Ritonavir and cobicistat as pharmacokinetic enhancers in pregnant women

1. Introduction

Ritonavir and cobicistat are commonly used as pharmacokinetic enhancers to boost plasma concentrations of antiretrovirals used to treat HIV infection, including the protease inhibitors atazanavir, darunavir, and lopinavir, the integrase inhibitor elvitegravir, and the nucleotide reverse transcriptase inhibitor tenofovir alafenamide. Ritonavir and cobicistat inhibit metabolism and/or transport of the coadministered antiretroviral, increase its plasma concentration and prolong half-life, allowing more convenient and better tolerated dosing regimens. The physiologic changes associated with pregnancy can have a major impact on drug disposition and may limit the effectiveness of ritonavir and cobicistat when used in pregnant women living with HIV.

2. Ritonavir

Ritonavir was initially approved as a protease inhibitor in 1996 at doses of 600 mg twice daily, but its use was limited by poor tolerability, low potency, high pill burden, and frequent drug interactions. Use of full-dose ritonavir was often accompanied by adverse events including gastrointestinal intolerance, lipid elevations, and oral paresthesia [1]. Ritonavir drug interactions are due to its potent inhibition of metabolizing enzymes and transporters, including cytochrome p450 3A4 (CYP3A4), the intestinal transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), the hepatic organic anion transporting polypeptides (OATPs), and the multiantimicrobial extrusion protein 1 (MATE1) [2]. Ritonavir also activates the pregnane X receptor (PXR), inducing the activity of CYP1A2, CYP2B6, CYP2C9, and CYP2C19 and glucuronidation enzymes [2].

Ritonavir is now used almost exclusively at doses of 100–200 mg per day as a pharmacoenhancer for CYP3A4-metabolized drugs [1]. Ritonavir-boosted protease inhibitors are recommended as part of alternative antiretroviral regimens used to treat adults living with HIV [3]. The pharmacokinetics of the protease inhibitors atazanavir, darunavir, and lopinavir with ritonavir boosting have been studied in pregnant women [4]. Drug exposures for each of these boosted protease inhibitors are significantly reduced during pregnancy. Ritonavir area under the concentration -time curve (AUC) is reduced by 30–50% during pregnancy compared to postpartum, suggesting that inadequate inhibition of hepatic metabolism plays a large role in the reduction in drug exposure of these boosted protease inhibitors during pregnancy. Increasing the size of atazanavir or lopinavir doses during pregnancy results in plasma exposures nearly equivalent to those in nonpregnant adults, while increasing the darunavir dose does not improve plasma darunavir concentrations [4,5]. Protease inhibitors are highly protein bound, and decreased protein binding during pregnancy will result in a higher concentration of the pharmacologically active free (unbound) drug concentration at a given total (bound plus unbound) concentration, which may limit the therapeutic impact of reductions in total drug exposure during pregnancy [6]. Use of increased doses of ritonavir during pregnancy has never been studied out of concern that larger ritonavir doses would not be well tolerated by pregnant women. Placental passage of ritonavir is low, with a median ratio of cord blood to maternal delivery plasma ritonavir concentrations of 0.18 [7].

Current recommendations for protease inhibitor dosing during pregnancy include use of an increased dose of atazanavir (400 mg with ritonavir 100 mg once daily), consideration of use of an increased twice-daily lopinavir/ritonavir dose (from 400 mg/100 mg to 600 mg/150 mg), and avoidance of the use of lopinavir/ritonavir once daily. Since darunavir exposure was decreased more with once-daily dosing than twice-daily dosing during pregnancy and increasing the dose of darunavir during pregnancy to 800 mg twice daily did not increase darunavir plasma concentrations, standard twice-daily darunavir/ritonavir dosing is recommended during pregnancy (600 mg/100 mg twice daily), while once-daily dosing is not recommended [4].

