Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340, In Vitro

Abstract

The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased the absorptive flux of potential candidates for clinical coadministration, including the HIV protease inhibitors atazanavir and darunavir and the lymphoid cell-and tissue-targeted prodrug of the nucleotide analog tenofovir, GS-7340, through monolayers of Caco-2 cells in vitro.C obicistat (COBI) is being developed as a pharamacoenhancer (booster) for coformulation with drugs that are metabolized by cytochrome P450 3A (CYP3A) enzymes. Similar to ritonavir (RTV; currently used as a pharmacoenhancer of protease inhibitors [PIs] used to treat human immunodeficiency virus [HIV]), COBI is a potent mechanism-based CYP3A inhibitor, and its coadministration with CYP3A substrates can lead to desired boosting effects and unintended drug-drug interactions. COBI has been found to have a number of potentially differentiating attributes relative to RTV: (i) it has more selective CYP3A inhibition over other CYP enzymes, (ii) it has improved solubility and coformulatability, (iii) it has a reduced induction potential mediated by the pregnane X receptor (PXR; also known as the nuclear receptor subfamily 1, group 1, member 2 [NR1I2]), and (iv) it has decreased effects on adipocytes in vitro (21). COBI's lack of anti-HIV activity also eliminates the potential for selection of PI resistance mutations when boosting non-HIV PI drugs (21). Clinically, COBI increases systemic levels of the CYP3A substrates midazolam and elvitegravir (EVG) to a similar extent as RTV (7, 13), and coadministration with COBI allows EVG to be administered once daily (16). A fixed-dose, once-daily, single-tablet regimen that includes EVG/COBI and the nucleos(t)ide reverse transcriptase inhibitors tenofovir disoproxil fumarate and emtricitabine, colloquially known as "QUAD," has completed registrational trials, including meeting its primary endpoints in phase 3 studies (2,3,19,20).Inhibition of efflux transporters expressed in the intestine can serve as a secondary mechanism for a pharmacoenhancer to increase systemic exposure to coadministered drugs by increasing their absorption. P-glycoprotein (Pgp; also known as multidrug resistance protein 1 [MDR1] or ATP-binding cassette subfamily B member 1 [ABCB1]) and the breast cancer resistance protein (BCRP; also known as ATP-binding cassette subfamily G member 2 [ABCG2]), both expressed at the apical side of the small intestine, have been highlighted by regulatory agencies and in the literature as key transporters affecting xenobiotic pharmacokinetics (5, 6). In addition to the role of CYP3A enzymes in RTV boosting, HIV PIs are known to be substrates for transporters, including Pgp (11). Determination of the relative roles of transport and CYP3A inhibition in limiting HIV PI exposure is difficult due to their being sub...

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

“…To determine the enzymes involved in the activation of TAF in primary human hepatocytes, cells were incubated with TAF together with known cathepsin A inhibitors (approved hepatitis C virus [HCV] nonstructural 3 [NS3] protease inhibitors telaprevir and boceprevir), carboxylesterase 1 inhibitor (bis-p-nitrophenyl phosphate [BNPP]), CYP3A4, and P glycoprotein (P-gp) inhibitor (cobicistat), or the combination of telaprevir and BNPP (8,(22)(23)(24). Consistent with the result described above, incubation with 0.5 M TAF resulted in approximately 350 pmol/ one million cells of TFV-DP in the absence of any inhibitors (data not shown).…”

“…3). TAF has also been shown to be a substrate for the efflux transporters P-gp and breast cancer resistance protein (BCRP) (22). Since telaprevir is also an inhibitor of the efflux transporter P-gp, inhibition of both the uptake and the efflux transporter may offset the effects.…”

Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

“…This finding suggests that the higher exposures may potentially be due to differences in the absorption of TAF in subjects with severe renal impairment compared to that in matched controls. Although the exact mechanism of the increase is unclear, there is evidence reported by Veau and colleagues in 2001 (12) and Naud and colleagues in 2007 (13) from animal models of a reduction in the activity of P-gp (of which TAF is a substrate) (14). A decrease in the P-gp-mediated transport of TAF could potentially result in increased absorption of the prodrug.…”

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[67,68] Several genetic polymorphisms may affect metabolizing or transporting enzymes function or expression thus affecting drug exposure. While pharmacogenetic studies have extensively studied ARVs plasma pharmacokinetics, limited data are available on their effect on CNS exposure.…”