aDivision of Clinical Pharmacology, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama
bDivision of Infectious Diseases, Northwestern University, Chicago, Illinois
cDivision of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Correspondence to Babafemi Taiwo, MBBS, Division of Infectious Diseases, Northwestern University, Chicago, IL 60611, USA. Tel: +1 312 695 5085; fax: +1 312 695 5088; e-mail: email@example.com
Received 7 October, 2011
Accepted 25 October, 2011
Gervasoni and Cattaneo  point out that a potential pharmacokinetic drug–drug interaction between raltegravir and darunavir ultimately affecting the results of the AIDS Clinical Trials Group (ACTG) A5262 trial cannot be ruled out. We agree with this statement, as A5262 was never designed to be a drug–drug interaction study. Indeed, we refrained from categorically rejecting the possibility of significant interactions and simply presented our finding that trough concentrations observed in A5262 were within the range reported in an intensive pharmacokinetic study of darunavir 800/100 mg daily .
In A5262, the darunavir troughs were different in the nonvirologic failure (1649 ng/ml) and virologic failure groups (1042 ng/ml), and undetectable raltegravir trough concentrations were associated with increased virologic failure. Importantly, A5262 was not designed to elicit optimal drug exposure variables, nor was it our intention to use the results as a basis for therapeutic drug monitoring (TDM). In applying TDM, the therapeutic range of the drug must first be defined, and this has not been adequately done for raltegravir or darunavir. Along this line, the suggestion by Gervasoni and Cattaneo  that darunavir area under the curve (24 h) is the relevant pharmacokinetic parameter raises important questions. What is the optimum exposure of darunavir in HIV-infected patients? Are troughs more important or is the area under the curve? Is there consensus on this exposure variable, and were those data generated from well designed dose-ranging studies or retrospective pharmacokinetic cohort analyses? Clearly, these issues are yet to be resolved in the literature. Without knowing what the ideal darunavir exposure target is, neither our team nor Gervasoni and Cattaneo  can state whether virologic failure occurred due to low darunavir troughs, regardless of whether raltegravir caused low darunavir exposure or not. There are in-vitro data to suggest the darunavir protein-binding-corrected 95% inhibitory concentration might be as low as 25 ng/ml , which is well below the darunavir trough concentrations in both virologic failure and nonvirologic failure participants in A5262. Previous pharmacokinetic studies of once-daily darunavir found no relevant relationships between darunavir pharmacokinetics and virologic efficacy or safety [4,5].
Gervasoni and Cattaneo  also state that no association between raltegravir pharmacokinetics and clinical outcome can be reasonably expected. They apparently based this assertion on raltegravir's pharmacokinetic variability and long residence time on the pre-integration complex, which exceeds the half-life of the complex itself. This presumably makes raltegravir inhibition of the enzyme complex irreversible, which was extrapolated to explain why raltegravir troughs are not related to response. According to Gervasoni and Cattaneo , it is unlikely that raltegravir trough concentrations can per se directly affect response to therapy of patients enrolled in the ACTG trial. Therefore, they posited that other ways in which raltegravir could indirectly impact on patient outcome, such as an interaction with darunavir, should be advocated. Although there may be a drug–drug interaction, it should be emphatically reiterated that A5262 was not designed to assess this. More importantly, the phase III study of the safety and efficacy of once daily versus twice daily raltegravir in combination therapy for treatment-naïve HIV-infected patients (QDMRK) clearly showed that raltegravir 800 mg once daily was inferior to 400 mg twice daily at 48 weeks ; the geometric mean trough concentrationh was 83 nmol/l for once-daily vs. 380 nmol/l for twice-daily dosing. The QDMRK study was a large dose fractionation study, and as such we now know that the raltegravir trough concentrations are indeed an important determinant of therapeutic response. The half-life of drug binding to the integration complex may be an important variable for certain dosing intervals but, if the dosing interval exceeds some threshold, then the integration complex can form and integrate during the period when raltegravir concentrations are low or absent. This is further demonstrated by data with dolutegravir (same mechanism of action as raltegravir), which exhibited a concentration–response relationship when a wide range of doses (25-fold) was used in early development . A recent article demonstrates the dissociative half-life of dolutegravir is 71 h, considerably longer than the 8.8 h for raltegravir . Thus, a concentration–response relationship was still determined for dolutegravir, even though the enzyme complex off-rate was eight times slower. Gervasoni and Cattaneo  are incorrect in assuming that the raltegravir trough concentrations do not affect response to therapy in A5262, and we cannot confirm nor rule out a drug–drug interaction between darunavir and raltegravir in this particular study.
Conflicts of interest
E.P.A. has served as a consultant to Tibotec and Merck. B.T. has served as an advisor and received research support and honoraria from Tibotec. J.J.E is a consultant to Abbott, GlaxoSmithKline, Merck, ViiV and Tibotec, and has received research support (to UNC) from GlaxoSmithKline and Merck.
A5262 was supported by Award Number U01AI068636 and U01AI68634 from the National Institute of Allergy and Infectious Diseases and supported by the National Institute of Mental Health (NIMH) and National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The project is supported in part by grants funded by the National Center for Research Resources.
A5262 study team members and site investigators.
1. Gervasoni C, Cattaneo D. Pharmacokinetic concerns related to the ACTG A5262 trial.AIDS
2. Boffito M, Moyle M, Hill A, Sekar V, Lefebvre E, De Pauw M, et al.The pharmacokinetic profile of darunavir with low-dose ritonavir (DRV/r) in various multiple-dose regimens over 120 h
[abstract P31]. In: 9th International Workshop on Clinical Pharmacology of HIV Therapy
; 7–9 April 2008; New Orleans, Louisiana, USA.
3. Acosta EP, Limoli KL, Trinh L, Parkin NT, King JR, Weidler J, et al
. Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data (N-145)
. In: 18th Conference on Retroviruses and Opportunistic Infections
; 27 February to 2 March 2011; Boston, Massachusetts, USA.
4. Sekar V, Abeele VC, Van Baelen B, Vis P, Lavreys L, De Pauw M, et al.Pharmacokinetic-pharmacodynamic (PK/PD) analyses of once-daily darunavir in the ARTEMIS study
[poster 42]. In: 9th International Workshop on Clinical Pharmacology of HIV Therapy
; 7–9 April 2008; New Orleans, Louisiana, USA.
5. Sekar V, De La Rosa G, Van de Casteele T, Spinosa-Guzman S, Vis P, Hoetelmans RMW. Pharmacokinetic (PK) and pharmacodynamic analyses of once- and twice-daily darunavir/ritonavir (DRV/r) in the ODIN trial. Poster 185.
In: 10th International Conference on Drug Therapy in HIV Infection
; 7–11 November 2010; Glasgow, UK.
6. Wenning L, Rizk M, Luo W, Hang Y, Su J, Campbell H, et al.PK/PD analyses for QDMRK: a phase 3 study of the safety and efficacy of once versus twice daily raltegravir in treatment-naïve HIV-infected patients
[oral abstract O_09]. In: 12th International Workshop on Clinical Pharmacology of HIV Therapy
; 13–15 April 2011; Miami, Florida, USA.
7. Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers
. Antimicrob Agents Chemother
8. Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, et al. Dolutegravir (S/GSK 1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase
. Antimicrob Agents Chemother