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 Chenadec; S. 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; 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

doi:10.1128/AAC.00863-15

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, 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 journal › Article › peer-review

13 Scopus citations

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 language	English (US)
Pages (from-to)	5727-5735
Number of pages	9
Journal	Antimicrobial agents and chemotherapy
Volume	59
Issue number	9
DOIs	https://doi.org/10.1128/AAC.00863-15
State	Published - Sep 1 2015
Externally published	Yes

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Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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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

Fauchet, F, Treluyer, JM, Illamola, SM, 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, JP, Laurent, C, Huyn, P, Le Chenadec, J, Delmas, S, Warszawski, J, Muret, P, Baazia, Y, Jeantils, V, Lachassine, E, Rodrigues, A, Sackho, A, Sagnet-Pham, I, Tassi, S, Breilh, D, Iriard, X, Andre, G, Douard, D, Reigadas, S, Roux, D, Louis, I, Morlat, P, Pedebosq, S, Barre, J, