Drug-Drug Interaction, Heathy Volunteer
Conditions
Keywords
PK, Pharmacokinetics, Givinostat, Midazolam, Dabigatran
Brief summary
Primary objective: 1. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose pharmacokinetics (PK) of intravenous or oral midazolam. 2. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose PK of oral dabigatran etexilate. Secondary objective: To assess the safety and tolerability of concomitant administration of givinostat plus midazolam and dabigatran etexilate.
Detailed description
This study was planned as a phase I, open-label, 3-part, fixed-sequence, nonrandomized study in healthy male and female subjects. The study evaluated the givinostat (ITF2357) potential drug-drug interaction (DDI) at level of CYP3A-mediated metabolism and P-glycoprotein (P-gp) transport with intravenous or oral midazolam and with oral dabigatran etexilate. More precisely, the study aimed at assessing the potential (inhibitory or inducing) effect of givinostat on the PK of midazolam IV, on the PK of oral midazolam and on the PK of dabigatran etexilate. The study lasted from Day 1 to Day 20. Subjects were confined from Day -1 to Day 20. On Days 6 and 17, single doses of 1 mg midazolam IV and 75 mg dabigatran etexilate, were administered 1 hour after the planned morning time of givinostat administration. On day 1, however, drugs were not administered 1h after gininostat. On Days 7 and 18, a single oral dose of 2.5 mg midazolam oral solution was administered 1 hour after the planned morning time of givinostat administration. On day 2, however, the drugs were not administered 1h after gininostat. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered. The following assessments were performed: * Blood collection for pharmacokinetic analysis on Days 1 to 4, 6 to 9 and 17 to 20. * Vital signs measurements (BP, PR and RR) on Days 1, 2, and 4 to 19. * 12-lead ECG on Days 3 to 19. * Blood collection for laboratory tests (hematology, biochemistry and coagulation on Days 4 and 9 and hematology on Days 6, 12, 15 and 18). Subjects were discharged from BlueClinical Phase I in the morning of Day 20 if allowed by the investigator based on their medical condition. The following procedures were performed: * Physical examination. * Collection of body weight. * Vital signs measurements (BP, PR, RR and body temperature). * 12-lead ECG. * Safety laboratory assessments (hematology, biochemistry, coagulation and urinalysis). * Serum pregnancy test for all female subjects. Subjects returned to the site 10 to 14 days after the end of study to undergo additional assessments as required per protocol. The total duration of Part 1 for each subject was up to approximately 8 weeks from Screening to Follow-up visit, divided as follows: * Screening: up to 21 days * Treatment Period: Days 1 to 20 * Safety follow-up visit: 12±2 days
Interventions
DRUGGivinostat 10 mg/mL
10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Days 1, 2, 6, 7, 17 and 18), and twice a day (50 mg as oral suspension), in the morning and in the evening, from the Day 4 to Day 18. On Day 19, only the morning dose was administered.
DRUGMidazolam 1mg/ml IV
Midazolam 1 mg/ml, solution for intravenous administration. Midazolam 1mg/ml IV, single dose, was administered on Days 1, 6 and 17, 1 hour after the planned morning time of givinostat administration. Midazolam IV were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.
DRUGMidazolam 2.5 mg oromucosal solution
Dose: 2.5 mg oromucosal solution. Midazolam 2.5 mg single oral solution was administered on Days 2, 7 and 18, 1 hour after the planned morning time of givinostat administration. Oral midazolam (and dabigatran etexilate) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose. Oral midazolam (and dabigatran etexilate) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before midazolam and dabigatran dosing until 2 hours postdose. Water was provided ad libitum at all other times. Midazolam (and dabigatran etexilate) were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.
DRUGDabigatran etexilate 75 mg oral hard capsules
Dose: 75 mg; Dosage form: hard capsules On Days 1, 6 and 17, dabigatran etexilate 75 mg was administered (with midazolam 1mg IV) 1 hour after the planned morning time of givinostat administration. Dabigatran etexilate (and midazolam) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose Oral dabigatran etexilate (and oral midazolam) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before dabigatran (and midazolam) dosing until 2 hours postdose. Water was provided ad libitum at all other times. Dabigatran etexilate (and Midazolam) was administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.
