants |
| Part 1 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 2 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 1 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 1 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 2 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 0 participants |
| Part 1 - ZP-059 40mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 3 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 5 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 1 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 2 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 2 - ZP-059 10mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 4 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 0 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 4 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 3 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 1 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 2 - ZP-059 20mg Bid | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 4 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 1 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 2 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 3 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 2 participants |
| Part 2 - ZP-059 40mg qd | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 4 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 8 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 7 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 9 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 1 participants |
| Part 3 - ZP-059 20mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 2 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 serious TEAE | 0 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 non treatment-related TEAE | 7 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 mild TEAE | 5 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 severe TEAE | 0 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 treatment-related TEAE | 0 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 TEAE | 7 participants |
| Part 3 - Oral Voriconazole 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Total number of subjects with at least 1 moderate TEAE | 2 participants |
Secondary
AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1
AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-12 for Part 1) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t Voriconazole | 24.36 h*ng/mL | Standard Deviation 1.45 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf N-oxide Voriconazole | 337.40 h*ng/mL | Standard Deviation 1.12 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t N-oxide Voriconazole | 298.15 h*ng/mL | Standard Deviation 1.11 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf Voriconazole | 40.00 h*ng/mL | Standard Deviation 1 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t Voriconazole | 73.89 h*ng/mL | Standard Deviation 1.16 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t N-oxide Voriconazole | 573.55 h*ng/mL | Standard Deviation 1.26 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf Voriconazole | 78.94 h*ng/mL | Standard Deviation 1.18 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf N-oxide Voriconazole | 652.99 h*ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf Voriconazole | 203.96 h*ng/mL | Standard Deviation 1.44 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t Voriconazole | 187.76 h*ng/mL | Standard Deviation 1.35 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf N-oxide Voriconazole | 865.80 h*ng/mL | Standard Deviation 1.07 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t N-oxide Voriconazole | 804.24 h*ng/mL | Standard Deviation 1.11 |
| Part 1 - ZP-059 40mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t Voriconazole | 328.37 h*ng/mL | Standard Deviation 1.19 |
| Part 1 - ZP-059 40mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-t N-oxide Voriconazole | 1835.81 h*ng/mL | Standard Deviation 1.09 |
| Part 1 - ZP-059 40mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf Voriconazole | 377.19 h*ng/mL | Standard Deviation 1.2 |
| Part 1 - ZP-059 40mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 | AUC0-inf N-oxide Voriconazole | 1977.21 h*ng/mL | Standard Deviation 1.11 |
Comparison: Statistics for Voriconazole AUC0-tp-value: <0.000190% CI: [0.424, 0.821]General power constant model
Comparison: Statistics for Voriconazole AUC0-tp-value: 0.036390% CI: [1.05, 1.362]General power linear model
Comparison: Statistics for Voriconazole AUC0-t, 40mg vs 5mgp-value: <0.000190% CI: [10.096, 17.994]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-tp-value: <0.000190% CI: [1.728, 1.963]General power constant model
Comparison: Statistics for N-oxide Voriconazole AUC0-tp-value: 0.020190% CI: [0.789, 0.96]General power linear model
Comparison: Statistics for N-oxide Voriconazole AUC0-t, 40mg vs 5mgp-value: <0.000190% CI: [5.253, 7.217]ANOVA
Comparison: Statistics for Voriconazole AUC0-infp-value: <0.000190% CI: [0.661, 0.958]General power constant model
Comparison: Statistics for Voriconazole AUC0-infp-value: 0.127890% CI: [0.99, 1.245]General power linear model
Comparison: Statistics for Voriconazole AUC0-inf, 40mg vs 5mgp-value: <0.000190% CI: [6.834, 13.012]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-infp-value: <0.000190% CI: [1.86, 2.106]General power constant model
Comparison: Statistics for N-oxide Voriconazole AUC0-infp-value: 0.008290% CI: [0.67, 0.912]General power linear model
Comparison: Statistics for N-oxide Voriconazole AUC0-inf, 40mg vs 5mgp-value: <0.000190% CI: [4.627, 7.421]ANOVA
Secondary
AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2
AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-24 for Part 2) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