3. Cobicistat

Cobicistat, initially approved in 2012, was developed as an alternative pharmacoenhancer with more favorable physiochemical properties than ritonavir. Cobicistat has no direct antiviral effects but is as strong an inhibitor of CYP3A4 and drug transporter as ritonavir [2]. Cobicistat is a weak in vitro activator of PXR, so is not likely to be an inducer of drug-metabolizing enzymes [2]. While ritonavir solubility is poor, limiting its ability to be coformulated with other antiretrovirals into more convenient fixed-dose combination products, cobicistat is readily coformulated with other antiretrovirals. Although cobicistat is available in a single drug formulation, it is most commonly used as part of fixed-dose combination products with other antiretrovirals, including the protease inhibitors atazanavir and darunavir, the integrase inhibitor elvitegravir, and the nucleotide reverse transcriptase inhibitor tenofovir alafenamide. Use of cobicistat-boosted combination formulations is recommended as alternative regimens for the treatment of adults living with HIV [3].

Experience with cobicistat in pregnant women is more limited than with ritonavir, but there are several reports of antiretroviral pharmacokinetics with use of cobicistat during pregnancy. Plasma cobicistat exposures are reduced by 44–54% during the second and third trimesters compared to postpartum [8]. When cobicistat is detectable in both cord blood and maternal blood at delivery, the median ratio of the cobicistat concentration in cord blood to that of maternal plasma is 0.09 [8]. Plasma concentrations of the targets of cobicistat boosting, including darunavir, elvitegravir, and atazanavir, are low with the use of cobicistat-boosted regimens in pregnancy [8–11]. When third-trimester pharmacokinetic parameters were compared to postpartum in women receiving elvitegravir/cobicistat, elvitegravir AUC was reduced by 44% and cobicistat AUC by 59% during the third trimester, and cobicistat AUC was negatively associated with elvitegravir apparent oral clearance [8]. Darunavir AUC is reduced by around 50% during the third trimester compared to postpartum [10,11]. Similar preliminary results have been presented on atazanavir exposure with the use of atazanavir/cobicistat during pregnancy [9]. As a result of these data, the product labels for cobicistat-containing formulations were changed in 2018 to state that these products are not recommended for initiation during pregnancy, and an alternative regimen is recommended for those who become pregnant during therapy with these products [12].

Cobicistat is also used to boost the nucleotide reverse transcriptase inhibitor tenofovir alafenamide. Tenofovir alafenamide is not a substrate for CYP3A4 metabolism, and cobicistat increases tenofovir alafenamide plasma concentrations due to its inhibition of the intestinal efflux transporters P-gp and BCRP and not by inhibition of CYP3A4 activity. Cobicistat is an effective booster of tenofovir alafenamide during pregnancy, in contrast to the experience with cobicistat and CYP3A4 substrates in pregnancy. Tenofovir alafenamide AUC is equivalent when dosed as 25 mg unboosted and 10 mg with cobicistat during pregnancy [13]. The difference in the ability of cobicistat to effectively boost tenofovir alafenamide and not CYP3A4 substrates during pregnancy suggests that while intestinal cobicistat concentrations during pregnancy are adequate to inhibit gut transporters, the bioavailability of cobicistat is too low during pregnancy to achieve plasma concentrations than can reach the liver and effectively inhibit hepatic CYP3A4 metabolism.

4. Expert opinion

Although ritonavir is not as effective a booster of CYP3A4-metabolized drugs during pregnancy as in nonpregnant adults, strategies such as increasing substrate doses and avoiding once-daily dosing schedules have been devised to overcome these limitations and allow ritonavir-boosted protease inhibitors to be used effectively during pregnancy. In contrast, cobicistat boosting of the CYP3A4 substrates elvitegravir, darunavir, and atazanavir during pregnancy is so poor that the product labels for the cobicistat-containing fixed-dose combination formulations of these drugs have been changed to state that the use of these products in pregnant women is not recommended [12]. Cobicistat is an effective booster of tenofovir alafenamide during pregnancy, acting via inhibition of gut transporters rather than hepatic CYP3A4 metabolism.

Unfortunately, because pregnant women are excluded from most premarketing clinical trials that lead to drug licensure, cobicistat-containing products were commercially available and widely used in pregnant women living with HIV for 6 years before post-marketing studies in pregnant women revealed their deficiencies when used during pregnancy. If drugs are to be used safely and effectively in pregnant women, then pregnant women should be included in clinical trials prior to licensing, so that when drugs are approved for use it is known whether and how they can be used during pregnancy [14,15]. New approaches to the design and conduct of pharmacokinetic studies, including use of physiologic-based pharmacokinetic modeling and simulations, may prove useful in accelerating and increasing the safety of dose-finding studies in pregnant women [16].