Sponsors
Italfarmaco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
The study was conducted as open label. Blinding procedures were not applicable
Intervention model description
An Open-label, Single-center trial in Healthy Subjects
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
A subject was considered eligible for the study if he/she fulfilled all the inclusion criteria: 1. Subject's written informed consent obtained prior to any study-related procedure. 2. Male or female subject, ≥18 and ≤55 years of age, at the time of signing the informed consent. 3. Body mass index (BMI) of 18.5 to 32.0 kg/m2 inclusive, and body weight ≥55 kg and ≤100 kg for females and body weight ≥60 kg and ≤110 kg for males. 4. Non-smoker or ex-smoker (i.e. someone who abstained from using tobaccoor nicotine-containing products for at least 3 months prior to Screening). 5. No clinically relevant diseases. 6. No major surgery within 4 weeks prior to dosing. 7. No clinically relevant abnormalities on physical examination. 8. No clinically relevant abnormalities on 12-lead ECG. 9. No clinically relevant abnormalities on clinical laboratory tests. 10. Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), Hepatitis B surface antigen (HBsAg) and anti-Hepatitis C virus antibodies (anti-HCVAb). 11. Female subjects are eligible if they are of non-childbearing potential or agree to use a non-hormonal highly effective contraceptive method from 28 days prior to Screening until at least 90 days after the last study drug administration. Nonchildbearing potential female is defined as: 1. Menopausal, i.e. no menses for ≥ 12 months without an alternative medical cause other than menopause, and a high FSH level. 2. Pre-menopausal female with documented hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy. A non-hormonal effective contraceptive method is defined as: 1. Intrauterine device. 2. Bilateral tubal occlusion. 3. Total abstinence of heterosexual intercourse, in accordance with the lifestyle of the subject. 4. Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner. 12. Male subjects who are sexually active with a female partner of childbearing potential (pregnant or non-pregnant) must use contraception (condom) from investigational product administration up to at least 90 days following the last study drug administration. 13. Male subjects must ensure that his non-pregnant female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception (see Section 8.5.3). 14. Male subjects must be willing not to donate sperm until 90 days following the last study drug administration. 15. Willingness and capability to comply with the requirements of the study and ability to understand the study procedures and the risks involved.
Exclusion criteria
A subject was excluded from the study if he/she fulfilled any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations. |
| %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of dabigatran on day 1,6,17 | Area under the curve (AUC) is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed. The total AUC (AUC0-∞) is the area under the curve from time 0 extrapolated to infinite time. * AUC0extrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞. * AUC0extrap of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatra |
| λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations. |
| Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | Maximum observed plasma concentration (Cmax) of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations. |
| Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of dabigatran on day 1,6,17 | Maximum observed plasma concentration (Cmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected in K2-EDTA collection tubes at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations. |
| Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | tmax =Time of occurrence of Cmax. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations. |
| Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of dabigatran on day 1,6,17 | The time of occurrence of maximum observed concentration (tmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations. |
| t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | T1/2 is the Apparent terminal elimination half-life, calculated as ln(2)/λz. t1/2 of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations. |
| t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of dabigatran on day 1,6,17 | Apparent terminal elimination half-life, calculated as ln(2)/λz. The t1/2 of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations. |
| AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations. |
| AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of dabigatran on day 1,6,17 | AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations. |
| AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | AUC0-inf=Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations. |
| AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of dabigatran on day 1,6,17 | AUC0-inf = Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. AUC0-inf of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations. |
| %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18. | Area under the curve or AUC is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum). Standard calculation of AUC involves using non-compartmental techniques to calculate the AUC from time 0 to the last measurable concentration. This is called AUC0-t and represents the observed exposure to a drug. The total AUC or AUC0-∞ is the area under the curve from time 0 extrapolated to infinite time. %AUCextrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34 | An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit. |
| Number of Adverse Events by Severity (Mild, Moderate, Severe) | Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to date 30-34 | An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit. |
Countries
Portugal
Participant flow
Recruitment details
Subjects were screened between Days -21 to -3 (both inclusive) of study part 1 to confirm that they met the subject selection criteria. Prior to any screening assessment, the Investigator (or an appropriate delegate) obtained informed consent from each subject in accordance with the procedures. 26 subjects were enrolled to study part 1. Please note that the overall figure n=104 is wrong; the system in fact automatically and inappropriately sums up the number of each IMP group.
