Doravirine and cabotegravir do not affect the pharmacokinetics of oral contraceptives
Neither doravirine nor oral cabotegravir alter the plasma pharmacokinetics (PK) of levonorgestrel (LNG) and ethinyl estradiol (EE) containing oral contraceptives, according to manufacturers’ data presented at the 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. [1 ,2]
Antiretrovirals are likely to be co-administered with oral contraceptives in HIV positive women. Some antiretrovirals also have the potential to be used for prevention in HIV negative women. Drug-drug interactions causing sub-therapeutic concentrations of the estrogen or progestin in oral contraceptives can result in contraceptive failure.
It is good practice for originator manufacturers to include oral contraceptives interaction studies with those for other commonly used medicines during antiretroviral drug development. Two posters showed no effect of the phase 3 clinical doses of the investigational drugs doravirine or oral cabotegravir.
Doravirine is an NNRTI primarily metabolised through oxidation via CYP3A4. It has not demonstrated inhibitory or inductive potential on CYPs in either in vitro or clinical studies or shown an interaction with enzymes that metabolise EE or LNG.
Merck investigators evaluated the effect of 100 mg doravirine, on the plasma PK of an oral contraceptive containing EE and LNG.
This study was open-label, 2-period, fixed sequence of multiple doses of doravirine on the single oral dose PK of a combination of EE/LNG (Nordette-28) in HIV negative women. Period 1: participants received a single dose of 0.03 mg EE/0.15 mg LNG. Period 2: participants received 100 mg doravirine once daily for 17 days, with a single oral dose of 0.03 mg EE/0.15 mg on day 14. There was a washout of at least 7 days between the two periods.
Twenty postmenopausal or oophorectomised women were recruited. Plasma samples were taken for up to 96 hours post-dose in each period.
The investigators reported geometric mean ratio (GMR) EE (Nordette-28 + doravirine/ Nordette-28): AUC 0.98 (90% CI: 0.94 to 1.03), and Cmax 0.83 (90% CI: 0.80 to 0.87). GMR LNG: AUC 1.21 (90% CI: 1.14 to 1.28), and Cmax 0.96 (90% CI: 0.88 to 1.05).
They concluded that multiple dosing of doravirine does not alter the plasma PK of EE or of LNG to a clinically meaningful extent. There are no restrictions on the use of oral contraceptives in phase 3 trials of doravirine.
Cabotegravir is an integrase inhibitor in development as an oral tablet and a long-acting injectable for treatment and pre- exposure prophylaxis.
Previous in vitro data suggest that the potential for interaction with LNG and EE-containing oral contraceptives is minimal and the study aimed to demonstrate this.
It was an open-label, fixed-sequence crossover study in HIV negative women. There were two consecutive treatment periods that spanned a single menstrual cycle. Period 1: participants received Microgynon (LNG 0.15 mg/EE 0.03mg) once daily days 1-10 with serial PK sampling of LNG and EE on day 10. Period 2: Participants received oral cabotegravir 30mg once daily with Microgynon on days 11-21 and underwent serial PK sampling of LNG, EE, and CAB on Day 21.
Twenty women were enrolled. The ViiV investigators reported that the PK profile of LNG/EE was unaffected by cabotegravir.
The GMR for LNG (LNG + cabotegravir relative to LNG alone): AUC 1.11 (90% CI: 1.06 to 1.16) and Cmax 1.05 (90% CI: 0.96 to1.15). GMR EE: AUC 1.05 (90% CI: 0.98 to 1.13), and Cmax and 0.92 (90% CI: 0.83 to 1.03).
Similarly in this study multiple doses of oral cabotegravir had no effect on the PK of LNG and EE suggesting it can be administered in combination with LNG/EE oral contraceptives without clinically significant drug-drug interactions.
A related poster authored by researchers from the US FDA showed findings from a database of drug-drug interactions of antivirals (including HIV and HCV treatment) trials conducted to evaluate the effect on oral contraceptives. The study was designed to understand the main design features of such trials. 
The authors collected design features and results of oral contraceptive/antiviral drug-drug interaction trials from labels and clinical PK reviews available at drugs@fda.
The database includes information on trial design (number of menstrual cycles, population, type of oral contraceptive) and results (PK parameters, pharmacodynamic markers, and clinical recommendations in labels).
The investigation revealed that 30% of drug-drug interaction trials with oral contraceptive submitted to 341 new drug applications (NDAs) of new molecular entities (NMEs) approved between 2000 and 2014 were with antivirals. Twenty-seven drug-drug interaction trials with oral contraceptives were conducted among approved antivirals.
The majority (82%) were open-label with a fixed sequence design. Five trials used a double-blind, cross-over design. Almost half of these (37% overall) were conducted within one 28-day ovulatory cycle, 33% over the course of three ovulatory cycles and 30% over two ovulatory cycles.
In most (85%) trials oral contraceptives were give in multiple doses. Almost all (96%) enrolled healthy women – including one trial that recruited postmenopausal women and another surgically sterilised women. Only one trial enrolled HIV positive women.
Almost half (44%) the participants were receiving stable doses of oral contraceptives before enrolling in 12 trials. Median number of women in a trial was 20 (range 12 to 52) and mean 24.
Norethindrone/EE combination was most commonly used in the trials (55%), followed by norgestimate/EE (31%). The primary objective of all trials was to evaluate the changes in the exposure of OC components with the co-administration of antivirals. Pharmacodynamic evaluation was performed in 37% of trials. Two antivirals (atazanavir and boceprevir) had drug-drug interaction studies with two different oral contraceptives. Labeling recommendations were based on exposure changes in 92.5% cases.
The investigators noted that there is no preferred study design and the answer to the exposure question can be achieved using any design, taking into consideration aspects such as safety considerations and logistical issues.
References are to the programme and abstracts 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, 26-28 May 2015, Washington DC, unless otherwise stated.
- Anderson MS et al. Effect of doravirine (MK-1439) on the pharmacokinetics of an oral contraceptive (ethinyl estradiol [EE] and levonorgestrel [LNG]). Poster abstract 60.
- Trezza C et al. Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl estradiol containing oral contraceptive in healthy adult females. Poster abstract 82.
- Younis I et al. The experience with drug-drug interaction studies between antiviral medications and oral contraceptives. Poster abstract 68.