Estetrol (E4)/Drospirenone (DRSP) Drug-drug Interaction (DDI) Study

Study Overview
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Brief Summary
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The present study is designed to determine the effect of valproic acid (VAL), a UGT2B7 inhibiting drug, on the pharmacokinetics (PK) of estetrol (E4)

Detailed Description
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In the present study, E4/DRSP will be administered alone (Treatment A) and in combination with VAL (Treatment B) following two sequences A-B or B-A.

Official Title
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An Open-label, Two-way Cross-over Study to Determine the Effect of Multiple Doses of Valproic Acid on the Pharmacokinetics and Safety of a Single Oral Dose of Estetrol/Drospirenone in Healthy Female Subjects

Conditions
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Contraception

Intervention / Treatment
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* Drug: E4/DRSP
* Drug: VAL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy premenopausal, aged 18-45 years (inclusive) at the time of signing informed consent. For subjects who are sexually active and are of childbearing potential: willing to use a highly effective non-hormonal method of contraception from screening until the follow-up assessment, such as (but not limited to): non-hormonal intra-uterine device (copper IUD), bilateral tubal occlusion, vasectomised partner, or sexual abstinence in a heterosexual relationship; this is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their partner, must comply with the contraceptive requirements as stated earlier. Body weight ≥45 kg, and a body mass index between 18.0 and 30.0 kg/m² (inclusive). Negative serum pregnancy test at screening and a negative urine pregnancy test at Day -1. Exclusion Criteria: The use of: any prescription drugs, including oral or vaginal hormonal contraceptives, from 28 days prior to first dose administration until study completion; any herbal medication or dietary supplements acting on cytochrome P450 3A4 (CYP3A4) functions (i.e., St John's Wort), from 28 days prior to first dose administration until study completion; any over-the-counter medication (including paracetamol or dietary supplements (including vitamins and herbal products ), from 14 days prior to first dose administration until study completion. Limited use (i.e., up to 1200 mg/day) of ibuprofen is allowed; any depot progestogen preparations or an injectable hormonal method of contraception, from 6 months prior to the first dose administration until study completion. History of hypersensitivity, serious adverse reaction, or existing contraindication to E4, DRSP or VAL, or excipients.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E4/DRSP (Treatment A) - E4/DRSP + VAL (Treatment B)<br>Sequence A-B: A single oral dose of E4 combined with DRSP (Treatment A) will be administered during the Period 1. After a washout, subjects will enter into the Period 2. They will receive the Treatment B which consists in multiple oral doses of VAL for 12 consecutive days and one single oral dose of E4/DRSP on Day 5 of the VAL administration. | Drug: E4/DRSP<br>* Administered as specified in the treatment arm.<br>* Other names: E4 and DRSP combined tablet;Drug: VAL<br>* Administered as specified in the treatment arm.<br>* Other names: Depakote®;|
| Experimental: E4/DRSP + VAL (Treatment B) - E4/DRSP (Treatment A)<br>Sequence B-A: During Period 1, subjects will receive the Treatment B (multiple oral doses of VAL for 12 consecutive days and one single oral dose of E4/DRSP on Day 5 of the VAL administration) . After a washout, subjects will enter into the Period 2 and receive the Treatment A (a single oral dose of E4 combined with DRSP). | Drug: E4/DRSP<br>* Administered as specified in the treatment arm.<br>* Other names: E4 and DRSP combined tablet;Drug: VAL<br>* Administered as specified in the treatment arm.<br>* Other names: Depakote®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) of E4 | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| Area under the plasma concentration versus time curve from time 0 to the last determined concentration (AUC0-tdlc) of E4 | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| Area under the plasma concentration versus time curve from time 0 to infiny (AUC0-inf) of E4 | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events as a measure of safety and tolerability |  | The total study duration (between 50 and 86 days) | 
| Cmax of DRSP | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| Cmax of E4-glucuronide metabolites | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| AUC0-tdlc of DRSP | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| AUC0-tdlc of E4-glucuronide metabolites | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| AUC0-inf of DRSP | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 
| AUC0-inf of E4-glucuronide metabolites | PK sampling | 0-168 hr post E4/DRSP dose in both periods 1 and 2 of the two sequences A-B and B-A | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estetrol, Drospirenone, Uridine diphosphate glucuronosyltransferase-2B7, Drug-drug interaction, Valproic acid