Participants by arm
| Arm | Count |
|---|---|
| Number of Subjects Enrolled Twenty-six (26) subjects (7 women and 19 men) were admitted to study Part 1. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Number of Subjects Enrolled |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants |
| Age, Continuous | 34 years STANDARD_DEVIATION 8.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment Portugal | 26 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 26 / 26 | 26 / 26 | 26 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 | 0 / 26 |
Outcome results
Primary
%AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Area under the curve (AUC) is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed. The total AUC (AUC0-∞) is the area under the curve from time 0 extrapolated to infinite time. * AUC0extrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞. * AUC0extrap of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatra
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 1.37 Percentage of AUC0-inf |
| Midazolam IV Alone (Day 1) | %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 1.27 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 6) | %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 1.79 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 6) | %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 1.69 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 17) | %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 2.23 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 17) | %AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 2.02 Percentage of AUC0-inf |
Primary
AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
AUC0-inf = Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. AUC0-inf of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 563.09 ng.h/mL |
| Midazolam IV Alone (Day 1) | AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 467.79 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 393.93 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 347.56 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 396.25 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 347.73 ng.h/mL |
Comparison: Total Dabigatran: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - AUC0-inf90% CI: [58.83, 83.2]
Comparison: Free Dabigatran: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - AUC0-inf90% CI: [59.08, 86.88]
Comparison: Total Dabigatran: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - AUC0-inf90% CI: [59.64, 83.03]
Comparison: Free Dabigatran: Potential Induction Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate. AUC0-inf90% CI: [60.79, 88.75]
Primary
AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
AUC0-inf=Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: Pharmacokinetic Analysis includes all subjects enrolled in Part 1 who provided evaluable pk data for at least one IMP. These were:~n=26 for (1-Hydroxy)midazolam IV alone, n=26 for Mid IV + givinostat (G) at days 6 and 17, for oral hydroxymid alone at day 2, oral Mid + G at day 7.~n=25 for 1-Hydroxymid + G at day 6, oral mid alone at day 2, oral (1-Hydroxy)mid + G at day 18.~n=24 for oral 1-Hydroxymid + G at day 7 n=23 for oral 1-hydroxymid + G at day 17
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 5720.13 pg.h/mL |
| Midazolam IV Alone (Day 1) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 46054.19 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 49532.66 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 6404.39 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 57112.86 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 7821.70 pg.h/mL |
| Oral Midazolam Alone (Day 2) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 39037.54 pg.h/mL |
| Oral Midazolam Alone (Day 2) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 11914.16 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 53379.48 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 15895.61 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 62904.03 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 19199.79 pg.h/mL |
Comparison: Midazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Midazolam IV: AUC0-inf90% CI: [103.35, 111.49]
Comparison: 1-Hydroxymidazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Midazolam IV - AUC0-inf90% CI: [106.21, 118.46]
Comparison: Midazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Midazolam IV - AUC0-inf90% CI: [119.44, 128.76]
Comparison: 1-Hydroxymidazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Midazolam IV. AUC0-inf90% CI: [126.15, 142.96]
Comparison: Midazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - AUC0-inf90% CI: [129.05, 149.18]
Comparison: 1-Hydroxymidazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Oral Midazolam: AUC0-inf90% CI: [124.19, 144.97]
Comparison: Midazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Oral Midazolam: AUC0-inf90% CI: [151.13, 175.28]
Comparison: 1-Hydroxymidazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - AUC0-inf90% CI: [147.8, 175.82]
Primary
AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 552.25 ng.h/mL |
| Midazolam IV Alone (Day 1) | AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 460.16 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 386.05 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 341.01 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 386.23 ng.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 332.71 ng.h/mL |
Comparison: Total Dabigatran: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics - AUC0-t90% CI: [58.43, 83.64]
