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Four-in-One Drug Affects Levels of Oral Contraceptives Components
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Levels of ethinyl estradiol were lower but levels of norelgestromin higher when healthy HIV-negative women took a hormonal oral contraceptive (OC) with QUAD, the once-daily four-in-one pill containing cobicistat-boosted elvitegravir plus tenofovir/emtricitabine [1]. Gilead Sciences investigators proposed that an OC should contain at least 30 micrograms of ethinyl estradiol when taken with QUAD.
QUAD, now in phase 3 trials, proved equivalent to the three-in-one antiretroviral Atripla in a phase 2 trial that enrolled antiretroviral-naive people [2]. Rates of drug-related central nervous system and psychiatric side effects were lower with QUAD than with Atripla.
If cobicistat-boosted elvitegravir (an integrase inhibitor) and QUAD are licensed, some women who try this new antiretroviral will undoubtedly be taking hormonal OCs. This open-label phase 1 trial aimed to assess the impact of QUAD on norelgestromin (the active metabolite of norgestimate, a progestin) and ethinyl estradiol, and vice versa, in healthy HIV-negative women taking 25 micrograms of ethinyl estradiol in OrthoTri-Cyclen Lo (NGM/EE), a representative hormonal OC.
Part A enrolled women taking a hormonal OC other than NGM/EE, who switched to NGM/EE for one menstrual cycle then enrolled in part B, the main study. Women already taking NGM/EE enrolled directly in part B. All women in part B took NGM/EE in two sequential 28-day cycles. In the second cycle, women also took QUAD on days 12 through 21. All doses were taken with a standard meal.
Researchers collected samples over 24 hours on day 21 of each cycle to compare concentrations of ethinyl estradiol and norelgestromin with and without QUAD, and to gauge the impact of the OC on concentrations of elvitegravir and cobicistat during the second cycle. The investigators assessed equivalence of the two OC components with and without QUAD by setting a 90% confidence interval (CI) equivalence boundary of 80% to 125% around the geometric least squares mean ratios (GMR) for area under the concentration-time curve (AUC) and maximum concentration (Cmax).
Eighteen women took NGM/EE in part B of the study, and 15 completed part B, taking NGM/EE with QUAD. Women averaged 30 years in age (range 19 to 45) and 64.4 kg in weight (range 48.5 to 83.3). Two thirds were white, 19% black, 9.5% Asian, and 4.8% American Indian or Alaskan Native. One third of the women identified themselves as Hispanic.
Taking QUAD with NGM/EE lowered ethinyl estradiol AUC 25% and Ctrough about 45%, while approximately doubling norelgestromin AUC, Cmax, and Ctrough:
Average ethinyl estradiol concentrations
AUC without QUAD 1050 pg x h/mL; AUC with QUAD 775 pg x h/mL; GMR 75.0 (90% CI 69.4 to 81.0)
Ctrough without QUAD 25.8 pg/mL; Ctrough with QUAD 13.7 pg/mL; GMR 56.5 (90% CI 51.9 to 61.5)
Average norelgestromin concentrations
AUC without QUAD 21,400 pg x h/mL; AUC with QUAD 48,300 pg x h/mL; GMR 226 (90% CI 215 to 237)
Cmax without QUAD 2150 pg/mL; Cmax with QUAD 4460 pg/mL; GMR 209 (90% CI 200 to 217)
Ctrough without QUAD 510 pg/mL; Ctrough with QUAD 1370 pg/mL; GMR 267 (90% CI 243 to 292)
When taken with NGM/EE, elvitegravir and cobicistat levels were similar to levels achieved in earlier trials without the OC. Progesterone levels did not change from low levels at baseline, and follicle-stimulating hormone levels fell approximately the same degree with and without QUAD. Luteinizing hormone declined more with QUAD plus NGM/EE than with NGM/EE alone.
No adverse events led to study dropout, and all treatment-emergent adverse events were mild or moderate (grade 1 or 2). More treatment-emergent adverse events, usually nausea or headache, arose during cotreatment with QUAD than with NGM/EE alone (15 versus 9 events).
Because of the ethinyl estradiol decrease seen with QUAD plus this hormonal OC, the Gilead investigators recommended that an OC contain at least 30 micrograms of ethinyl estradiol when taken with QUAD. Stanford University's Terrence Blaschke noted that OCs are among the least forgiving drugs when a dose is missed. Because of the high risk of pregnancy with a missed dose, he suggested that 30 micrograms of ethinyl estradiol may still be insufficient for women prone to forgetting doses.
References
1. German P, Wang M, Warren D, Kearney BP. Pharmacokinetic interaction between norgestimate/ethinyl estradiol and EVG/COBI/FTC/TDF single tablet regimen. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_17.
2. Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011;25:F7-F12.
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