Answer
All non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized in the liver by CYP3A isoenzymes. Efavirenz (EFV) and nevirapine (NVP) are also substrates of CYP2B6 enzymes, and etravirine (ETR) is a substrate of CYP2C9 and CYP2C19 enzymes. Coadministration with drugs that induce or inhibit these enzymes can alter NNRTI drug concentrations, resulting in virologic failure or adverse effects. [3]
All NNRTIs (except rilpivirine [RPV]) induce or inhibit CYP isoenzymes. EFV acts as a mixed inducer and inhibitor, but, similarly to NVP, it primarily induces CYP3A and 2B6 enzymes. ETR also induces CYP3A but inhibits CYP2C9 and 2C19 enzymes.
Examples of medications that interact with NNRTIs include azole antifungals (ketoconazole, itraconazole), rifamycins (eg, rifabutin, rifampin), benzodiazepines (eg, midazolam, triazolam), HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), and methadone.
For more information, see the NIH Guidelines for Drug Interactions between NNRTIs and Other Drugs.
Table 1. NNRTIs Drugs and Their Metabolic Pathways [3] (Open Table in a new window)
Generic (Brand) |
Metabolized by (ie, Substrate of) |
Induces |
Inhibits |
Doravirine (Pifeltro) DOR |
CYP3A4, 3A5 |
- | - |
Delavirdine (Rescriptor) DLV |
CYP3A4 (primarily) CYP2D6 (possibly) |
- |
CYP3A4 (potent) CYP2D6 CYP2C9 CY2C19 |
Efavirenz (Sustiva) EFV |
CYP2B6 (primarily) CYP2A6 CYP3A4 |
CYP3A4 (stronger inducer than inhibitor) CYP2B6 |
CYP3A4 CYP2C9 CYP2C19 |
Etravirine (Intelence) ETR |
CYP3A4 CYP2C9 CYP2C19 |
CYP3A4 P-gp |
CYP2C9 CYP2C19 |
Nevirapine (Viramune, Viramune XR) NVP |
CYP3A4 CYP2B6 |
CYP3A4 CYP2B6 |
- |
Rilpivirine RPV |
CYP3A4 |
- |
- |