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

Study Overview
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Brief Summary
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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.

Official Title
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A Prospective, Randomized, Three-period Crossover, Interaction Study to Evaluate the Pharmacokinetics of Doravirine and Tenofovir Disoproxil Fumarate Co-administered With Cross-sex Hormonal Therapy in Adult HIV-negative Transgender Women

Conditions
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Transgender Health, Gender Dysphoria, Transgender Women, Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: Doravirine/Lamivudine/Tenofovir
* Drug: Spironolactone 100mg
* Drug: Estradiol 2mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Three period crossover
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Period I<br>Sequence E, Treatment A: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate alone Sequence F, Treatment C: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone | Drug: Doravirine/Lamivudine/Tenofovir<br>* 100mg/300mg/300mg orally for one dose, daily<br>* Other names: Delstrigo;Drug: Spironolactone 100mg<br>* 200mg orally for two doses, twice-daily<br>* Other names: Aldactone;Drug: Estradiol 2mg<br>* 4mg orally for two doses, twice-daily<br>|
| Other: Period II<br>Sequence E and F, Treatment B: Single-dose estradiol and spironolactone co-administered with placebo | Drug: Spironolactone 100mg<br>* 200mg orally for two doses, twice-daily<br>* Other names: Aldactone;Drug: Estradiol 2mg<br>* 4mg orally for two doses, twice-daily<br>Other: Placebo<br>* Placebo for one dose, daily<br>|
| Other: Period III<br>Sequence E, Treatment C: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone Sequence F, Treatment A: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate alone | Drug: Doravirine/Lamivudine/Tenofovir<br>* 100mg/300mg/300mg orally for one dose, daily<br>* Other names: Delstrigo;Drug: Spironolactone 100mg<br>* 200mg orally for two doses, twice-daily<br>* Other names: Aldactone;Drug: Estradiol 2mg<br>* 4mg orally for two doses, twice-daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Doravirine area under the plasma concentration versus time curve from 0 hours to infinity (AUC0-∞) | Doravirine AUC derived from plasma sampling | 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 | 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 | 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 | 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 | 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 | 24 hours post-dose for all participants | 
| Estradiol area under the plasma concentration versus time curve from 0 hours to infinity (AUC0-∞) | Estradiol AUC derived from plasma sampling | 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 | 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 | 12 hours post-dose for all participants |