Schizophrenia
Conditions
Keywords
Schizophrenia, Staccato Loxapine
Brief summary
The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single inhaled dose of (administered in 1 or 2 puffs) Staccato Loxapine in healthy volunteers.
Detailed description
Safety and pharmacokinetic data obtained from 50 subjects (between the ages of 18 to 55 years) entered into this randomized, placebo-controlled study. To obtain 50 enrolled subjects, screening procedures and inclusion/exclusion criteria were evaluated for 126 subjects during a variable screening period of up to 21 days. Once enrolled, subjects were randomized to either Staccato Loxapine or Staccato placebo. Plasma samples for pharmacokinetic analysis were collected beginning on Day 0, pre-dose and continuing for 24 hr post dose. Blood samples for the PK analysis of loxapine and its metabolites (8-OH loxapine, 7-OH loxapine and amoxapine) were obtained at time 0 (immediately before dosing), at 30 sec, 1, 2, 3, 5, 10, 30, 45 min, 1, 2, 4, 6, 12, 24 hr after dosing. Plasma concentrations of loxapine and metabolites were used to estimate the following PK parameters for loxapine and its metabolites: area under the plasma concentration time curve from time 0 extrapolated to infinity (AUCinf), AUC from time 0 to time tlast, the last quantifiable concentration (AUClast), maximum observed plasma concentration (Cmax), observed time of Cmax (tmax), terminal phase elimination rate constant (ke), apparent terminal elimination half life calculated from ke (T½ ), apparent total body clearance / fraction absorbed calculated from AUCinf and dose (CL/F) (for loxapine and the metabolites where permitted by measurable concentrations). Safety was evaluated by the incidence of adverse events, clinical laboratory testing (blood chemistry, hematology, and urinalysis), physical examination, vital signs, pulse oximetry, postural vital signs, 12-lead electrocardiogram, pulmonary function tests, continuous 12-lead Holter monitoring, sedation assessments, akathisia assessments.
Interventions
DRUGinhaled Loxapine 0.625 mg
Single 0.625 mg (lowest) dose of inhaled loxapine
Single 1.25 mg (2nd) dose of inhaled loxapine
Single 2.5 mg (3rd) dose of inhaled loxapine
Single 5 mg (4th) dose of inhaled loxapine
Single 10 mg (5th) dose of inhaled loxapine
DRUGinhaled Placebo (0 mg)
Single placebo dose of inhaled loxapine
Sponsors
Alexza Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male and female subjects between the ages of 18 to 55 years, inclusive. 2. Subjects with a body mass index (BMI) ≥21 and ≤30. 3. Subjects who speak, read, and understand English and are willing and able to provide written informed consent on an IRB-approved form prior to the initiation of any study procedures. 4. Subjects who are willing and able to be confined to the Clinical Research Unit (CRU) for approximately 2 days and comply with the study schedule and study requirements. 5. Subjects who are in good general health as determined by a complete medical history, physical examination, 12-lead ECG, spirometry, blood chemistry profile, hematology, and urinalysis.
Exclusion criteria
1. Subjects who regularly consume large amounts of xanthine-containing substances (i.e., more than 5 cups of coffee or equivalent amounts of xanthine-containing substances per day). 2. Subjects who have taken prescription or nonprescription medication (with the exception of vitamins and acetaminophen if medically necessary) within 5 days of Visit 2 (Baseline). 3. Subjects who have had an acute illness within 5 days of Visit 2 (Baseline). 4. Subjects who have received an investigational drug within 30 days (or within 5 half lives of the investigational drug, if \>30 days) prior to Visit 2 (Baseline). 5. Subjects who have smoked tobacco within the last year. 6. Subjects who have a history within the past 2 years of drug or alcohol dependence or abuse as defined by DSM-4. 7. Subjects with a history of HIV positivity. 8. Subjects with a history of allergy or intolerance to dibenzoxazepines (amoxapine and loxapine). 9. Subjects with a known history of contraindications to anticholinergics (bowel obstructions, urinary retention, acute glaucoma). 10. Subjects with a history of pheochromocytoma, seizure disorder, Parkinson's disease, or Restless Leg Syndrome (RLS). 11. Subjects who test positive for alcohol or have a positive urine drug screen at Visit 1 or Visit 2. 12. Subjects who have hypotension (systolic blood pressure ≤90 mmHg, diastolic blood pressure ≤50 mmHg), or hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg). 13. Subjects who have a clinically significant ECG abnormality. 14. Subjects with a history of unstable angina, syncope, coronary artery disease, myocardial infarction, congestive heart failure (CHF), stroke, transient ischemic attack (TIA), or a neurological disorder. 15. Subjects who have a history of pulmonary disease that precludes administration of Staccato Loxapine (asthma, bronchitis, bronchospasm, emphysema). 16. Subjects who have an FEV1 less than 80% of predicted values on spirometry assessments at Visit 1. 17. Female subjects who are breastfeeding or have a positive pregnancy test at Visit 1 or Visit 2. 18. Female participants of child-bearing potential or within 1 year of menopause, and sexually active are excluded unless they use a medically acceptable and effective birth control method throughout the study and for 1 week following the end of the study. Medically acceptable methods of contraception include abstinence, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization, and birth control pills. Unacceptable methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone. 19. Subjects who have any other disease or condition, by history, physical examination, or laboratory abnormalities that in the investigator's opinion, would present undue risk to the subject, or may confound the interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | Tmax = time from inhalation to to maximum observed loxapine concentration |
| Half-life | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | Half-life of the terminal elimination phase of loxapine concentrations |
| ke | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | elimination rate constant |
| Clearance | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | clearance (CL/F) of lozxapine |
| Cmax | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | maximum concentration of loxapine observed |
| Dose Proportionality (AUCinf) by Power Analysis | predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours | Dose proportionality by power analysis examines the linear regression of the log-AUC versus log-Dose on a by-patient basis across all doses administered. The slope and 90% confidence interval (CI) provide a clear, quantitative (best practices) assessment of the relationship of drug delivered to dose administered. The units on such analyses are generally those of slope (rise over run), with 1.000 being perfect. Although any positive slope might be considered clinically useful, a 90% CI within the criteria of 0.800-1.250 may be considered a delivery system which is as good as it gets. |
Countries
United States
Participant flow
Recruitment details
Fifty subjects were recruited by and studied in the clinical researech unit (CRU). Study dates: 30 September 2005 through 22 November 2005
Pre-assignment details
To obtain 50 enrolled subjects, screening procedures and inclusion/exclusion criteria were evaluated for 126 subjects during a variable screening period of up to 21 days. No enrolled participants were excluded from the trial.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Staccato placebo inhalation device(s) | 14 |
| Staccato Loxapine 0.625 mg inhalation of loxapine from a single 0.625 mg device | 7 |
| Staccato Loxapine 1.25 mg inhalation of loxapine from a two 0.625 mg devices | 8 |
| Staccato Loxapine 2.5 mg inhalation of loxapine from a single 2.5 mg device | 6 |
| Staccato Loxapine 5 mg inhalation of loxapine from a single 5 mg device | 7 |
| Staccato Loxapine 10 mg inhalation of loxapine from a two 5 mg devices | 8 |
| Total | 50 |
Baseline characteristics
| Characteristic | Staccato Loxapine 0.625 mg | Staccato Loxapine 1.25 mg | Staccato Loxapine 2.5 mg | Placebo | Staccato Loxapine 5 mg | Staccato Loxapine 10 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 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 |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 6 Participants | 14 Participants | 7 Participants | 8 Participants | 50 Participants |
| Age, Continuous | 33.4 years STANDARD_DEVIATION 10.44 | 28 years STANDARD_DEVIATION 7.11 | 28.2 years STANDARD_DEVIATION 6.05 | 37.8 years STANDARD_DEVIATION 10.55 | 30.1 years STANDARD_DEVIATION 13.53 | 27.4 years STANDARD_DEVIATION 7.65 | 31.7 years STANDARD_DEVIATION 10.14 |
| Region of Enrollment United States | 7 Participants | 8 Participants | 6 Participants | 14 Participants | 7 Participants | 8 Participants | 50 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 4 Participants | 8 Participants | 5 Participants | 3 Participants | 27 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 2 Participants | 6 Participants | 2 Participants | 5 Participants | 23 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 7 | 0 / 8 | 0 / 6 | 0 / 7 | 0 / 8 |
| other Total, other adverse events | 6 / 14 | 4 / 7 | 5 / 8 | 3 / 6 | 5 / 7 | 8 / 8 |
| serious Total, serious adverse events | 0 / 14 | 0 / 7 | 0 / 8 | 0 / 6 | 0 / 7 | 0 / 8 |
Outcome results
Primary
Clearance
clearance (CL/F) of lozxapine
Time frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours
Population: PK Population (N=36) All subjects exposed to inhaled loxapine who provided concentration data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Staccato Loxapine 0.625 mg | Clearance | 56.2 L/hour | Standard Deviation 14.1 |
| Staccato Loxapine 1.25 mg | Clearance | 55.9 L/hour | Standard Deviation 13.7 |
| Staccato Loxapine 2.5 mg | Clearance | 61.1 L/hour | Standard Deviation 18.8 |
| Staccato Loxapine 5 mg | Clearance | 53.8 L/hour | Standard Deviation 9.74 |
| Staccato Loxapine 10 mg | Clearance | 78 L/hour | Standard Deviation 25.8 |
Primary
Cmax
maximum concentration of loxapine observed
Time frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours
Population: PK Population (N=36) All subjects exposed to inhaled loxapine who provided concentration data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Staccato Loxapine 0.625 mg | Cmax | 6.5 ng/mL | Standard Deviation 8.79 |
| Staccato Loxapine 1.25 mg | Cmax | 9.7 ng/mL | Standard Deviation 3.49 |
| Staccato Loxapine 2.5 mg | Cmax | 62.9 ng/mL | Standard Deviation 63 |
| Staccato Loxapine 5 mg | Cmax | 105 ng/mL | Standard Deviation 80.6 |
| Staccato Loxapine 10 mg | Cmax | 134 ng/mL | Standard Deviation 118.8 |
Primary
Dose Proportionality (AUCinf) by Power Analysis
Dose proportionality by power analysis examines the linear regression of the log-AUC versus log-Dose on a by-patient basis across all doses administered. The slope and 90% confidence interval (CI) provide a clear, quantitative (best practices) assessment of the relationship of drug delivered to dose administered. The units on such analyses are generally those of slope (rise over run), with 1.000 being perfect. Although any positive slope might be considered clinically useful, a 90% CI within the criteria of 0.800-1.250 may be considered a delivery system which is as good as it gets.
Time frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours
Population: PK Population (N=36) All subjects exposed to inhaled loxapine who provided concentration data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Staccato Loxapine 0.625 mg | Dose Proportionality (AUCinf) by Power Analysis | 11.9 hr*mcg/L | Standard Deviation 3.7 |
| Staccato Loxapine 1.25 mg | Dose Proportionality (AUCinf) by Power Analysis | 23.4 hr*mcg/L | Standard Deviation 4.87 |
| Staccato Loxapine 2.5 mg | Dose Proportionality (AUCinf) by Power Analysis | 44.6 hr*mcg/L | Standard Deviation 14.7 |
| Staccato Loxapine 5 mg | Dose Proportionality (AUCinf) by Power Analysis | 95.5 hr*mcg/L | Standard Deviation 16.6 |
| Staccato Loxapine 10 mg | Dose Proportionality (AUCinf) by Power Analysis | 140.6 hr*mcg/L | Standard Deviation 44.6 |
Comparison: Dose proportionality by power analysis examines the linear regression of the log-AUC versus log-Dose on a by-patient basis across all doses administered. The slope and 90% confidence interval (CI) provide a clear, quantitative (best practices) assessment of the relationship of drug delivered to dose administered.90% CI: [0.832, 0.987]
Primary
Half-life
Half-life of the terminal elimination phase of loxapine concentrations
Time frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours
Population: PK Population (N=36) All subjects exposed to inhaled loxapine who provided concentration data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Staccato Loxapine 0.625 mg | Half-life | 5.2 hours | Standard Deviation 1.3 |
| Staccato Loxapine 1.25 mg | Half-life | 6.56 hours | Standard Deviation 1.44 |
| Staccato Loxapine 2.5 mg | Half-life | 6.92 hours | Standard Deviation 1.94 |
| Staccato Loxapine 5 mg | Half-life | 6.2 hours | Standard Deviation 1.14 |
| Staccato Loxapine 10 mg | Half-life | 6.14 hours | Standard Deviation 2.16 |
Primary
ke
elimination rate constant
Time frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours
Population: PK Population (N=36) All subjects exposed to inhaled loxapine who provided concentration data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Staccato Loxapine 0.625 mg | ke | .143 /hour | Standard Error 0.047 |
| Staccato Loxapine 1.25 mg | ke | .111 /hour | Standard Error 0.026 |
| Staccato Loxapine 2.5 mg | ke | .108 /hour | Standard Error 0.033 |
| Staccato Loxapine 5 mg | ke | .115 /hour | Standard Error 0.02 |
| Staccato Loxapine 10 mg | ke | .122 /hour | Standard Error 0.032 |
Primary
Tmax
Tmax = time from inhalation to to maximum observed loxapine concentration
Time frame: predose, 0.5, 1, 2, 3, 5, 10, 30 and 45 min, 1, 2, 4, 6, 12, and 24 hours
Population: PK Population (N=36) All subjects exposed to inhaled loxapine who provided concentration data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Staccato Loxapine 0.625 mg | Tmax | 12.6 minutes | Standard Deviation 21.3 |
| Staccato Loxapine 1.25 mg | Tmax | 2.15 minutes | Standard Deviation 1.31 |
| Staccato Loxapine 2.5 mg | Tmax | 2.87 minutes | Standard Deviation 3.62 |
| Staccato Loxapine 5 mg | Tmax | 2.13 minutes | Standard Deviation 0.687 |
| Staccato Loxapine 10 mg | Tmax | 5.25 minutes | Standard Deviation 10 |