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

Phase 1

Completed

Conditions: Transgender Health
Gender Dysphoria
Transgender Women
Human Immunodeficiency Virus

Interventions: Drug: Doravirine/Lamivudine/Tenofovir
Drug: Spironolactone 100mg
Drug: Estradiol 2mg
Other: Placebo

Registration Number: NCT04283656

Lead Sponsor: Thomas Jefferson University

Brief Summary: 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.

Detailed Description: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 8

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment A	Doravirine/Lamivudine/Tenofovir	Single-dose oral Doravirine/lamivudine/tenofovir disoproxil
Treatment B	Spironolactone 100mg	Single-dose estradiol and spironolactone co-administered with placebo
Treatment B	Estradiol 2mg	Single-dose estradiol and spironolactone co-administered with placebo
Treatment B	Placebo	Single-dose estradiol and spironolactone co-administered with placebo
Treatment C	Doravirine/Lamivudine/Tenofovir	Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone
Treatment C	Spironolactone 100mg	Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone
Treatment C	Estradiol 2mg	Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone

Primary Outcome Measures

Name	Time	Method
Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)	Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants	Doravirine AUC derived from plasma sampling with geometric mean ratio compared between treatment arms
Doravirine Maximum Concentration (Cmax)	Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants	Doravirine maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms
Doravirine Trough Concentration (C24)	24 hours post-dose for all participants	Doravirine observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms
Tenofovir Disoproxil Fumarate Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)	Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants	Tenofovir AUC derived from plasma sampling with geometric mean ratio compared between treatment arms
Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax)	Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants	Tenofovir maximum observed concentration during the dosing interval
Tenofovir Disoproxil Fumarate Trough Concentration (C24)	24 hours post-dose for all participants	Tenofovir observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms
Estradiol Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)	Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants	Estradiol area under the plasma concentration versus time curve from 0 hours to infinity (AUC) derived from plasma sampling
Estradiol Maximum Concentration (Cmax)	Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants	Estradiol maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms
Estradiol Trough Concentration (C12)	12 hours post-dose for all participants	Estradiol observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms