Estradiol and Spironolactone Plasma Pharmacokinetics Among Brazilian Transgender Women Using HIV Pre-Exposure Prophylaxis: Analysis of Potential Interactions

Abstract

Background and objective: An important barrier to HIV prevention among transgender women (TGW) is the concern that oral pre-exposure prophylaxis (PrEP) negatively affects the efficacy of feminizing hormone therapy (FHT). We aimed to assess the impact of PrEP on FHT pharmacokinetics (PK) among TGW from Brazil.

Methods: We performed a drug-drug interaction sub-study among TGW enrolled in a daily oral PrEP demonstration study (PrEParadas, NCT03220152). Participants had a first PK assessment (PK1) 15 days after FHT (estradiol valerate 2-6 mg plus spironolactone 100-200 mg) initiation and then started PrEP (tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg). A second PK evaluation was performed 12 weeks later (PK2). Blood samples were collected prior and after the directly observed dosing (0, 0.5, 1, 2, 4, 6, 8, and 24 hours). Pharmacokinetic parameters of estradiol, spironolactone, and metabolites were estimated by non-compartmental analysis (Monolix 2021R2, Lixoft^®) and compared as geometric mean ratios (GMRs, 90% confidence interval [CI]).

Results: Among 19 TGW who completed the substudy, median age was 26 years (interquartile range: 23-27.5). Estradiol area under the plasma concentration-time curve (AUC_τ) and trough concentrations did not differ between PK1 and PK2 evaluations (GMR [90% CI]: 0.89 [0.76-1.04] and 1.06 [0.94-1.20], respectively). Spironolactone and canrenone AUC_τ were statistically lower at PK2 than PK1 (0.76 [0.65-0.89] and 0.85 [0.78-0.94], respectively). Canrenone maximum concentration was also lower at PK2 than PK1 (0.82 [0.74-0.91]).

Conclusion: Estradiol PK was not influenced by PrEP concomitant use. The small differences observed in some spironolactone and canrenone PK parameters should not prevent the concomitant use of estradiol-based FHT and PrEP.

Trial registration: This trial (NCT03220152) was registered on July 18, 2017.

Fig. 1

Study scheme. FHT feminizing hormone therapy, PK pharmacokinetic, PK1 first PK evaluation, participants on FHT only (enrollment) and TDF/FTC initiated by the end of the PK1 visit; PK2: second PK evaluation, participants on FHT plus PrEP (TDF/FTC). Estradiol pre-dose levels (C_trough) were evaluated at Weeks 4 (W4), 7 (W7), and 9 (W9)

Fig. 2

Study flow chart of study participants. FHT feminizing hormone therapy; PK pharmacokinetic; PK1 first PK evaluation, participants on FHT only (enrollment) and TDF/FTC initiated by the end of the PK1 visit; PK2: second PK evaluation, participants on FHT plus PrEP (TDF/FTC). *Excluded during data analysis

Fig. 3

Plasma estradiol, estrone and estrone sulfate concentration over 24 h in transgender women study participants. Plasma estradiol (a, b), estrone (c, d), and estrone sulfate (e, f) concentration versus time curves (sample times: pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours) are shown for the indicated doses at PK1 and PK2. Data are shown as means with error bars indicating standard deviations. E2V doses at PK1: 2 mg (n = 16); 4 mg (n = 3); 6 mg (n = 0); E2V doses at PK2: 2 mg (n = 10); 4 mg (n = 8); 6 mg (n = 1—Suppl. Fig. 1). E2: estradiol; E2V: estradiol valerate; E1: estrone; SE1: estrone sulfate; FHT feminizing hormone therapy, PK pharmacokinetic, PK1 first PK evaluation (n = 19), participants on FHT only (enrollment) and TDF/FTC initiated by the end of the PK1 visit; PK2: second PK evaluation, participants on FHT plus PrEP (TDF/FTC) (n = 19)

Fig. 4

Plasma spironolactone and canrenone concentration over 24 hours in transgender women study participants. Plasma spironolactone (a, b) and canrenone (c, d) concentration versus time curves (sample times: pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours) are shown for the indicated doses at PK1 and PK2. Data are shown as means with error bars indicating standard deviations. SPR doses at PK1: 100 mg (n = 18); 200 mg (n = 1); SPR doses at PK2: 100 mg (n = 10); 200 mg (n = 9). SPR: spironolactone; CRN: canrenone; FHT feminizing hormone therapy, PK pharmacokinetic, PK1 first PK evaluation, (n = 19), participants on FHT only (enrollment) and TDF/FTC initiated by the end of the PK1 visit; PK2: second PK evaluation, participants on FHT plus PrEP (TDF/FTC) (n = 19)