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Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART

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Abstract

Aims

To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety.

Methods

Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2–ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration–time curve (AUC) and maximum (Cmax) and trough concentrations (Ctrough) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety

Results

A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and Ctrough were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir Cmax (median 3.6, range 2.1–5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2–8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range −0.7 to 1.4 vs. median 0.6, range −0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs.

Conclusion

The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

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Acknowledgements

Steering committee of the COPHAR2 ANRS-111 trial: principal investigators: D. Salmon- Céron, X. Duval, statistics: F. Mentré; other members: S. Auleley, M. Biour, M.J. Commoy, B. Diquet, C. Goujard, C. Katlama, C. Lascoux, M. Legrand, A. Métro, G. Peytavin, E. Rey, A.M. Taburet, J.M. Tre´luyer.

Safety committee: S. Auleley, M. Biour, A. Métro, C. Lascoux, D. Salmon-Céron. Pharmacological monitoring committee: X. Duval, E. Rey, J.M. Tréluyer. Independent committee: C. Rouzioux, C. Piketti, P. Flandre, M. Zenut, P. Marquet.

Clinical centers: Dr. Bentata, Dr. Mansouri, Mme Touam, Pr. Sereni, Dr. Lascoux, Dr. Pintado, Dr. Goujard, Mme Mole, Dr. Sellier, Dr. Bendenoun, Dr. Rami, Mme Parrinello, Dr. Jeantils, Mme Tassi, Pr. Vittecoq, Dr. Teicher, Mme Mallet, Pr. Dupont, Dr. Lahoulou, Soeur Azar, Pr. Rosembaum, Dr. Slama, Dr. Naï-Ighil Baakili, Dr. Courtial-Destembert, Pr. Vildé, Pr. Leport, Dr. Duval, Dr. Al Kaied, Pr. Salmon, Dr. Spiridon, Dr. Lesprit, Mme Chesnel, Pr. Katlama, Dr. Schneider, Mme Schoen, Pr. Molina, Dr. Ponscarme, Dr. Colin de verdière, Pr. Morlat, Dr. Bonarek, Dr. Joly, Dr. Ralaimazava, Mme Meridda, Mme Le Gac, P. Raffi, Dr. Allavena, Mme Hüe, Mme Sicot, Dr. Perré, Dr. Leautez, Dr. Aubry, Mme Suaud, Pr. Dellamonica, Dr. Rahelinirina, Pr. Michelet, Dr. Bouvier, Pr. Bazin, Dr. Goubin, Pr. May, Dr. Boyer, Pr. Rouveix, Dr. Dupont, Mme Berthé.

Pharmacological centers: Dr. Rey, Pr. Tréluyer, Dr. Abbara, Dr. Audoul, Dr. Tran, Dr. Sauvageon, Dr. Poirier, Dr. Taburet, Dr. Vincent, Dr. Aymard, Dr. Peytavin, Dr. Lamotte, Dr. Dailly, Dr. Garraffo, Dr. Lavrut, Dr. Mollimard, Dr. Titier, Dr. Tribut, Dr. Hulin, Dr. Huet, Dr. Delhotal, Dr. Hoizey.

Virological centers: Pr. Nicolas-Chanoine, Dr. Sousan, Pr. Dény, Dr. Baazia, Dr. Alloui, Pr. Brun-Vézinet, Dr. Chams, Pr. Fleury, Dr. Pellegrin, Dr. Garrigue, Pr. Fremut, Dr. Vabret, Pr. Lebon, Dr. Krivine, Pr. Calvez, Dr. Gourlain, Dr. Amellal, Pr. Bouvier-Alias, Pr. Norman, Dr. Idri, Pr. Chambreuil, Dr. Poirier, Pr. Mazeron, Pr. Le Faou, Dr. Vénard, Pr. Billaudel, Dr. Ferre, Pr. Rouzioux, Dr. Burgard, Pr. Lefevre, Dr. Cottalorda, Pr. Dussaix, Dr. Bensidhoum, Pr. Colimon, Dr. Ruffault, Dr. Maillard, Pr. Morinet, Dr. Palmer, Pr. Nicolas, Dr. Zalta.

Monitoring: S. Auleley, E. Marcault, F. Mentré. Statistics: E. Bougen, F. Mentré, X. Panhard.

The authors thank the study participants and the Agence de Recherche Nationale sur le SIDA (ANRS, Essai 111) for financial support.

We also acknowledge Dr. Emmanuelle Comets, Pr. Marc Lavielle and Dr. Emmanuelle Génin for their valuable advices during the analysis.

J. Bertrand was supported by a grant from Servier Research Group, France.

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Authors and Affiliations

  1. UMR 738, INSERM, Université Paris Diderot, UFR de Médecine, 16, rue Henri Huchard, 75018, Paris, France

    Julie Bertrand

  2. EA3620, Université Paris Descartes, Paris, France

    Jean-Marc Treluyer

  3. Service de Pharmacologie Clinique, Hôpital Cochin-Saint-Vincent-de-Paul, AP-HP, Paris, France

    Jean-Marc Treluyer

  4. UMR 738, AP-HP, INSERM, Université Paris Diderot, Paris, France

    Xavière Panhard & France Mentré

  5. Service de Pharmacologie Clinique, Hôpital Cochin-Saint-Vincent-de-Paul, AP-HP, Paris, France

    Agnes Tran & Elisabeth Rey

  6. UMR 738, INSERM, Université Paris Diderot, Paris, France

    Solange Auleley & Xavier Duval

  7. Service de Médecine Interne, Hôpital Cochin-Saint-Vincent-de-Paul, AP-HP, Paris, France

    Dominique Salmon-Céron

  8. UF de Biostatistiques, Hôpital Bichat, Paris, France

    Xavière Panhard & France Mentré

  9. Centre d’Investigation Clinique, Hôpital Bichat, AP-HP, Paris, France

    Xavier Duval

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  1. Julie Bertrand
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the COPHAR2-ANRS 111 Study Group

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Correspondence to Julie Bertrand.

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Bertrand, J., Treluyer, JM., Panhard, X. et al. Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART. Eur J Clin Pharmacol 65, 667–678 (2009). https://doi.org/10.1007/s00228-009-0660-5

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