Drug Drug Interaction
Conditions
Keywords
PK, Pharmacokinetics, Givinostat, Clarythromycin
Brief summary
Primary objective: To assess the potential effect of oral Clarithromycin on the single-dose pharmacokinetics of Givinostat. Secondary objective: To assess the safety and tolerability of concomitant administration of Givinostat plus Clarithromycin.
Detailed description
This study was planned as a phase I, open-label, 3-part, fixed-sequence, non-randomized study in healthy male and female subjects. The study (Part 2) aimed at assessing the potential effect of Clarythromycin on the single dose pharmacokynetics of Givinostat. The total duration of Part 2 was divided as follows: * Screening: up to 21 days. * Treatment Period: Days 1 to 11. * Safety follow-up visit: 12±2 days. Subjects were confined at site from Day -1 to Day 11. On Days 1 and 8, a single dose of 50 mg Givinostat, as oral suspension, was administered 1 hour after the planned morning time of Clarithromycin administration. From Day 4 to Day 10, clarithromycin 500 mg film-coated tablets were administered twice a day, in the morning and in the evening. The following assessments were performed: * Blood collection for pharmacokinetic analysis on Days 1 to 4 and 8 to 11. * Vital signs measurements on Days 1 and 4 to 10. * 12-lead ECG on Days 1, 3, 7 and 8. * Blood collection for laboratory tests (hematology and biochemistry) on Day 3. Subjects were discharged in the morning of Day 11 after completing end of study procedures.
Interventions
DRUGGivinostat
ITF2357 Givinostat 10mg/mL. Dose: 10 mg/mL; Dosage form: oral suspension.
DRUGClarithromycin
Clarithromycin 500 mg immediate-release oral film-coated tablet (Klacid®) was administered twice a day, in the morning and in the evening.
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.
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 tobacco or 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 |
|---|---|---|
| t1/2 of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of Givinostat | t1/2 is the apparent terminal elimination half-life, calculated as ln(2)/λz. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat. |
| Cmax of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of Givinostat | Maximum observed plasma concentration (Cmax) of givinostat. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat. |
| AUC0-t of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of Givinostat | AUC0-t = area under the curve from time zero to last sampling time with quantifiable concentrations. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of Givinostat, on Days 1 and 8, for the determination of Givinostat. |
| AUC0-inf of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration 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. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat. |
| %AUCextrap of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of Givinostat | %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-∞. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat |
| Tmax of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of Givinostat | Tmax =The time of occurrence of maximum observed concentration of Givinostat. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat. |
| λz of Givinostat, Following Single Doses of the Parent Drug | In the turn of 72 hours after administration of Givinostat | λz is the 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. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of Treatment Emergent Adverse Events (TEAE) | Throughout 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. |
Countries
Portugal
Participant flow
Recruitment details
20 patients were enrolled. One discontinued after first dosing, so while safety and PK analysis populations were composed of 20 subjects, the drug-drug interaction comparable bioavailability is calculated on 19 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Total Subjects Enrolled At Day 1 patients received Givinostat 50 mg. At Days 4-7 patients received Clarithromycin 500 mg b.i.d. At Day 8 patients received Givinostat 50 mg + Clarithromycin 500 mg b.i.d At Days 9-10 patients received Clarithromycin 500 mg b.i.d.
Givinostat: ITF2357 Givinostat 10mg/mL. Dose: 10 mg/mL; Dosage form: oral suspension.
Clarithromycin: Clarithromycin 500 mg immediate-release oral film-coated tablet (Klacid®) administered twice a day, in the morning and in the evening. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Total Subjects Enrolled |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 31 years STANDARD_DEVIATION 5.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 6 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 | 14 Participants |
| Region of Enrollment Portugal | 20 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 16 / 20 | 16 / 19 | 16 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
AUC0-inf of Givinostat, 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. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat.
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. This explains why patients analyzed in each arm are n=19 and not n=20
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Givinostat Alone (Day 1) | AUC0-inf of Givinostat, Following Single Doses of the Parent Drug | 349.25 ng.h/mL | Geometric Coefficient of Variation 20.1 |
| Givinostat Co-Administered With Clarithromycin (Day 8) | AUC0-inf of Givinostat, Following Single Doses of the Parent Drug | 411.69 ng.h/mL | Geometric Coefficient of Variation 12.7 |
90% CI: [112.13, 123.92]
Primary
AUC0-t of Givinostat, Following Single Doses of the Parent Drug
AUC0-t = area under the curve from time zero to last sampling time with quantifiable concentrations. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of Givinostat, on Days 1 and 8, for the determination of Givinostat.
