Drug Interaction Potentiation
Conditions
Brief summary
This is a single center, open-label, fixed sequence study to investigate the effect of multiple oral dosing of Inarigivir Soproxil and a single oral dose of Midazolam in Healthy Subjects
Interventions
DRUGMidazolam
Midazolam
DRUGInarigivir
Inarigivir
Sponsors
PRA Health Sciences
F-star Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Gender : male or female 2. Age : 18-55 years, inclusive, at screening 3. Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening 4. Status : healthy subjects 5. At screening, females must be non-pregnant and non-lactating, or of non-childbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year post-menopausal \[amenorrhoea duration of 12 consecutive months\]); non-pregnancy will be confirmed for all females by a serum pregnancy test conducted at screening, and a urine pregnancy test at each admission and at follow-up 6. Female subjects of childbearing potential, with a fertile male sexual partner, must agree to use adequate contraception from screening until 90 days after the follow-up visit. Adequate contraception is defined as using a non-hormonal intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom; please note that hormonal contraceptives are not allowed. Also, total abstinence, in accordance with the lifestyle of the subject, is acceptable 7. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject (and his female partner) is defined as using hormonal contraceptives or an intrauterine device, combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the subject is acceptable 8. All prescribed medication, including hormonal contraceptives for female subjects, must have been stopped at least 30 days prior to admission to the clinical research center 9. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (eg, St. John's Wort) must have been stopped at least 14 days prior to admission to the clinical research center. An exception is made for paracetamol, which is allowed up to admission to the clinical research center 10. Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) from 72 hours prior to admission to the clinical research center 11. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, electrocardiogram (ECG) and vital signs, as judged by the PI 12. Willing and able to sign the ICF
Exclusion criteria
1. Employee of PRA or the Sponsor 2. History of relevant drug and/or food allergies 3. Using tobacco products within 60 days prior to the first drug administration 4. History of alcohol abuse or drug addiction (including soft drugs like cannabis products) 5. Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines \[including ecstasy\], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants and alcohol) at screening and admission to the clinical research center 6. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits) 7. Positive screen for hepatitis B surface antigen (HBsAg), anti-HCV antibodies or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies 8. Participation in a drug study within 60 days prior to the first drug administration in the current study. Participation in more than 4 other drug studies in the 12 months prior to the first drug administration in the current study 9. Donation or loss of more than 100 mL of blood within 60 days prior to the first drug administration. Donation or loss of more than 1.5 liters of blood (for male subjects) / more than 1.0 liters of blood (for female subjects) in the 10 months prior to the first drug administration in the current study 10. Significant and/or acute illness within 5 days prior to the first drug administration that may impact safety assessments, in the opinion of the PI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax) | Day 1 Treatment A and Day 19 Treatment D, respectively | Comparison of Cmax for midazolam between Treatments A and D. |
| Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-t) | Day 1 Treatment A and Day 19 Treatment D, respectively | Comparison of AUC0-t for midazolam between Treatments A and D. |
| Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-inf ) | Day 1 Treatment A and Day 19 Treatment D, respectively | Comparison of AUC0-inf for midazolam between Treatments A and D. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination | Day -1 to Day 20 and Follow-up (5-9 days post-treatment) | Safety and tolerability were measured via clinical laboratory evaluations, vital signs, 12-lead ECG, or physical examination |
| PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC) | Day 3 and Day 6 to 19 | A summary of the main plasma PK parameters for inarigivir, Rp-SB 9000, Sp-SB 9000, and Rp-SB 9000 and Sp-SB 9000 combined after a single oral dose of 400 mg inarigivir on Day 3 (Treatment B) and after the last of 14 consecutive daily oral doses of 400 mg inarigivir from Day 6 to 19 (Treatment D) |
| PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax) | Day 3 and Day 6 to 19 | A summary of the main plasma PK parameters for inarigivir, Rp-SB 9000, Sp-SB 9000, and Rp-SB 9000 and Sp-SB 9000 combined after a single oral dose of 400 mg inarigivir on Day 3 (Treatment B) and after the last of 14 consecutive daily oral doses of 400 mg inarigivir from Day 6 to 19 (Treatment D) |
Countries
Netherlands
Participant flow
Pre-assignment details
Each subject was expected to complete treatment groups A, B, C and D; sequentially.