Time frame: Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t Voriconazole - Day 1 | 69.65 h*ng/mL | Standard Deviation 1.39 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf Voriconazole - Day 1 | 78.20 h*ng/mL | Standard Deviation 1.4 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t Voriconazole - Day 10 | 91.00 h*ng/mL | Standard Deviation 1.36 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf Voriconazole - Day 10 | 97.78 h*ng/mL | Standard Deviation 1.35 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t N-oxide Voriconazole - Day 1 | 391.28 h*ng/mL | Standard Deviation 1.19 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf N-oxide Voriconazole - Day 1 | 439.14 h*ng/mL | Standard Deviation 1.2 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf N-oxide Voriconazole - Day 10 | 752.99 h*ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t N-oxide Voriconazole - Day 10 | 728.68 h*ng/mL | Standard Deviation 1.31 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t Voriconazole - Day 10 | 256.04 h*ng/mL | Standard Deviation 1.41 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t N-oxide Voriconazole - Day 10 | 1784.63 h*ng/mL | Standard Deviation 1.4 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf Voriconazole - Day 10 | 258.66 h*ng/mL | Standard Deviation 1.44 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf N-oxide Voriconazole - Day 10 | 1807.93 h*ng/mL | Standard Deviation 1.47 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t N-oxide Voriconazole - Day 1 | 769.65 h*ng/mL | Standard Deviation 1.15 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf N-oxide Voriconazole - Day 1 | 849.27 h*ng/mL | Standard Deviation 1.17 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t Voriconazole - Day 1 | 139.29 h*ng/mL | Standard Deviation 1.21 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf Voriconazole - Day 1 | 155.72 h*ng/mL | Standard Deviation 1.16 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf Voriconazole - Day 1 | 358.13 h*ng/mL | Standard Deviation 1.2 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t N-oxide Voriconazole - Day 10 | 3353.43 h*ng/mL | Standard Deviation 1.27 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t Voriconazole - Day 1 | 329.28 h*ng/mL | Standard Deviation 1.19 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf Voriconazole - Day 10 | 493.04 h*ng/mL | Standard Deviation 1.29 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf N-oxide Voriconazole - Day 1 | 2001.85 h*ng/mL | Standard Deviation 1.24 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t Voriconazole - Day 10 | 480.22 h*ng/mL | Standard Deviation 1.27 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-t N-oxide Voriconazole - Day 1 | 1990.76 h*ng/mL | Standard Deviation 1.23 |
| Part 1 - ZP-059 20mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 | AUC0-inf N-oxide Voriconazole - Day 10 | 3174.66 h*ng/mL | Standard Deviation 1.19 |
Comparison: Statistics for Voriconazole AUC0-t Day 1p-value: 0.000490% CI: [1.528, 2.617]ANOVA
Comparison: Statistics for Voriconazole AUC0-t Day 1p-value: <0.000190% CI: [3.612, 6.187]ANOVA
Comparison: Statistics for Voriconazole AUC0-t day 10p-value: <0.000190% CI: [2.017, 3.925]ANOVA
Comparison: Statistics for Voriconazole AUC0-t Day 10p-value: <0.000190% CI: [3.783, 7.361]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-t Day 1p-value: <0.000190% CI: [1.615, 2.396]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-t Day 1p-value: <0.000190% CI: [4.178, 6.196]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-t Day 10p-value: 0.000290% CI: [1.791, 3.349]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-t Day 10p-value: <0.000190% CI: [3.365, 6.294]ANOVA
Comparison: Statistics for Voriconazole AUC0-inf Day 1p-value: 0.000590% CI: [1.524, 2.602]ANOVA
Comparison: Statistics for Voriconazole AUC0-inf Day 1p-value: <0.000190% CI: [3.505, 5.984]ANOVA
Comparison: Statistics for Voriconazole AUC0-inf Day 10p-value: 0.000390% CI: [1.851, 3.781]ANOVA
Comparison: Statistics for Voriconazole AUC0-inf Day 10p-value: <0.000190% CI: [3.587, 7.088]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-inf Day 1p-value: <0.000190% CI: [1.569, 2.384]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-inf Day 1p-value: <0.000190% CI: [3.608, 5.759]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-inf Day 10p-value: 0.000790% CI: [1.694, 3.402]ANOVA
Comparison: Statistics for N-oxide Voriconazole AUC0-inf Day 10p-value: <0.000190% CI: [2.975, 5.974]ANOVA
Secondary
AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3
AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-96 for Part 3) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-t Voriconazole | 290.02 h*ng/mL | Standard Deviation 1.87 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-inf Voriconazole | 269.61 h*ng/mL | Standard Deviation 1.56 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-t N-oxide Voriconazole | 1128.69 h*ng/mL | Standard Deviation 1.27 |
| Part 1 - ZP-059 5mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-inf N-oxide Voriconazole | 1154.35 h*ng/mL | Standard Deviation 1.26 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-inf N-oxide Voriconazole | 21788.46 h*ng/mL | Standard Deviation 1.2 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-t Voriconazole | 3726.68 h*ng/mL | Standard Deviation 1.91 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-t N-oxide Voriconazole | 21504.52 h*ng/mL | Standard Deviation 1.2 |
| Part 1 - ZP-059 10mg | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 | AUC0-inf Voriconazole | 3800.41 h*ng/mL | Standard Deviation 1.92 |
Secondary
AUCtau for Voriconazole and N-oxide Voriconazole - Part 2
Area under the serum concentration time curve for the dosing interval
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 82.82 h*ng/mL | Standard Deviation 1.3 |
| Part 1 - ZP-059 5mg | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 620.89 h*ng/mL | Standard Deviation 1.28 |
| Part 1 - ZP-059 10mg | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 215.56 h*ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1438.74 h*ng/mL | Standard Deviation 1.31 |
| Part 1 - ZP-059 20mg | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 427.57 h*ng/mL | Standard Deviation 1.25 |
| Part 1 - ZP-059 20mg | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 2803.51 h*ng/mL | Standard Deviation 1.2 |
Secondary
Bioavailability of Voriconazole - AUC-inf
The AUC0-inf estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The AUC0-inf was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, AUC0-inf was estimated on Day 1. In part 2, AUC0-in f was estimated on Day 10.
