Raltegravir drug interactions
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Drug Interactions
Effect of Raltegravir on the Pharmacokinetics of Other Agents
Raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).
In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir.
Effect of Other Agents on the Pharmacokinetics of Raltegravir
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, in adults the dose of ISENTRESS should be increased during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration]. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.
Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.
Coadministration of ISENTRESS with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminum and magnesium antacid within 2 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, coadministration of ISENTRESS with aluminum and/or magnesium-containing antacids is not recommended. Coadministration of ISENTRESS with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS is coadministered with calcium carbonate-containing antacids, no dose adjustment is recommended.
All interaction studies were performed in adults.
Selected drug interactions are presented in Table 7 [see Clinical Pharmacology][1]
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References
Adapted from the FDA Package Insert.