Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions [Antiviral Agents]

Identifying and understanding potential drug–drug interactions (DDIs) is vital for treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and cytochrome P450 3A (CYP3A) substrates, and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with CYP3A substrates, midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Co-administration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that co-administered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (Yee et al, Clin Drug Investig 2017; 37: 659-667; Khalilieh et al, J Clin Pharmacol 2018; 58: 1044-1052), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but became less pronounced with time (Yee et al, Antimicrob Agents Chemother 2017; 61: e01757-16). Overall, the co-administration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while co-administration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a less potent CYP3A inducer than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.

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