Time frame: On Day 1 in Parts 1-3 and on Day 10 in Part 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Bioavailability of Voriconazole - AUC-inf | Parts 1, 2, and 3 - Day 1 | 203.96 h*ng/mL | Standard Deviation 1.44 |
| Part 1 - ZP-059 10mg | Bioavailability of Voriconazole - AUC-inf | Parts 1, 2, and 3 - Day 1 | 155.72 h*ng/mL | Standard Deviation 1.16 |
| Part 1 - ZP-059 10mg | Bioavailability of Voriconazole - AUC-inf | Part 2 - Day 10 | 258.66 h*ng/mL | Standard Deviation 1.44 |
| Part 1 - ZP-059 20mg | Bioavailability of Voriconazole - AUC-inf | Parts 1, 2, and 3 - Day 1 | 269.61 h*ng/mL | Standard Deviation 1.56 |
| Part 1 - ZP-059 40mg | Bioavailability of Voriconazole - AUC-inf | Parts 1, 2, and 3 - Day 1 | 3800.41 h*ng/mL | Standard Deviation 1.92 |
Comparison: Part 3 ZP-059 20mg: Oral Voriconazole (200mg VFEND®)90% CI: [0.059, 0.075]
Comparison: ZP-059 20mg: Part 3 / Part 190% CI: [0.85, 1.891]
Comparison: ZP-059 20mg: Part 3 / Part 2 Day 190% CI: [1.953, 3.544]
Comparison: ZP-059 20mg: Part 3 / Part 2 Day 1090% CI: [1.386, 2.52]
Secondary
Bioavailability of Voriconazole - Cmax
The Cmax estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The Cmax was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, Cmax was estimated only on Day1. In Part 2, Cmax was estimated on Day 10.
Time frame: On Day 1 in Parts 1-3 and on Day 10 in Part 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Bioavailability of Voriconazole - Cmax | Parts 1, 2, and 3 - Day 1 | 53.37 ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | Bioavailability of Voriconazole - Cmax | Part 2 - Day 10 | 57.11 ng/mL | Standard Deviation 1.33 |
| Part 1 - ZP-059 10mg | Bioavailability of Voriconazole - Cmax | Parts 1, 2, and 3 - Day 1 | 40.42 ng/mL | Standard Deviation 1.33 |
| Part 1 - ZP-059 20mg | Bioavailability of Voriconazole - Cmax | Parts 1, 2, and 3 - Day 1 | 108.08 ng/mL | Standard Deviation 1.42 |
| Part 1 - ZP-059 40mg | Bioavailability of Voriconazole - Cmax | Parts 1, 2, and 3 - Day 1 | 863.22 ng/mL | Standard Deviation 1.44 |
Comparison: Part 3 - ZP-059 20mg: Oral Voriconazole (200mg VFEND)90% CI: [0.107, 0.146]
Comparison: ZP-059 20mg: Part 3 / Part 190% CI: [1.545, 2.853]
Comparison: ZP-059 20mg: Part 3 / Part 2 Day 190% CI: [1.953, 3.544]
Comparison: ZP-059 20mg: Part 3 / Part 2 Day 1090% CI: [1.386, 2.52]
Secondary
CL/F for Voriconazole - Part 1
Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | CL/F for Voriconazole - Part 1 | 131.2 L/h | Standard Deviation 1.04 |
| Part 1 - ZP-059 10mg | CL/F for Voriconazole - Part 1 | 124.6 L/h | Standard Deviation 1.17 |
| Part 1 - ZP-059 20mg | CL/F for Voriconazole - Part 1 | 97.7 L/h | Standard Deviation 1.39 |
| Part 1 - ZP-059 40mg | CL/F for Voriconazole - Part 1 | 108.7 L/h | Standard Deviation 1.22 |
Secondary
CL/F for Voriconazole - Part 2
Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | CL/F for Voriconazole - Part 2 | 120.9 L/h | Standard Deviation 1.29 |
| Part 1 - ZP-059 10mg | CL/F for Voriconazole - Part 2 | 93.1 L/h | Standard Deviation 1.32 |
| Part 1 - ZP-059 20mg | CL/F for Voriconazole - Part 2 | 93.5 L/h | Standard Deviation 1.25 |
Secondary
CL/F for Voriconazole - Part 3
Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | CL/F for Voriconazole - Part 3 | 74.2 L/h | Standard Deviation 1.57 |
| Part 1 - ZP-059 10mg | CL/F for Voriconazole - Part 3 | 52.4 L/h | Standard Deviation 1.93 |
Secondary
Cmax for Voriconazole and N-oxide Voriconazole - Part 1
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 8.44 ng/mL | Standard Deviation 1.27 |
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 57.70 ng/mL | Standard Deviation 1.12 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 103.16 ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 18.52 ng/mL | Standard Deviation 1.39 |
| Part 1 - ZP-059 20mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 53.37 ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 20mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 145.79 ng/mL | Standard Deviation 1.3 |
| Part 1 - ZP-059 40mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 94.33 ng/mL | Standard Deviation 1.18 |
| Part 1 - ZP-059 40mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 286.63 ng/mL | Standard Deviation 1.15 |
Comparison: Statistics for Voriconazole Cmaxp-value: 0.257590% CI: [-0.06, 0.308]General power constant model
Comparison: Statistics for Voriconazole Cmaxp-value: 0.049190% CI: [1.03, 1.316]General power linear model
