Effect of Testosterone Therapy on Cytochrome P450 3A and P-Glycoprotein Activities Using Midazolam and Digoxin as...

Gender-affirming testosterone therapy is one part of the standard of care for more than 1 million transgender adults in the United States. Testosterone therapy may influence the activities of drug-metabolizing enzymes and transporters, but knowledge about its effect on the pharmacokinetics of other medications is limited. We determined the effects of gender-affirming testosterone therapy on apparent cytochrome P450 (CYP) 3A and P-glycoprotein activities using midazolam and digoxin as model probe substrates among transgender adults.

This was a longitudinal (pre-treatment and with concomitant testosterone therapy), prospective, non-randomized, open-label, three-phase probe substrate study. Eligible participants started testosterone therapy based on clinical need. Participants received one oral dose of midazolam 2 mg and digoxin 0.25 mg (simultaneous dosing) under fasted conditions before starting gender-affirming testosterone therapy (baseline), and at 1-month and 3-months on gender-affirming testosterone therapy. Midazolam, 1'-hydroxymidazolam, 4-hydroxymidazolam, digoxin, and total testosterone concentrations were determined by liquid chromatography-tandem mass spectrometry assays. We estimated single-dose pharmacokinetic parameters of midazolam, its metabolites, and digoxin using standard noncompartmental methods. Pharmacokinetic parameters were compared with testosterone therapy at 1-month and 3-months to baseline as geometric mean ratios (90% confidence intervals) and paired t-tests after log transformation. A p < 0.025 was considered significant.

Among 14 participants (mean age: 24 ± 3 years; weight: 82.9 ± 20.9 kg; race/ethnicity: 71% White, non-Hispanic, 14% Hispanic, 7% Asian, 7% mixed race), nine participants started weekly testosterone injections (20 mg to 80 mg once weekly) and five started daily transdermal testosterone applications (12.5 mg to 50 mg once daily gel or cream, 2 mg daily patch). Mean total testosterone concentrations at 3 months increased more than 20-fold from baseline concentrations (25 ± 7 ng/dL to 507 ± 263 ng/dL). Geometric mean midazolam and metabolite pharmacokinetic parameters and digoxin parameters were not significantly different at baseline and with testosterone therapy.

Gender-affirming testosterone therapy did not significantly affect CYP3A or P-glycoprotein activities. Gender-affirming testosterone therapy may have minimal effects on the pharmacokinetics of other medications that are substrates of CYP3A and P-glycoprotein. Caution may be warranted for medications with a narrow therapeutic index.