Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions

Area of Science:

• Pharmacology
• Virology
• Drug Metabolism

Background:

• Drug-drug interactions (DDIs) are critical in managing human immunodeficiency virus type 1 (HIV-1) infection.
• Doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), is a key component in HIV-1 treatment regimens.
• Understanding doravirine's interactions with cytochrome P450 3A (CYP3A) is essential for safe and effective therapy.

Purpose of the Study:

• To evaluate the pharmacokinetic interactions between doravirine and drugs metabolized by or that modulate CYP3A activity.
• To assess the clinical significance of these interactions for HIV-1 treatment.
• To provide guidance on coadministration of doravirine with various CYP3A-related agents.

Main Methods:

• Review of in vitro data and clinical drug-drug interaction (DDI) trials.
• Pharmacokinetic analysis of doravirine in the presence of CYP3A substrates (ethinyl estradiol, levonorgestrel).
• Evaluation of doravirine exposure with CYP3A inhibitors (ritonavir, ketoconazole) and inducers (rifampin, rifabutin, efavirenz).

Main Results:

• Doravirine showed no significant impact on the pharmacokinetics of CYP3A substrates ethinyl estradiol and levonorgestrel.
• Coadministration with CYP3A inhibitors (ritonavir, ketoconazole) increased doravirine exposure by approximately 3-fold, deemed not clinically meaningful.
• CYP3A inducers significantly decreased doravirine exposure (rifampin by 88%, rifabutin by 50%, efavirenz by 62% initially).

Conclusions:

• Coadministration of doravirine with CYP3A inhibitors and substrates is supported by current data.
• Coadministration with strong CYP3A inducers, such as rifampin, is not recommended due to significant reduction in doravirine exposure.
• Concomitant use with rifabutin is acceptable with adjusted dosing (twice daily), but effects of other moderate inducers remain unknown.