Evaluating Drug Interactions Between Doravirine With Estradiol and Spironolactone in Healthy Transgender Women

Thomas Jefferson University8 enrolled

Overview

Transgender women living with Human Immunodeficiency Virus (HIV) may prioritize gender-affirming hormonal therapy over antiretroviral drug therapy. Hormonal therapy typically consists of oral estradiol and spironolactone, which induce drug-metabolizing enzymes after prolonged administration. This study evaluates the bi-directional potential drug interaction between the antiretroviral drug, doravirine, when co-administered with estradiol and spironolactone.

This study will consist of healthy transgender women volunteers randomized to a 1:1 sequence ("E" or "F") There are three periods and in each period there are one of three treatments Treatment A: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate alone Treatment B: Single-dose estradiol and spironolactone co-administered with placebo Treatment C: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone The primary outcome measures are the drug concentrations The primary comparisons are geometric mean ratios of drugs with potential perpetrators of drug interactions using a crossover method

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Transgender Health Gender Dysphoria

Interventions

Doravirine/Lamivudine/TenofovirDRUG

100mg/300mg/300mg orally for one dose, daily

Spironolactone 100mgDRUG

200mg orally for two doses, twice-daily

Estradiol 2mgDRUG

4mg orally for two doses, twice-daily

PlaceboOTHER

Placebo for one dose, daily

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy self-identified transgender women (male-to-female) between 18-45 years old at the time of screening * Have not undergone an orchiectomy * Receiving oral estradiol and spironolactone for \>/= 3 months prior to study entry with a self-reported adherence to prescribed doses of \>/= 90% * Agree to abstain from alcohol consumption throughout the duration of the study * Be willing to briefly interrupt hormonal therapy prior to and during the study * If on pre-exposure prophylaxis (PrEP) therapy containing tenofovir alafenamide or tenofovir disoproxil fumarate, willing to discontinue PrEP at least 2 weeks before study start and for the duration of the study * Agree to use condoms for all sexual activity prior to the start and throughout the duration of the study * Evidence of a personal signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study Exclusion Criteria: * Presence of clinically significant acute or chronic disease, that in the investigator's opinion, would compromise the participant's safety during the study * Use of injectable or transdermal estradiol * Use of any other hormonal replacement therapy, wit h the exception of oral estradiol and spironolactone * Current use of any antiretroviral drug. This will not be exclusionary if participants reported discontinuing within 30 days of screening * Creatinine clearance \</= 60 mL/min, as estimated by the Cockcroft-Gault equation * Known anaphylactic or severe systemic reactions to any components of doravirine, lamivudine, or tenofovir disoproxil fumarate * Positive HIV, hepatitis B or Hepatitis C virus at screening. Evidence of prior hepatitis B infection and immunity is not exclusionary. Positive hepatitis C antibody with negative viral load or documented antiviral hepatitis C treatment with one post treatment non-detectable hepatitis C viral load is not exclusionary * Recent significant blood or plasma donation

Outcomes

Primary Outcomes

Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)

Doravirine AUC derived from plasma sampling with geometric mean ratio compared between treatment arms

Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants

Doravirine Maximum Concentration (Cmax)

Doravirine maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms

Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants

Doravirine Trough Concentration (C24)

Doravirine observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms

Time frame: 24 hours post-dose for all participants

Tenofovir Disoproxil Fumarate Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)

Tenofovir AUC derived from plasma sampling with geometric mean ratio compared between treatment arms

Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants

Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax)

Tenofovir maximum observed concentration during the dosing interval

Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants

Tenofovir Disoproxil Fumarate Trough Concentration (C24)

Tenofovir observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms

Time frame: 24 hours post-dose for all participants

Estradiol Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)

Estradiol area under the plasma concentration versus time curve from 0 hours to infinity (AUC) derived from plasma sampling

Time frame: Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants

Estradiol Maximum Concentration (Cmax)

Estradiol maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms

Time frame: Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants

Estradiol Trough Concentration (C12)

Estradiol observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms

Time frame: 12 hours post-dose for all participants

Evaluating Drug Interactions Between Doravirine With Estradiol and Spironolactone in Healthy Transgender Women

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes