In Vitro Evaluation of the Drug Interaction Potential of Doravirine

Abstract

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

Keywords: HIV; doravirine; drug interactions.

FIG 1

Cytochrome P450 (CYP)-mediated oxidation of doravirine to metabolite M9.

FIG 2

Velocity versus substrate concentration plots for rCYP3A4-catalyzed (A) and rCYP3A5-catalyzed (B) formation of M9 from doravirine. K_m, Michaelis-Menten constant; rCYP3A4/5, recombinant CYP3A4/5; V_max, maximum velocity.

FIG 3

Uptake of doravirine 1 μM into cells. (A) Human hepatocytes in the absence and presence of a cocktail of transporter inhibitors. (B) HEK293 and HEK293-OATP1B1 cells. As a positive control, the inhibitory effect of bromosulfophthalein (BSP; 100 μM) on the uptake of [³H]estradiol 17β­glucuronide ([³H]E₂17βG; 1 μM [left]) was also assessed. The middle graph shows the time course of doravirine uptake, and the right graph shows inhibition of doravirine uptake by organic anion transporting polypeptide 1B1 (OATP1B1) inhibitor BSP (100 μM). (C) HEK293 and HEK293-OATP1B3 cells. As a positive control, the inhibitory effect of BSP (100 μM) on the uptake of [³H]cholecystokinin 8 ([³H]CCK8; 5 nM [left]) was also assessed. The middle graph shows the time course of doravirine uptake, and the right graph shows inhibition of doravirine uptake by OATP1B3 inhibitor BSP (100 μM). All data are means ± SEMs.

FIG 4

Inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) by doravirine. (A) As a positive control, the inhibitory effect of cyclosporine A (CsA; 10 μM) on the uptake of [³H]pitavastatin (0.1 μM) in OATP1B1 stably transfected MDCKII cells was assessed. (B) Inhibitory effect of doravirine on the uptake of [³H]pitavastatin (0.1 μM) in OATP1B1 stably transfected MDCKII cells. (C) Doravirine inhibition of OATP1B1-mediated [³H]pitavastatin (0.1 μM) uptake (percentage of control). All data are means ± SEMs.