Comparison: Statistics for Voriconazole Cmax, 40mg vs 5mgp-value: <0.000190% CI: [8.435, 14.803]ANOVA
Comparison: Statistics for N-oxide Voriconazole Cmaxp-value: <0.000190% CI: [1.135, 1.363]General power constant model
Comparison: Statistics for N-oxide Voriconazole Cmaxp-value: 0.000390% CI: [0.634, 0.843]General power linear model
Comparison: Statistics for N-oxide Voriconazole Cmax, 40mg vs 5mgp-value: <0.000190% CI: [3.946, 6.254]ANOVA
Secondary
Cmax for Voriconazole and N-oxide Voriconazole - Part 2
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
Time frame: Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 102.78 ng/mL | Standard Deviation 1.3 |
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 71.66 ng/mL | Standard Deviation 1.24 |
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 10 | 21.38 ng/mL | Standard Deviation 1.21 |
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 1 | 19.87 ng/mL | Standard Deviation 1.29 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 144.43 ng/mL | Standard Deviation 1.11 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 10 | 57.11 ng/mL | Standard Deviation 1.33 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 1 | 40.42 ng/mL | Standard Deviation 1.33 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 217.76 ng/mL | Standard Deviation 1.23 |
| Part 1 - ZP-059 20mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 10 | 127.54 ng/mL | Standard Deviation 1.2 |
| Part 1 - ZP-059 20mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 1 | 96.77 ng/mL | Standard Deviation 1.16 |
| Part 1 - ZP-059 20mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 412.40 ng/mL | Standard Deviation 1.21 |
| Part 1 - ZP-059 20mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 339.11 ng/mL | Standard Deviation 1.15 |
Comparison: Statistics for Voriconazole Cmax Day 1p-value: 0.000390% CI: [1.562, 2.65]ANOVA
Comparison: Statistics for Voriconazole Cmax Day 1p-value: <0.000190% CI: [3.74, 6.345]ANOVA
Comparison: Statistics for Voriconazole Cmax Day 10p-value: <0.000190% CI: [2.081, 3.429]ANOVA
Comparison: Statistics for Voriconazole Cmax Day 10p-value: <0.000190% CI: [4.647, 7.658]ANOVA
Comparison: Statistics for N-oxide Voriconazole Cmax Day 1p-value: <0.000190% CI: [1.688, 2.406]ANOVA
Comparison: Statistics for N-oxide Voriconazole Cmax Day 1p-value: <0.000190% CI: [3.964, 5.65]ANOVA
Comparison: Statistics for N-oxide Voriconazole Cmax Day 10p-value: <0.000190% CI: [1.655, 2.711]ANOVA
Comparison: Statistics for N-oxide Voriconazole Cmax day 10p-value: <0.000190% CI: [3.135, 5.135]ANOVA
Secondary
Cmax for Voriconazole and N-oxide Voriconazole - Part 3
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 3 | Voriconazole | 108.08 ng/mL | Standard Deviation 1.42 |
| Part 1 - ZP-059 5mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 3 | N-oxide Voriconazole | 151.43 ng/mL | Standard Deviation 1.25 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 3 | Voriconazole | 863.22 ng/mL | Standard Deviation 1.44 |
| Part 1 - ZP-059 10mg | Cmax for Voriconazole and N-oxide Voriconazole - Part 3 | N-oxide Voriconazole | 1589.05 ng/mL | Standard Deviation 1.25 |
Secondary
Css,av for Voriconazole and N-oxide Voriconazole - Part 2
Css,av or Css(ave): Average drug concentration at steady state; Steady-state concentration (Css) occurs when the amount of a drug being absorbed is the same amount that's being cleared from the body when the drug is given continuously or repeatedly
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 6.91 ng/mL | Standard Deviation 1.3 |
| Part 1 - ZP-059 5mg | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 51.75 ng/mL | Standard Deviation 1.28 |
| Part 1 - ZP-059 10mg | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 17.95 ng/mL | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 119.88 ng/mL | Standard Deviation 1.31 |
| Part 1 - ZP-059 20mg | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 35.64 ng/mL | Standard Deviation 1.25 |
| Part 1 - ZP-059 20mg | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 233.63 ng/mL | Standard Deviation 1.2 |
Secondary
Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2
Peak trough fluctuation in serum concentrations within one dosing interval at steady state. Fluctuation - Over the Dosing Interval - is expressed as percentage concentration.
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 281.0 percentage concentration | Standard Deviation 1.15 |
