Population approach to analyze the pharmacokinetics of free and total lopinavir in HIV-infected pregnant women and consequences for dose adjustment

Floris Fauchet, Jean Marc Treluyer, Silvia M. Illamola, Claire Pressiat, Gabrielle Lui, Elodie Valade, Laurent Mandelbrot, Jerome Lechedanec, Sandrine Delmas, Stéphane Blanche, Josiane Warszawski, Saik Urien, Roland Tubiana, Déborah Hirt, J. Ngondi, N. Chernai, J. P. Teglas, C. Laurent, P. Huyn, J. Le ChenadecS. Delmas, J. Warszawski, P. Muret, Y. Baazia, V. Jeantils, E. Lachassine, A. Rodrigues, A. Sackho, I. Sagnet-Pham, S. Tassi, D. Breilh, X. Iriard, G. Andre, D. Douard, S. Reigadas, D. Roux, I. Louis, P. Morlat, S. Pedebosq, J. Barre, E. Estrangin, E. Fauveau, V. Garrait, P. Ledudal, C. Pichon, L. Richier, A. Thebault, C. Touboul, D. Bornarel, V. Chambrin, L. Clech, P. Dubreuil, L. Foix L'helias, O. Picone, H. Schoen, M. Stralka, C. Crenn-Hebert, C. Floch-Tudal, E. Hery, H. Ichou, F. Meier, V. Tournier, S. Walter, P. Chevojon, A. Devidas, M. Granier, M. Khanfar-Boudjemai, C. Malbrunot, R. Nguyen, B. Ollivier, E. Radideau, I. Turpault, T. Jault, A. Barrail, C. Colmant, C. Fourcade, C. Goujard, C. Pallier, D. Peretti, A. M. Taburet, L. Bocket, S. D'Angelo, F. Godart, Y. Hammou, N. Houdret, F. Mazingue, B. Thielemans, C. Brochier, L. Cotte, F. Januel, T. Le Thi, M. C. Gagneux, A. Bozio, J. Massardier, K. Kebaïli, K. Ben Akli, B. Heller-Roussin, C. Riehl, S. Roos, F. Taccot, C. Winter, J. Arias, C. Brunet-François, E. Dailly, L. Flet, V. Gournay, F. Mechinaud, V. Reliquet, N. Winner, G. Peytavin, C. Bardin, N. Boudjoudi, A. Compagnucci, C. Guerin, A. Krivine, E. Pannier, D. Salmon, J. M. Treluyer, G. Firtion, D. Ayral, N. Ciraru-Vigneron, M. C. Mazeron, N. Rizzo Badoin, H. Trout, A. Benachi, C. Boissand, D. Bonnet, S. Boucly, S. Blanche, M. L. Chaix, C. Duvivier, S. Parat, V. Cayol, S. Oucherif, C. Rouzioux, J. P. Viard, M. Bonmarchand, I. De Montgolfier, M. Dommergues, M. H. Fievet, M. Iguertsira, M. Pauchard, F. Quetin, C. Soulie, R. Tubiana, A. Faye, S. Magnier, E. Bui, B. Carbonne, A. Daguenel Nguyen, N. Harchi, M. C. Meyohas, J. M. Poirier, J. Rodriguez, F. Hervé, G. Pialloux, A. Dehee, C. Dollfus, I. Tillous Borde, G. Vaudre, A. Wallet, M. C. Allemon, P. Bolot, A. Boussairi, C. Chaplain, S. Edrief, D. Ekoukou, N. Ghibaudo, J. M. Kana, M. A. Khuong, M. Weil, N. Entz-Werle, A. Livolsi, P. Lutz, L. Beretz, M. Cheneau, M. L. Partisani, M. P. Schmitt, P. Acar, E. Armand, A. Berrebi, C. Guibaud Plo, M. Lavit, F. Nicot, J. Tricoire, F. Ajana, T. Huleux

Research output: Contribution to journalArticle

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Abstract

The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.

Original languageEnglish (US)
Pages (from-to)5727-5735
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number9
DOIs
StatePublished - Sep 1 2015

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    Fauchet, F., Treluyer, J. M., Illamola, S. M., Pressiat, C., Lui, G., Valade, E., Mandelbrot, L., Lechedanec, J., Delmas, S., Blanche, S., Warszawski, J., Urien, S., Tubiana, R., Hirt, D., Ngondi, J., Chernai, N., Teglas, J. P., Laurent, C., Huyn, P., ... Huleux, T. (2015). Population approach to analyze the pharmacokinetics of free and total lopinavir in HIV-infected pregnant women and consequences for dose adjustment. Antimicrobial agents and chemotherapy, 59(9), 5727-5735. https://doi.org/10.1128/AAC.00863-15