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Cobicistat as a Pharmacoenhancer in Pregnancy and Postpartum: Progress to Date and Next Steps

Combination antiretroviral therapy with fixed-dose drug combinations (FDCs) that allow for once-daily, single-tablet regimens for the management of HIV infection, are now available. Many of these FDCs include cobicistat, a pharmacoenhancer that inhibits cytochrome P450 (CYP) metabolism of protease and integrase inhibitors, enhancing and prolonging their plasma concentrations. Pregnant women were excluded from the drug development programs for these FDCs. Only recently, years after these products were first approved for use in nonpregnant adults, data from postmarketing studies has come forward, describing the pharmacokinetics of these products in pregnancy. These studies have demonstrated that cobicistat is not an effective pharmacoenhancer in pregnancy, and the US Food and Drug Administration (FDA) has recently revised labeling for these products to recommend that they should not be used in pregnancy.1 Cobicistat (Tybost) was developed as an alternative antiretroviral pharmacoenhancer to ritonavir. Ritonavir is a potent inhibitor of the CYP enzymes CYP3A4, CYP2D6, CYP2C19, CYP2C8, and CYP2C9, as well as a known inducer of CYP1A2, CYP2B6, and uridine 5′-diphospho-glucuronosyltransferase.2 Ritonavir also inhibits P-glycoprotein, breast cancer resistance protein, organic anion transporters and multidrug and toxin extrusion cellular transport mechanisms in the liver, gastrointestinal tract, and kidneys.2 Ritonavir has poor water solubility and tolerability, making coformulation difficult. Cobicistat is a potent inhibitor of CYP3A4 and aweak inhibitor of CYP2D6, organic anion transporting polypeptides (OATP1B1, OATP1B3), and P-glycoprotein.2 Cobicistat is well tolerated and easily coformulated with other antiretrovirals, and a 150-mg once-daily dose of cobicistat has a pharmacokinetic (PK) boosting effect comparable with ritonavir 100 mg once daily. The FDA approval of cobicistat was primarily based on 2 PK studies, along with clinical efficacy data from phase III trials of atazanavir/cobicistat3 and darunavir coadministeredwith ritonavir. Cobicistat was granted FDA approval in August 2012 as part of a coformulation that also includes elvitegravir, tenofovir, and emtricitabine for use as initial therapy for adults with HIV-1 infection.4,5 However, on June 27, 2012, Gilead submitted the New Drug Application to the FDA for cobicistat as a free-standing agent with either atazanavir or darunavir. The New Drug Application for the safety and efficacy of cobicistat was supported by 48-week data from a crucial phase III study (Study 114) in which cobicistat met its primary objective of noninferiority to ritonavir when both agents were administered with a background regimen of atazanavir sulfate plus Truvada (emtricitabine and tenofovir disoproxil fumarate).3 In Study 114, 692 participants were randomized in a one-to-one ratio to receive either atazanavir 300 mg plus cobicistat 150 mg once daily or atazanavir 300 mg plus ritonavir 100 mg once daily. All subjects received simultaneous treatment