| Part 1 - ZP-059 5mg | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 162.8 percentage concentration | Standard Deviation 1.08 |
| Part 1 - ZP-059 10mg | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 284.9 percentage concentration | Standard Deviation 1.24 |
| Part 1 - ZP-059 10mg | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 141.8 percentage concentration | Standard Deviation 1.21 |
| Part 1 - ZP-059 20mg | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 350.8 percentage concentration | Standard Deviation 1.1 |
| Part 1 - ZP-059 20mg | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 163.8 percentage concentration | Standard Deviation 1.3 |
Secondary
Kel for Voriconazole and N-oxide Voriconazole - Part 1
Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 0.30 1/h | Standard Deviation 1.52 |
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 0.19 1/h | Standard Deviation 1.08 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 0.19 1/h | Standard Deviation 1.21 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 0.23 1/h | Standard Deviation 1.09 |
| Part 1 - ZP-059 20mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 0.22 1/h | Standard Deviation 1.17 |
| Part 1 - ZP-059 20mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 0.20 1/h | Standard Deviation 1.27 |
| Part 1 - ZP-059 40mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | Voriconazole | 0.19 1/h | Standard Deviation 1.22 |
| Part 1 - ZP-059 40mg | Kel for Voriconazole and N-oxide Voriconazole - Part 1 | N-oxide voriconazole | 0.16 1/h | Standard Deviation 1.26 |
Secondary
Kel for Voriconazole and N-oxide Voriconazole - Part 2
Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.
Time frame: Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 10 | 0.16 1/h | Standard Deviation 1.41 |
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 1 | 0.19 1/h | Standard Deviation 1.35 |
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 0.15 1/h | Standard Deviation 1.16 |
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 0.20 1/h | Standard Deviation 1.08 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 0.22 1/h | Standard Deviation 1.11 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 0.14 1/h | Standard Deviation 1.24 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 1 | 0.20 1/h | Standard Deviation 1.25 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 10 | 0.13 1/h | Standard Deviation 1.29 |
| Part 1 - ZP-059 20mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 0.17 1/h | Standard Deviation 1.21 |
| Part 1 - ZP-059 20mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 0.18 1/h | Standard Deviation 1.44 |
| Part 1 - ZP-059 20mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 10 | 0.15 1/h | Standard Deviation 1.15 |
| Part 1 - ZP-059 20mg | Kel for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole - Day 1 | 0.21 1/h | Standard Deviation 1.08 |
Secondary
Kel for Voriconazole and N-oxide Voriconazole - Part 3
Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 3 | Voriconazole | 0.14 1/h | Standard Deviation 1.26 |
| Part 1 - ZP-059 5mg | Kel for Voriconazole and N-oxide Voriconazole - Part 3 | N-oxide Voriconazole | 0.15 1/h | Standard Deviation 1.19 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 3 | Voriconazole | 0.10 1/h | Standard Deviation 1.31 |
| Part 1 - ZP-059 10mg | Kel for Voriconazole and N-oxide Voriconazole - Part 3 | N-oxide Voriconazole | 0.11 1/h | Standard Deviation 1.34 |
Secondary
MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 | MR AUC0-t | 3.89 ratio | Standard Deviation 1.92 |
| Part 1 - ZP-059 5mg | MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 | MR AUC0-inf | 4.38 ratio | Standard Deviation 1.48 |
| Part 1 - ZP-059 10mg | MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 | MR AUC0-t | 5.77 ratio | Standard Deviation 1.81 |
| Part 1 - ZP-059 10mg | MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 | MR AUC0-inf | 5.74 ratio | Standard Deviation 1.79 |
Secondary
MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)
Time frame: Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-inf N-oxide Voriconazole - Day 10 | 7.70 ratio | Standard Deviation 1.4 |
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-t N-oxide Voriconazole - Day 10 | 8.01 ratio | Standard Deviation 1.4 |
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-t N-oxide Voriconazole - Day 1 | 5.62 ratio | Standard Deviation 1.5 |
