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Is There a Drug-Drug Interaction Between Darunavir/Ritonavir and Raltegravir?
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JAIDS Journal of Acquired Immune Deficiency Syndromes:

1 May 2012

Fabbiani, Massimiliano MD, PhD*; Navarra, Pierluigi MD; Cauda, Roberto MD*; De Luca, Andrea MD*,; Di Giambenedetto, Simona MD, PhD
*Institute of Clinical Infectious Diseases and
Institute of Pharmacology, Catholic University of Sacred Heart, Rome, Italy
Infectious Diseases Unit, Siena University Hospital, Siena, Italy

To the Editors:

We have read with interest the study by Jackson et al,1 recently published in your journal, that investigated plasma and intracellular pharmacokinetics of darunavir/ritonavir (800/100 mg once daily) and raltegravir (800 mg once and 400 mg twice daily) alone or coadministered in a group of 24 HIV-infected individuals. The authors' main conclusions were that no remarkable interactions between darunavir/ritonavir and raltegravir were observed. However, although no modification of raltegravir pharmacokinetic (PK) was observed after darunavir/ritonavir intensification, some darunavir PK parameters showed a significant change after raltegravir discontinuation. In particular, in patients taking darunavir/ritonavir 800/100 mg once daily plus raltegravir 400 mg twice daily plus 2 nucleoside reverse transcriptase inhibitors (NRTIs; n = 13, group 1), significantly higher darunavir area under the curve (AUC) and Ctrough were observed both in plasma (24% and 37% increase, respectively) and in intracellular environment (24% and 45% increase, respectively) after raltegravir removal. Moreover, raltegravir discontinuation lead to a significantly higher plasma AUC (14% increase) also in patients taking darunavir/ritonavir 800/100 mg once daily plus raltegravir 800 mg once daily plus 2 NRTIs (n = 11, group 2); no changes in intracellular AUC and plasma or intracellular darunavir Ctrough were observed in this group, but the smaller number of subjects included could have limited the statistical power to detect such differences. The authors suggested that these changes could be the consequence of the high interindividual PK variability observed in plasma and intracellular darunavir concentrations rather than a true drug-drug interaction.

On the basis of current knowledge, we believe that further evidence is required before drawing this conclusion. The issue of potential PK drug interactions between raltegravir and darunavir is debated and its clarification would be quite important for the management of HIV-infected patients. Given the different metabolic pathways of the 2 drugs,2,3 a drug-drug interaction would have not been predictable. However, some recently published articles4,5 have provided data in support of an unexpected drug-drug interaction between these 2 drugs. In a previous observational study performed during routine clinical practice,4 our research group observed a significantly lower plasma darunavir Ctrough in patients taking darunavir/ritonavir 600/100 mg twice daily plus raltegravir 400 mg twice daily plus 2 NRTIs when compared with those not receiving raltegravir. In line with this, Cattaneo et al5 observed that coadministration of raltegravir was associated with a 40% reduction in darunavir Cmax and estimated AUC and also a 60% increase in the estimated darunavir clearance compared with patients not receiving raltegravir. Moreover, 2 further studies found lower plasma darunavir concentrations when it was coadministered with raltegravir, even if these findings could also be partly related to interactions with other concomitant antiretroviral drugs (tenofovir or enfuvirtide).6,7 Taken together, the observations by Jackson et al and by the other aforementioned studies seem to suggest a potential drug-drug interaction between the 2 drugs.

The mechanism at the basis of this interaction remains unclear and needs adequate investigations. Darunavir is primarily metabolized by cytochrome CYP3A4, whereas raltegravir undergoes metabolism through hepatic glucuronidation; as a consequence, an influence of raltegravir on darunavir metabolism would be negligible. However, because darunavir is a substrate of p-glycoprotein and other transporters, drugs that can modulate the activities of these pumps could influence darunavir distribution and affect darunavir plasma and intracellular concentrations. Because recent studies demonstrated that raltegravir is a substrate of p-glycoprotein and a potential inducer of ABCC1,8,9 an interaction at this level could be hypothesized and needs to be adequately investigated. Moreover, this mechanism might also explain the unexpected but clearly documented effect of raltegravir on the PK of atazanavir,10 which is also a substrate of p-glycoprotein, like darunavir and other protease inhibitors.

Because population PK data show that plasma darunavir Ctrough usually far exceed 0.550 μg/mL (the IC50 for protease inhibitor-resistant virus)11 and the reduction in darunavir levels with concomitant raltegravir appears to be modest, the clinical significance of this interaction is probably negligible in the majority of patients taking combined antiretroviral regimens. Several data seem to support this conclusion. A high efficacy of raltegravir combined to darunavir plus an optimized background therapy was demonstrated in clinical trials performed in treatment-experienced patients.12 Moreover, a previous study showed a higher proportion of treatment-experienced patients with viral load <50 copies per milliliter when raltegravir and darunavir where coadministered, despite lower darunavir plasma levels.4 However, in selected clinical circumstances, such potential interaction should be taken into consideration. In a previous study,6 4 of 14 (28.6%) patients receiving a dual therapy with darunavir/ritonavir 800/100 mg once daily plus raltegravir 400 mg twice daily obtained darunavir plasma trough levels below the threshold of 0.550 μg/mL; this could be suboptimal in certain settings, like in naive subjects starting antiretroviral therapy with high viral load that could theoretically require a higher drug concentration. Interestingly, a recent single-arm AIDS Clinical Trials Group study performed in naive subjects starting antiretroviral therapy with darunavir/ritonavir 800/100 mg once daily plus raltegravir 400 mg twice daily showed unexpectedly high rates of virological failure at 48 weeks (26%) with a high rate of development of integrase resistance, particularly in patients with baseline viral load >100,000 copies per milliliter.13 Suboptimal adherence could be an explanation for the results of this trial, but the concomitant role of a detrimental drug interaction of raltegravir on darunavir exposure might be an alternative hypothesis. However, the potential clinical significance of a drug-drug interaction between darunavir/ritonavir and raltegravir was not confirmed by a randomized study comparing raltegravir (arm 1) or tenofovir/emtricitabine (arm 2) both in combination with darunavir/ritonavir 800/100 mg once daily in naive subjects: no significant differences in the rates of virological failure were observed between the 2 arms at 24 weeks but 48 weeks results are pending and no PK data are yet available.14 Moreover, a further large multicenter randomized trial exploring the efficacy of darunavir/ritonavir 800/100 mg once daily plus raltegravir 400 mg twice daily in naive patients is ongoing and its results will provide additional data on clinical efficacy and PK of this drug combination.15

In conclusion, in our opinion, the possibility of an unexpected drug-drug interaction between darunavir/ritonavir and raltegravir cannot be fully excluded on the basis of currently available results. Indeed, several data suggest that a certain effect of raltegravir on darunavir/ritonavir PK might exist, despite the fact that its mechanism remains to be determined. The clinical significance of this potential interaction in selected settings would be clarified when long-term results of ongoing randomized clinical trials exploring this combination will become available.