Comparison: Free Dabigatran: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - AUC0-t90% CI: [58.67, 86.98]
Comparison: Total Dabigatran: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - AUC0-t90% CI: [58.82, 83.15]
Comparison: Free Dabigatran: Potential Induction Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - AUC0-t90% CI: [59.92, 87.25]
Primary
AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP,
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 44094.42 pg.h/mL |
| Midazolam IV Alone (Day 1) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 5050.60 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 47333.50 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 5362.65 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 53692.16 pg.h/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 6210.86 pg.h/mL |
| Oral Midazolam Alone (Day 2) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 36483.20 pg.h/mL |
| Oral Midazolam Alone (Day 2) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 10871.00 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 50134.44 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 14264.35 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 57559.53 pg.h/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 17208.29 pg.h/mL |
Comparison: Midazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Midazolam IV - AUC0-t90% CI: [103.35, 111.49]
Comparison: 1-Hydroxymidazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Midazolam IV - AUC0-t90% CI: [100.84, 111.8]
Comparison: Midazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Midazolam IV - AUC0-t90% CI: [117.56, 126.12]
Comparison: 1-Hydroxymidazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Midazolam IV - AUC0-t90% CI: [115.08, 131.41]
Comparison: Midazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - AUC0-t90% CI: [128.09, 147.43]
Comparison: 1-Hydroxymidazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - AUC0-t90% CI: [122.47, 140.59]
Comparison: Midazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Oral Midazolam. - AUC0-t90% CI: [147.49, 168.76]
Comparison: 1-Hydroxymidazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Oral Midazolam: - AUC0-t90% CI: [145.23, 172.54]
Primary
%AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Area under the curve or AUC is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum). Standard calculation of AUC involves using non-compartmental techniques to calculate the AUC from time 0 to the last measurable concentration. This is called AUC0-t and represents the observed exposure to a drug. The total AUC or AUC0-∞ is the area under the curve from time 0 extrapolated to infinite time. %AUCextrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP,
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 3.87 Percentage of AUC0-inf |
| Midazolam IV Alone (Day 1) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 9.72 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 6) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 3.96 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 6) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 13.20 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 17) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 5.12 Percentage of AUC0-inf |
| Midazolam IV Co-administered With Givinostat (Day 17) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 15.97 Percentage of AUC0-inf |
| Oral Midazolam Alone (Day 2) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 5.02 Percentage of AUC0-inf |
| Oral Midazolam Alone (Day 2) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 6.95 Percentage of AUC0-inf |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 5.33 Percentage of AUC0-inf |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 8.42 Percentage of AUC0-inf |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 5.79 Percentage of AUC0-inf |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | %AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 8.80 Percentage of AUC0-inf |
Primary
Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Maximum observed plasma concentration (Cmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected in K2-EDTA collection tubes at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 69.44 ng/mL |
| Midazolam IV Alone (Day 1) | Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 60.19 ng/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 51.17 ng/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 44.03 ng/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 45.35 ng/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 37.41 ng/mL |
Comparison: Total Dabigatran: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - Cmax90% CI: [60.77, 89.33]
Comparison: Free Dabigatran: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - Cmax90% CI: [57.94, 85.5]
Comparison: Total Dabigatran: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate - Cmax90% CI: [53.33, 79.98]
Comparison: Free Dabigatran: Potential Induction Effect of Givinostat on the Pharmacokinetics of Dabigatran Etexilate. Cmax90% CI: [50.86, 75.95]
Primary
Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
Maximum observed plasma concentration (Cmax) of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 50482.44 pg/mL |
| Midazolam IV Alone (Day 1) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 1426.41 pg/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 53345.17 pg/mL |
| Midazolam IV Co-administered With Givinostat (Day 6) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 1306.05 pg/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 46510.23 pg/mL |