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-inf N-oxide Voriconazole - Day 1 | 5.68 ratio | Standard Deviation 1.52 |
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUCtau N-oxide Voriconazole - Day 10 | 7.50 ratio | Standard Deviation 1.39 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-t N-oxide Voriconazole - Day 10 | 6.97 ratio | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-t N-oxide Voriconazole - Day 1 | 5.53 ratio | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-inf N-oxide Voriconazole - Day 1 | 5.45 ratio | Standard Deviation 1.29 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-inf N-oxide Voriconazole - Day 10 | 6.99 ratio | Standard Deviation 1.34 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUCtau N-oxide Voriconazole - Day 10 | 6.68 ratio | Standard Deviation 1.3 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUCtau N-oxide Voriconazole - Day 10 | 6.56 ratio | Standard Deviation 1.2 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-inf N-oxide Voriconazole - Day 10 | 7.11 ratio | Standard Deviation 1.18 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-t N-oxide Voriconazole - Day 1 | 6.04 ratio | Standard Deviation 1.27 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-t N-oxide Voriconazole - Day 10 | 6.98 ratio | Standard Deviation 1.16 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 | MR AUC0-inf N-oxide Voriconazole - Day 1 | 5.55 ratio | Standard Deviation 1.2 |
Secondary
MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-t | 12.25 ratio | Standard Deviation 1.36 |
| Part 1 - ZP-059 5mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-inf | 10.92 ratio | Standard Deviation 1.2 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-inf | 8.18 ratio | Standard Deviation 1.39 |
| Part 1 - ZP-059 10mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-t | 7.76 ratio | Standard Deviation 1.4 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-t | 4.28 ratio | Standard Deviation 1.43 |
| Part 1 - ZP-059 20mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-inf | 4.92 ratio | Standard Deviation 1.42 |
| Part 1 - ZP-059 40mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-t | 5.59 ratio | Standard Deviation 1.14 |
| Part 1 - ZP-059 40mg | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 | MR AUC0-inf | 6.12 ratio | Standard Deviation 1.08 |
Secondary
MR Cmax for N-oxide Voriconazole - Part 1
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | MR Cmax for N-oxide Voriconazole - Part 1 | 6.84 ratio | Standard Deviation 1.27 |
| Part 1 - ZP-059 10mg | MR Cmax for N-oxide Voriconazole - Part 1 | 5.57 ratio | Standard Deviation 1.73 |
| Part 1 - ZP-059 20mg | MR Cmax for N-oxide Voriconazole - Part 1 | 2.73 ratio | Standard Deviation 1.51 |
| Part 1 - ZP-059 40mg | MR Cmax for N-oxide Voriconazole - Part 1 | 3.04 ratio | Standard Deviation 1.31 |
Secondary
MR Cmax for N-oxide Voriconazole - Part 3
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | MR Cmax for N-oxide Voriconazole - Part 3 | 1.40 ratio | Standard Deviation 1.44 |
| Part 1 - ZP-059 10mg | MR Cmax for N-oxide Voriconazole - Part 3 | 1.84 ratio | Standard Deviation 1.54 |
Secondary
MR Cmax N-oxide Voriconazole - Part 2
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
Time frame: Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | MR Cmax N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 3.61 ratio | Standard Deviation 1.5 |
| Part 1 - ZP-059 5mg | MR Cmax N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 4.81 ratio | Standard Deviation 1.38 |
| Part 1 - ZP-059 10mg | MR Cmax N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 3.57 ratio | Standard Deviation 1.4 |
| Part 1 - ZP-059 10mg | MR Cmax N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 3.81 ratio | Standard Deviation 1.34 |
| Part 1 - ZP-059 20mg | MR Cmax N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 1 | 3.50 ratio | Standard Deviation 1.22 |
| Part 1 - ZP-059 20mg | MR Cmax N-oxide Voriconazole - Part 2 | N-oxide Voriconazole - Day 10 | 3.23 ratio | Standard Deviation 1.37 |
Secondary
Rac for Voriconazole and N-oxide Voriconazole - Part 2
Accumulation ratio. The drug accumulation ratio (Rac) is the ratio of accumulation of a drug under steady state conditions as compared to a single dose. The higher the value, the more the drug accumulates in the body. An Rac of 1 means no accumulation.
