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

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

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

Study Overview

• Status: Completed
• Conditions: Contraception
• Intervention / Treatment: Drug: E4/DRSP; Drug: VAL

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham
    • Ruddington, Nottingham, United Kingdom, NG11 6JS
      • Quotient Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: E4/DRSP (Treatment A) - E4/DRSP + VAL (Treatment B); 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; Administered as specified in the treatment arm.; Other Names: E4 and DRSP combined tablet; Drug: VAL; Administered as specified in the treatment arm.; Other Names: Valproic acid; Depakote®
Experimental: E4/DRSP + VAL (Treatment B) - E4/DRSP (Treatment A); 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; Administered as specified in the treatment arm.; Other Names: E4 and DRSP combined tablet; Drug: VAL; Administered as specified in the treatment arm.; Other Names: Valproic acid; Depakote®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Estetra
• Collaborators: Quotient Sciences
• Investigators: Principal Investigator: Sharan Sidhu, Quotient Sciences

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2018
• Primary Completion (Actual): October 8, 2018
• Study Completion (Actual): October 8, 2018

Study Registration Dates

• First Submitted: April 19, 2018
• First Submitted That Met QC Criteria: April 19, 2018
• First Posted (Actual): May 1, 2018

Study Record Updates

• Last Update Posted (Actual): December 14, 2018
• Last Update Submitted That Met QC Criteria: December 13, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Drospirenone; Drug-drug interaction; Estetrol; Valproic acid; Uridine diphosphate glucuronosyltransferase-2B7
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: MIT-Es0001-C110; 2017-004280-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No