| Midazolam IV Co-administered With Givinostat (Day 17) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 1335.02 pg/mL |
| Oral Midazolam Alone (Day 2) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 12695.07 pg/mL |
| Oral Midazolam Alone (Day 2) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 4451.49 pg/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 15744.30 pg/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 5229.06 pg/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 17678.67 pg/mL |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 6303.67 pg/mL |
Comparison: Midazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Midazolam IV.~Cmax90% CI: [91.72, 121.74]
Comparison: 1-Hydroxymidazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Midazolam IV - Cmax90% CI: [86.16, 97.31]
Comparison: Midazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Midazolam IV - Cmax90% CI: [75.97, 111.73]
Comparison: 1-Hydroxymidazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Midazolam IV - Cmax90% CI: [83.72, 104.63]
Comparison: Midazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - Cmax90% CI: [114.38, 134.47]
Comparison: 1-Hydroxymidazolam: Potential Inhibitory Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - Max90% CI: [104.78, 131.69]
Comparison: Midazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - Cmax90% CI: [128.71, 150.67]
Comparison: 1-Hydroxymidazolam: Potential Inducing Effect of Givinostat on the Pharmacokinetics of Oral Midazolam - Cmax90% CI: [122.36, 163.88]
Primary
t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Apparent terminal elimination half-life, calculated as ln(2)/λz. The t1/2 of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 7.96 hours |
| Midazolam IV Alone (Day 1) | t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 7.28 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 8.01 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 7.03 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 8.74 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 8.05 hours |
Primary
t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
T1/2 is the Apparent terminal elimination half-life, calculated as ln(2)/λz. t1/2 of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: Pharmacokinetic Analysis includes all subjects enrolled in Part 1 who provided evaluable pk data for at least one IMP. These were: n=26 for (1-Hydroxy)midazolam IV alone, n=25 for (1-Hydroxy)midazolam + givinostat at day 6, n=23 for (1-Hydroxy)midazolam + givinostat at day 17, n=25 for oral (1-Hydroxy)midazolam alone at day 2, n=25 for oral (1-Hydroxy)midazolam + givinostat at day 18 , n=26 for oral midazolam + givinostat at day 7, n=24 for oral 1-Hydroxymidazolam + givinostat at day 7.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | midazolam | 5.27 hours |
| Midazolam IV Alone (Day 1) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 4.02 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | midazolam | 5.22 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 5.00 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | midazolam | 6.62 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 5.74 hours |
| Oral Midazolam Alone (Day 2) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | midazolam | 5.48 hours |
| Oral Midazolam Alone (Day 2) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 4.62 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | midazolam | 5.84 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 6.09 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | midazolam | 6.73 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-hydroxymidazolam | 6.43 hours |
Primary
Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
The time of occurrence of maximum observed concentration (tmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 2.00 hours |
| Midazolam IV Alone (Day 1) | Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 2.00 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 2.00 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 2.00 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | total dabigatran | 2.00 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug | free dabigatran | 2.00 hours |
Primary
Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
tmax =Time of occurrence of Cmax. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP,
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 0.03 hours |
| Midazolam IV Alone (Day 1) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 0.50 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 0.03 hours |
| Midazolam IV Co-administered With Givinostat (Day 6) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 0.50 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 0.03 hours |
| Midazolam IV Co-administered With Givinostat (Day 17) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 0.51 hours |
| Oral Midazolam Alone (Day 2) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 0.55 hours |
| Oral Midazolam Alone (Day 2) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 0.55 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 0.50 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 0.50 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | midazolam | 0.50 hours |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug | 1-hydroxymidazolam | 0.50 hours |
Primary
λz of Dabigatran (Total and Free), Following Single Doses of Givinostat
Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP,
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | Total Dabigatran | 0.087 1/h |
