In Vitro Evaluation of the Drug Interaction Potential of Doravirine [Antiviral Agents]

Doravirine is a novel non-nucleoside 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 (CYP) 3A 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 (OATP) 1B1 or 1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) or of UGT1A1, nor 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 ≥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, organic anion transporter (OAT)1 and OAT3, organic cation transporter 2, and multidrug and toxin extrusion (MATE)1 and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, albeit with different catalytic efficiency. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but support that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

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