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Rac for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 1.19 ratio | Standard Deviation 1.17 |
| Part 1 - ZP-059 5mg | Rac for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1.59 ratio | Standard Deviation 1.11 |
| Part 1 - ZP-059 10mg | Rac for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 1.55 ratio | Standard Deviation 1.29 |
| Part 1 - ZP-059 10mg | Rac for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1.87 ratio | Standard Deviation 1.2 |
| Part 1 - ZP-059 20mg | Rac for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 1.30 ratio | Standard Deviation 1.27 |
| Part 1 - ZP-059 20mg | Rac for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1.41 ratio | Standard Deviation 1.1 |
Secondary
Rlinear for Voriconazole and N-oxide Voriconazole - Part 2
Rlinear means linearity ratio for Area Under the Serum Concentration-Time Curve from time zero to infinity.
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 1.06 ratio | Standard Deviation 1.14 |
| Part 1 - ZP-059 5mg | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1.42 ratio | Standard Deviation 1.12 |
| Part 1 - ZP-059 10mg | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 1.38 ratio | Standard Deviation 1.25 |
| Part 1 - ZP-059 10mg | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1.70 ratio | Standard Deviation 1.21 |
| Part 1 - ZP-059 20mg | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 1.19 ratio | Standard Deviation 1.26 |
| Part 1 - ZP-059 20mg | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 1.30 ratio | Standard Deviation 1.17 |
Secondary
Swing for Voriconazole and N-oxide Voriconazole - Part 2
Swing for voriconazole and N-oxide voriconazole = \[(Cmax - Cmin) / Cmin\]\*100%
Time frame: Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Swing for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 4.60 percentage concentration | Standard Deviation 1.16 |
| Part 1 - ZP-059 5mg | Swing for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 10.50 percentage concentration | Standard Deviation 1.48 |
| Part 1 - ZP-059 10mg | Swing for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 3.81 percentage concentration | Standard Deviation 1.48 |
| Part 1 - ZP-059 10mg | Swing for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 9.62 percentage concentration | Standard Deviation 1.68 |
| Part 1 - ZP-059 20mg | Swing for Voriconazole and N-oxide Voriconazole - Part 2 | Voriconazole | 55.16 percentage concentration | Standard Deviation 1.63 |
| Part 1 - ZP-059 20mg | Swing for Voriconazole and N-oxide Voriconazole - Part 2 | N-oxide Voriconazole | 20.65 percentage concentration | Standard Deviation 2.7 |
Secondary
Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1
Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax Voriconazole | 1.57 hours | Standard Deviation 1.11 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax N-oxide voriconazole | 1.57 hours | Standard Deviation 1.11 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 Voriconazole | 2.67 hours | Standard Deviation 1.42 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 N-oxide voriconazole | 3.60 hours | Standard Deviation 1.08 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax N-oxide voriconazole | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 Voriconazole | 3.07 hours | Standard Deviation 1.09 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 N-oxide voriconazole | 3.59 hours | Standard Deviation 1.21 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax Voriconazole | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 Voriconazole | 3.20 hours | Standard Deviation 1.17 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax N-oxide voriconazole | 1.85 hours | Standard Deviation 1.29 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 N-oxide voriconazole | 3.38 hours | Standard Deviation 1.27 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax Voriconazole | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 40mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 N-oxide voriconazole | 4.43 hours | Standard Deviation 1.26 |
| Part 1 - ZP-059 40mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax N-oxide voriconazole | 1.65 hours | Standard Deviation 1.15 |
| Part 1 - ZP-059 40mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | Tmax Voriconazole | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 40mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 | T1/2 Voriconazole | 3.63 hours | Standard Deviation 1.22 |
Secondary
Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2
Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