| Midazolam IV Alone (Day 1) | λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | Free dabigatran | 0.095 1/h |
| Midazolam IV Co-administered With Givinostat (Day 6) | λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | Total Dabigatran | 0.087 1/h |
| Midazolam IV Co-administered With Givinostat (Day 6) | λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | Free dabigatran | 0.099 1/h |
| Midazolam IV Co-administered With Givinostat (Day 17) | λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | Total Dabigatran | 0.079 1/h |
| Midazolam IV Co-administered With Givinostat (Day 17) | λz of Dabigatran (Total and Free), Following Single Doses of Givinostat | Free dabigatran | 0.086 1/h |
Primary
λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Time frame: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Population: Pharmacokinetic Analysis includes all subjects enrolled in Part 1 who provided evaluable pk data for at least one IMP. These were:~n=26 for (1-Hydroxy)midazolam IV alone, n=26 for Mid IV + givinostat (G) at days 6 and 17, for oral hydroxymid alone at day 2, oral Mid + G at day 7.~n=25 for 1-Hydroxymid + G at day 6, oral mid alone at day 2, oral (1-Hydroxy)mid + G at day 18.~n=24 for oral 1-Hydroxymid + G at day 7 n=23 for IV 1-hydroxymid + G at day 17
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 0.131 1/h |
| Midazolam IV Alone (Day 1) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 0.172 1/h |
| Midazolam IV Co-administered With Givinostat (Day 6) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 0.133 1/h |
| Midazolam IV Co-administered With Givinostat (Day 6) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 0.139 1/h |
| Midazolam IV Co-administered With Givinostat (Day 17) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 0.105 1/h |
| Midazolam IV Co-administered With Givinostat (Day 17) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 0.121 1/h |
| Oral Midazolam Alone (Day 2) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 0.127 1/h |
| Oral Midazolam Alone (Day 2) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 0.150 1/h |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 0.119 1/h |
| Oral Midazolam Co-Administered With Givinostat (Day 7) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 0.114 1/h |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | Midazolam | 0.103 1/h |
| Oral Midazolam Co-Administered With Givinostat (Day 18) | λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat | 1-Hydroxymidazolam | 0.108 1/h |
Secondary
Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe)
An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit.
Time frame: During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34
Population: All subjects who receive at least one dose of an IMP in Part 1 of the study constitute the Part 1 Safety Analysis Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 26 Participants |
| Midazolam IV Alone (Day 1) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 2 Participants |
| Midazolam IV Co-administered With Givinostat (Day 6) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 2 Participants |
| Midazolam IV Co-administered With Givinostat (Day 6) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 26 Participants |
| Midazolam IV Co-administered With Givinostat (Day 17) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 26 Participants |
| Midazolam IV Co-administered With Givinostat (Day 17) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 2 Participants |
| Oral Midazolam Alone (Day 2) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 26 Participants |
| Oral Midazolam Alone (Day 2) | Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 2 Participants |
Secondary
Number of Adverse Events by Severity (Mild, Moderate, Severe)
An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit.
Time frame: Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to date 30-34
Population: All subjects who receive at least one dose of an IMP in Part 1 of the study constitute the Part 1 Safety Analysis Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midazolam IV Alone (Day 1) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 28 number of TEAE |
| Midazolam IV Alone (Day 1) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE severe | 0 number of TEAE |
| Midazolam IV Alone (Day 1) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 0 number of TEAE |
| Midazolam IV Co-administered With Givinostat (Day 6) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 25 number of TEAE |
| Midazolam IV Co-administered With Givinostat (Day 6) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE severe | 0 number of TEAE |
| Midazolam IV Co-administered With Givinostat (Day 6) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 0 number of TEAE |
| Midazolam IV Co-administered With Givinostat (Day 17) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 2 number of TEAE |
| Midazolam IV Co-administered With Givinostat (Day 17) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 74 number of TEAE |
| Midazolam IV Co-administered With Givinostat (Day 17) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE severe | 0 number of TEAE |
| Oral Midazolam Alone (Day 2) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE mild severity | 127 number of TEAE |
| Oral Midazolam Alone (Day 2) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE severe | 0 number of TEAE |
| Oral Midazolam Alone (Day 2) | Number of Adverse Events by Severity (Mild, Moderate, Severe) | AE moderate severity | 2 number of TEAE |