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AIDS:
doi: 10.1097/QAD.0b013e32834e9d9e
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Pharmacokinetic concerns related to the AIDS Clinical Trial Group (ACTG) A5262 trial

Gervasoni, Cristinaa; Cattaneo, Dariob

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aThird Division of Infectious Diseases

bUnit of Clinical Pharmacology, Luigi Sacco University Hospital, Università di Milano, Milan, Italy.

Correspondence to Cristina Gervasoni, MD, Third Division of Infectious Diseases, Luigi Sacco University Hospital, via GB Grassi 74, 20157 Milan, Italy. E-mail: cristina.gervasoni@unimi.it

Received 16 September, 2011

Accepted 25 October, 2011

Taiwo et al. [1] have recently reported results of the AIDS Clinical Trial Group (ACTG) A5262 trial, specifically designed to investigate a two-drug, reverse transcriptase inhibitor-sparing regimen of darunavir/ritonavir (DRV/r) with raltegravir (RAL) for initial antiretroviral therapy. The proposed regimen met the protocol definition of ‘acceptable virologic efficacy’, but only 60% of participants reached viral load less than 50 copies/ml at week 48 in spite of an unanticipated high incidence of virologic failure and integrase resistance especially in patients with baseline viral load more than 100 000 copies/ml.

Taiwo et al. [1] have attempted to find out potential explanations for these unexpected results. Particularly, they have explored the potential contribution of DRV and RAL pharmacokinetics on the study findings. Average DRV and RAL trough concentrations were not significantly different for patients with and without virologic failure. However, sensitivity analyses evidenced a significant role of DRV levels, which were significantly lower in patients with virologic failure compared with those without virologic failure (1042 vs. 1649 ng/ml, P = 0.017). This scenario was further complicated by findings from Cox models, showing that having RAL trough concentrations below the assay detection limit immediately before or at one or more previous visit was also highly significantly associated with increased hazard of virologic failure. So, which conclusions on the value of DRV and RAL therapeutic monitoring can be drawn from this study?

We and others [2,3] have previously shown that RAL trough concentrations are associated with large interindividual variability and, most importantly, largely failed to correlate with RAL area under the time–concentration curve (AUC)0-12, taken as the golden standard pharmacokinetic parameter for the quantification of daily drug exposure. Moreover, recent studies have demonstrated that RAL has a resistance time on the integrase/DNA pre-integration complex that exceeds the half-life of the pre-integration complex in the cells [4,5]. Consequently, as the inhibition induced by RAL is functionally irreversible, no association between RAL pharmacokinetics and clinical outcome can be reasonably expected [6]. According to these findings, it is unlikely that RAL trough concentrations can per se directly affect response to therapy of patients enrolled in the ACTG trial. Therefore, other ways in which RAL could indirectly impact on patient outcome should be advocated.

A clear indication from the ACTG trial is that, according to sensitivity analyses, DRV concentrations were significantly lower in patients with virologic failure compared with those without virologic failure. Therefore, any factor able to affect DRV pharmacokinetics could theoretically impact on patient outcome. An intriguing hypothesis is that co-administration of RAL may lower plasma concentrations of DRV, as recently documented by Fabbiani et al.[7], ultimately resulting in suboptimal DRV exposure and poor response to combined RAL and DRV therapy. Unfortunately, no matched control patients given DRV/r at comparable dosage without RAL were available from the ACTG trial to compare DRV plasma trough concentrations in patients given or not given RAL. The authors have, however, rejected the hypothesis of a drug–drug interaction because the DRV trough concentrations measured in the ACTG trial were ‘within the range previously reported in an intensive pharmacokinetic study of DRV 800/100 mg daily’ [8]. Taiwo et al. [1] failed, however, to consider an important methodological drawback of their study. Particularly, they based their assumptions on the assessment of trough DRV concentration as the solely pharmacokinetic drug parameter, which is not appropriate for the assessment of drug–drug interactions. Indeed, by performing detailed DRV pharmacokinetic evaluations in 25 HIV-infected patients [9], we have recently shown that co-administration of RAL did not impact on DRV trough levels, but was associated with highly significantly lower DRV AUC0-24 compared with values measured in patients not given RAL (Fig. 1).

Fig. 1
Fig. 1
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According to these findings, a potential pharmacokinetic drug–drug interaction between RAL and DRV ultimately affecting the results of the ACTG A5262 trial cannot be ruled out. This potential interaction should be investigated further and taken into account when DRV with RAL-based HAART regimens are implemented in the setting of HIV.

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Acknowledgements

Both authors have read and approved the text.

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Conflicts of interest

D.C. has received educational/travel grants from Merck Sharp & Dome (MSD) and from Janssen-Cilag.

C.G. has received educational grants from Merck Sharp & Dome (MSD), Janssen-Cilag, Bristol Myers Squibb and Abbott.

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References

1. Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC, et al.Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 2011; 25:2113–2122.

2. Cattaneo D, Ripamonti D, Gervasoni C, Landonio S, Meraviglia P, Baldelli S, et al.Limited sampling strategies for the estimation of raltegravir daily exposure in HIV-infected patients. J Clin Pharmacol 2011 [Epub ahead of print].

3. Burger D, Colbers EPH, van Luin M, Koopmans PP. AUC0-3h of raltegravir is correlated to AUC0-12h: a novel approach for therapeutic drug monitoring of raltegravir [abstract 41]. In: 11th International Workshop on Clinical Pharmacology of HIV Therapy; 7–9 April 2010; Sorrento, Italy.

4. Grobler JA, McKenna PM, Ly S. Functionally irreversible inhibition of integration by slowly dissociating strand transfer inhibitor [abstract O-10]. In: 10th International Workshop on Clinical Pharmacology of HIV Therapy; 15–17 April 2009; Amsterdam, the Netherlands.

5. McSharry J, Weng Q, Zager K, Soldani K, Kulawy R, Drusano G. Pharmacodynamics of raltegravir, an HIV integrase inhibitor in an in vitro hollow fiber infection model system [abstract A-960]. In: ICAAC/IDSA; October 2008; Washington, District of Columbia, USA.

6. Brainard DM, Wenning LA, Stone JA, Wagner JA, Iwamoto M. Clinical pharmacology profile of raltegravir, an HIV-1 integrase strand transfer inhibitor. J Clin Pharmacol 2011; 51:1376–1402.

7. Fabbiani M, Di Giambenedetto S, Ragazzoni E, D’Ettorre G, Parruti G, Prosperi M, et al. Darunavir/ritonavir and raltegravir coadministered in routine clinical practice: potential role for an unexpected drug interaction. Pharmacol Res 2011; 63:249–253.

8. Boffito M, Moyle M, Hill A, Sekar V, Lefebvre E, De Pauw M. The pharmacokinetic profile of darunavir with low-dose ritonavir (DRV/r) in various multiple-dose regimens over 120h [abstract P-31]. In: 9th International Workshop on Clinical Pharmacology of HIV Therapy; 7–9 April 2008; New Orleans, Louisiana, USA.

9. Cattaneo D, Gervasoni C, Cozzi V, Baldelli S, Fucile S, Meraviglia P, et al.Influence of raltegravir on the pharmacokinetics of darunavir in HIV-1-infected patients. Pharmacol Res 2011 [Epub ahead of print].

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