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. This explains why patients analyzed in each arm are n=19 and not n=20
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Givinostat Alone (Day 1) | AUC0-t of Givinostat, Following Single Doses of the Parent Drug | 344.67 ng.h/mL | Geometric Coefficient of Variation 20.4 |
| Givinostat Co-Administered With Clarithromycin (Day 8) | AUC0-t of Givinostat, Following Single Doses of the Parent Drug | 406.61 ng.h/mL | Geometric Coefficient of Variation 13 |
90% CI: [112.24, 124]
Primary
%AUCextrap of Givinostat, Following Single Doses of the Parent Drug
%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-∞. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. This explains why patients analyzed in each arm are n=19 and not n=20
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Givinostat Alone (Day 1) | %AUCextrap of Givinostat, Following Single Doses of the Parent Drug | 1.28 percentage of AUC0-∞ | Geometric Coefficient of Variation 23.3 |
| Givinostat Co-Administered With Clarithromycin (Day 8) | %AUCextrap of Givinostat, Following Single Doses of the Parent Drug | 1.17 percentage of AUC0-∞ | Geometric Coefficient of Variation 29.7 |
Primary
Cmax of Givinostat, Following Single Doses of the Parent Drug
Maximum observed plasma concentration (Cmax) of givinostat. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat.
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.~Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. This explains why patients analyzed in the combo arm are n=19 and not n=20
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Givinostat Alone (Day 1) | Cmax of Givinostat, Following Single Doses of the Parent Drug | 53.57 ng/mL | Geometric Coefficient of Variation 24.2 |
| Givinostat Co-Administered With Clarithromycin (Day 8) | Cmax of Givinostat, Following Single Doses of the Parent Drug | 75.35 ng/mL | Geometric Coefficient of Variation 21.9 |
90% CI: [129.73, 149.86]
Primary
t1/2 of Givinostat, Following Single Doses of the Parent Drug
t1/2 is the apparent terminal elimination half-life, calculated as ln(2)/λz. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat.
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. This explains why patients analyzed in each arm are n=19 and not n=20.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Givinostat Alone (Day 1) | t1/2 of Givinostat, Following Single Doses of the Parent Drug | 6.18 hours | Geometric Coefficient of Variation 4.9 |
| Givinostat Co-Administered With Clarithromycin (Day 8) | t1/2 of Givinostat, Following Single Doses of the Parent Drug | 6.70 hours | Geometric Coefficient of Variation 23 |
Primary
Tmax of Givinostat, Following Single Doses of the Parent Drug
Tmax =The time of occurrence of maximum observed concentration of Givinostat. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat.
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. Please note that in the combo arm, one of the 20 PK subjects early withdrew from the study before taking the drug combination. This explains why patients analyzed in the combo arm are n=19 and not n=20.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Givinostat Alone (Day 1) | Tmax of Givinostat, Following Single Doses of the Parent Drug | 2.00 hours |
| Givinostat Co-Administered With Clarithromycin (Day 8) | Tmax of Givinostat, Following Single Doses of the Parent Drug | 1.50 hours |
Primary
λz of Givinostat, Following Single Doses of the Parent Drug
λz is the 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. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat
Time frame: In the turn of 72 hours after administration of Givinostat
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. Please note that one of the 20 PK subjects early withdrew from the study before taking any study drug. This explains why patients analyzed in each arm are n=19 and not n=20
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Givinostat Alone (Day 1) | λz of Givinostat, Following Single Doses of the Parent Drug | 0.112 1/hour | Geometric Coefficient of Variation 4.9 |
| Givinostat Co-Administered With Clarithromycin (Day 8) | λz of Givinostat, Following Single Doses of the Parent Drug | 0.103 1/hour | Geometric Coefficient of Variation 23.2 |
Secondary
Severity of Treatment Emergent Adverse Events (TEAE)
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 day 30-34
Population: Pharmacokinetic Analysis Population: subjects enrolled in the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation. For one of the 20 PK subjects, though, data at day 8 are missing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Givinostat Alone (Day 1) | Severity of Treatment Emergent Adverse Events (TEAE) | mild | 43 number of events |
| Givinostat Alone (Day 1) | Severity of Treatment Emergent Adverse Events (TEAE) | moderate | 3 number of events |
| Givinostat Alone (Day 1) | Severity of Treatment Emergent Adverse Events (TEAE) | severe | 0 number of events |
| Givinostat Alone (Day 1) | Severity of Treatment Emergent Adverse Events (TEAE) | total | 46 number of events |
| Givinostat Co-Administered With Clarithromycin (Day 8) | Severity of Treatment Emergent Adverse Events (TEAE) | total | 41 number of events |
| Givinostat Co-Administered With Clarithromycin (Day 8) | Severity of Treatment Emergent Adverse Events (TEAE) | mild | 41 number of events |
| Givinostat Co-Administered With Clarithromycin (Day 8) | Severity of Treatment Emergent Adverse Events (TEAE) | severe | 0 number of events |
| Givinostat Co-Administered With Clarithromycin (Day 8) | Severity of Treatment Emergent Adverse Events (TEAE) | moderate | 0 number of events |
| Total Enrolled | Severity of Treatment Emergent Adverse Events (TEAE) | total | 46 number of events |
| Total Enrolled | Severity of Treatment Emergent Adverse Events (TEAE) | moderate | 3 number of events |
| Total Enrolled | Severity of Treatment Emergent Adverse Events (TEAE) | severe | 0 number of events |
| Total Enrolled | Severity of Treatment Emergent Adverse Events (TEAE) | mild | 43 number of events |