Case reports of significant interactions between etravirine and raltegravir
Four cases in HIV-positve subjects were reported, in a letter in the 27 April 2009 edition of AIDS, where lower than anticipated raltegravir concentrations were observed when given with etravirine. 
The first case had raltegravir trough concentrations of 189 and 313 ng/ml on two occasions whilst on darunavir/ritonavir, enfuvirtide and raltegravir. After switching enfuvirtide for etravirine, raltegravir trough concentrations decreased to 10 ng/ml and then to 5 ng/ml one month later.
The second case started a combination of tenofovir/FTC, etravirine and raltegravir. Tenofovir trough concentrations were in the expected range, but raltegravir trough concentrations were considered low (30 ng/ml). Increasing raltegravir from 800 mg/day to 1200 mg/day resulted in an increase in trough concentration (67 ng/ml).
The third case had low raltegravir trough concentrations on two occasions (12 and 9 ng/ml) whilst receiving darunavir/ritonavir, etravirine and raltegravir.
The final case switched to tenofovir, etravirine and raltegravir. Etravirine trough concentrations were within the normal range, but raltegravir trough concentrations were low (29 ng/ml).
In all these cases, raltegravir concentrations were below the mean trough concentration previously observed in initial clinical trials (63 ng/ml, range 29-118 ng/ml).  In two of the cases, concentrations were below the in vitro IC95 for raltegravir of 14.6 ng/ml.
An interaction study in healthy volunteers showed that coadministration of raltegravir and etravirine decreased raltegravir trough concentrations by 34%, with minimal effect on AUC and Cmax (~10% decrease).  In this study, the authors concluded that no dose adjustment for either drug was necessary. However, given the wide inter-individual variability in the pharmacokinetics of raltegravir and these reports from HIV+ subjects, a more cautious approach may be required.
The authors cite an ICAAC 2008 presentation to state that a PK-PD relationship has been identified for raltegravir and hence the possible interest in TDM.  It should be pointed out that Wenning et al indicate that C12h showed little or no association with efficacy but that Call and to a lesser extent Cmin were associated with efficacy responses.
A main factor in raltegravir PK is food intake. Although the current recommendations are to take raltegravir without regard to food, there are nevertheless substantial differences in PK depending on the timing of food relative to drug intake.
- Solas C, Mokthari S, et al. Etravirine-raltegravir, a marked interaction in HIV-1 infected patients: about four cases. Menard A, AIDS, 2009, 23(7): 869-871.
- Markowitz M et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006; 43:509-515.
- Anderson MS et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother 2008; 52:4228-4232.
- Wenning L et al. Pharmacokinetic/pharmacodynamic (PK/PD) analyses for raltegravir (RAL) in phase III studies in treatment experienced HIV-infected patients following 48 weeks of treatment. In: 48th ICAAC; 28 October 2008; Washington, DC. Poster presentation #H-4054.