Participants by arm
| Arm | Count |
|---|---|
| Sequential Single, Multi-day & Combo Midazolam and Inarigivir A: All subjects will receive a single oral dose of 2 mg Midazolam on Day 1
B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3
C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18
D: All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Period C | Adverse Event | 1 |
| Treatment Period C | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Sequential Single, Multi-day & Combo Midazolam and Inarigivir |
|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 9 |
| BMI | 25.5 kg/m^2 STANDARD_DEVIATION 3.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 11 Participants |
| Region of Enrollment Netherlands | 17 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 4 / 17 | 4 / 17 | 7 / 17 | 2 / 15 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-inf )
Comparison of AUC0-inf for midazolam between Treatments A and D.
Time frame: Day 1 Treatment A and Day 19 Treatment D, respectively
Population: This outcome measure was prespecified for treatment groups A and D only.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Midazolam | Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-inf ) | 31.5 h.ng/ml |
| Treatment D: Inarigivir With Midazolam | Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-inf ) | 30.5 h.ng/ml |
Primary
Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-t)
Comparison of AUC0-t for midazolam between Treatments A and D.
Time frame: Day 1 Treatment A and Day 19 Treatment D, respectively
Population: This outcome measure was prespecified for treatment groups A and D only.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Midazolam | Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-t) | 29.9 h.ng/ml |
| Treatment D: Inarigivir With Midazolam | Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-t) | 28.7 h.ng/ml |
Primary
Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax)
Comparison of Cmax for midazolam between Treatments A and D.
Time frame: Day 1 Treatment A and Day 19 Treatment D, respectively
Population: All subjects who received at least one dose of midazolam and had sufficient concentration-time data to reliably estimate PK parameters
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Midazolam | Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax) | 12.4 ng/mL |
| Treatment D: Inarigivir With Midazolam | Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax) | 13.0 ng/mL |
Secondary
Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination
Safety and tolerability were measured via clinical laboratory evaluations, vital signs, 12-lead ECG, or physical examination
Time frame: Day -1 to Day 20 and Follow-up (5-9 days post-treatment)
Population: All participants analyzed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A: Midazolam | Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination | 0 Participants |
| Treatment B and C: Inarigivir | Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination | 0 Participants |
| Treatment D: Inarigivir With Midazolam | Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination | 0 Participants |
| Treatment D: Inarigivir With Midazolam | Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination | 0 Participants |
Secondary
PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC)
A summary of the main plasma PK parameters for inarigivir, Rp-SB 9000, Sp-SB 9000, and Rp-SB 9000 and Sp-SB 9000 combined after a single oral dose of 400 mg inarigivir on Day 3 (Treatment B) and after the last of 14 consecutive daily oral doses of 400 mg inarigivir from Day 6 to 19 (Treatment D)
Time frame: Day 3 and Day 6 to 19
Population: All subjects in treatment arms B and D who received inarigivir and had sufficient concentration-time data to reliably estimate PK parameters
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A: Midazolam | PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC) | Day 3 AUC0-t (h.ng/mL) | 0.914 h.ng/ml |
| Treatment A: Midazolam | PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC) | Day 3AUC0-inf (h.ng/mL) | 1.19 h.ng/ml |
| Treatment B and C: Inarigivir | PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC) | Day 19 AUC0-t (h.ng/mL) | 0.951 h.ng/ml |
Secondary
PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax)
A summary of the main plasma PK parameters for inarigivir, Rp-SB 9000, Sp-SB 9000, and Rp-SB 9000 and Sp-SB 9000 combined after a single oral dose of 400 mg inarigivir on Day 3 (Treatment B) and after the last of 14 consecutive daily oral doses of 400 mg inarigivir from Day 6 to 19 (Treatment D)
Time frame: Day 3 and Day 6 to 19
Population: All subjects in treatment arms B and D who received inarigivir and had sufficient concentration-time data to reliably estimate PK parameters
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A: Midazolam | PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax) | 0.886 ng/mL |
| Treatment B and C: Inarigivir | PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax) | 0.991 ng/mL |