Tenofovir Has Minimal Interaction with Indinavir, Lopinavir/Ritonavir, Lamivudine or Efavirenz

  • Lack of Clinically Relevant Drug-Drug Interactions Between Tenofovir DF and Efavirenz, Indinavir, Lamivudine and Lopinavir/Ritonavir in Healthy Subjects (Oral Session 3, Abstract 171)
    Authored by B. Kearney, J. Flaherty, J. Wolf, et al.

Tenofovir disoproxil fumarate (tenofovir DF) is a nucleotide analog reverse transcriptase inhibitor (NtRTI) recently approved for use in the United States and Europe. The interactions of tenofovir with other antiretrovirals have not been completely resolved at this point. However, in a study presented at the 8th ECCATHI potential drug-drug interactions between tenofovir and other commonly used HIV agents were explored. This study was a phase I, randomized, open-label, multiple-dose, three-way crossover pharmacokinetic drug interaction study of tenofovir with lamivudine (3TC), indinavir (IDV), lopinavir/ritonavir (LPV/r) and efavirenz (EFV). The pharmacokinetic (PK) profiles for each of these drugs alone as well as in combination with tenofovir was determined in healthy subjects. All drugs were administered in a fasting state except for lopinavir/ritonavir where food was given as per its labeling requirement.

The enrolled subjects were divided into four cohorts: 3TC 150mg BID; indinavir 800mg Q8h; lopinavir/ritonavir 400/100mg BID; and efavirenz 600mg QD. Each participant received the following treatment regimens: treatment A (tenofovir 300mg daily alone), treatment B (tenofovir plus the drug of their individual cohort) and treatment C (their individual cohort drug alone). PK parameters were calculated by noncompartmental methods, ratios of geometric means (using a least-squares method) and 90% confidence intervals for Cmax. Drug exposures (the area under the curve [AUC]) for each drug were calculated.

No serious adverse events were noted when tenofovir was added to each regimen. The authors report, "all adverse events were mild to moderate severity and did not differ substantially for drugs given alone versus together." The PK profile for tenofovir, when administered with the other drugs revealed:

  1. No alteration in PK with 3TC or efavirenz.

  2. A slightly higher (14%) Cmax of tenofovir with indinavir, but with unaltered AUC.

  3. Higher (30%) Cmax and AUC of tenofovir with lopinavir/ritonavir.

The effect of tenofovir on the PK profiles of the other drugs were:

  1. A delay of 0.9hr in Tmax and a decrease (24%) in Cmax of 3TC without alteration of the AUC of 3TC.

  2. Slightly lower (11%) IDV Cmax, but no change in AUC.

  3. Lopinavir Cmax and AUC lower (15%), lopinavir inhibitory quotient unchanged and no significant change in Cmin.

  4. No alterations in Cmax or AUC of efavirenz.

The authors conclude that the "coadministration of tenofovir with 3TC, indinavir, lopinavir/ritonavir or efavirenz does not result in clinically relevant drug-drug interactions [and] adverse events reported are known to be common for the antiretrovirals evaluated." The changes observed in lopinavir/ritonavir pharmacokinetics with tenofovir are "consistent with data following administration of tenofovir with high fat meal" and, furthermore, the "small changes observed in lopinavir/ritonavir pharmacokinetic parameters when administered with tenofovir are not likely to be of clinical relevance." And finally, the "administration of multiple doses of tenofovir with 3TC, indinavir, lopinavir/ritonavir and efavirenz appears to be safe in these healthy volunteers."

Since tenofovir has been recently approved, these data add confidence to our ability to use it in combination with other antiretrovirals. Another poster presented potentially important information regarding the interaction of didanosine with tenofovir, and this will be reviewed in a subsequent article.