Time frame: Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax N-oxide Voriconazole - Day 10 | 1.57 hours | Standard Deviation 1.11 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax Voriconazole - Day 1 | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 Voriconazole - Day 10 | 4.40 hours | Standard Deviation 1.41 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 Voriconazole - Day 1 | 3.60 hours | Standard Deviation 1.36 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 N-oxide Voriconazole - Day 10 | 4.52 hours | Standard Deviation 1.16 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax N-oxide Voriconazole - Day 1 | 1.65 hours | Standard Deviation 1.15 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax Voriconazole - Day 10 | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 N-oxide Voriconazole - Day 1 | 3.45 hours | Standard Deviation 1.08 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 Voriconazole - Day 1 | 3.53 hours | Standard Deviation 1.25 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax Voriconazole - Day 10 | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax N-oxide Voriconazole - Day 1 | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax N-oxide Voriconazole - Day 10 | 1.57 hours | Standard Deviation 1.11 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax Voriconazole - Day 1 | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 Voriconazole - Day 10 | 5.15 hours | Standard Deviation 1.29 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 N-oxide Voriconazole - Day 1 | 3.20 hours | Standard Deviation 1.11 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 N-oxide Voriconazole - Day 10 | 5.04 hours | Standard Deviation 1.24 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 Voriconazole - Day 10 | 4.48 hours | Standard Deviation 1.15 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax N-oxide Voriconazole - Day 1 | 1.65 hours | Standard Deviation 1.15 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 N-oxide Voriconazole - Day 10 | 4.14 hours | Standard Deviation 1.21 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 N-oxide Voriconazole - Day 1 | 3.82 hours | Standard Deviation 1.44 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax Voriconazole - Day 10 | 1.50 hours | Standard Deviation 1 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | T1/2 Voriconazole - Day 1 | 3.24 hours | Standard Deviation 1.08 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax N-oxide Voriconazole - Day 10 | 2.33 hours | Standard Deviation 1.45 |
| Part 1 - ZP-059 20mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 | Tmax Voriconazole - Day 1 | 1.57 hours | Standard Deviation 1.11 |
Secondary
Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3
Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
Time frame: Day 1 of the respective treatment period 1 or 2 (Pre-dose, 0.25h, 0.75h 1.5h, 2h ,3h ,4h ,6h ,8h ,12h ,16h , 24h ,48h after dosing)
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | Tmax Voriconazole | 0.43 hours | Standard Deviation 3.64 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | Tmax N-oxide Voriconazole | 1.74 hours | Standard Deviation 1.31 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | T1/2 Voriconazole | 5.13 hours | Standard Deviation 1.27 |
| Part 1 - ZP-059 5mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | T1/2 N-oxide Voriconazole | 4.68 hours | Standard Deviation 1.19 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | T1/2 N-oxide Voriconazole | 6.42 hours | Standard Deviation 1.35 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | Tmax Voriconazole | 1.16 hours | Standard Deviation 1.4 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | T1/2 Voriconazole | 6.93 hours | Standard Deviation 1.32 |
| Part 1 - ZP-059 10mg | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 | Tmax N-oxide Voriconazole | 2.76 hours | Standard Deviation 1.52 |
Secondary
Vz/F for Voriconazole - Part 1
Vz/F=Apparent volume of distribution during terminal phase.
Time frame: Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | Vz/F for Voriconazole - Part 1 | 614.3 liters | Standard Deviation 1.09 |
| Part 1 - ZP-059 10mg | Vz/F for Voriconazole - Part 1 | 553.1 liters | Standard Deviation 1.14 |
| Part 1 - ZP-059 20mg | Vz/F for Voriconazole - Part 1 | 450.9 liters | Standard Deviation 1.25 |
| Part 1 - ZP-059 40mg | Vz/F for Voriconazole - Part 1 | 569.6 liters | Standard Deviation 1.2 |
Secondary
Vz/F for Voriconazole - Part 3
Vz/F=Apparent volume of distribution during terminal phase.
Time frame: Only at Day 10
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | Vz/F for Voriconazole - Part 3 | 767.1 Liters | Standard Deviation 1.47 |
| Part 1 - ZP-059 10mg | Vz/F for Voriconazole - Part 3 | 714.3 Liters | Standard Deviation 1.25 |
| Part 1 - ZP-059 20mg | Vz/F for Voriconazole - Part 3 | 604.9 Liters | Standard Deviation 1.13 |
Secondary
Vz/F for Voriconazole - Part 3
Vz/F=Apparent volume of distribution during terminal phase.
Time frame: Day 1 of the respective treatment period 1 or 2
Population: PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - ZP-059 5mg | Vz/F for Voriconazole - Part 3 | 549.0 Liters | Standard Deviation 1.46 |
| Part 1 - ZP-059 10mg | Vz/F for Voriconazole - Part 3 | 526.0 Liters | Standard Deviation 1.69 |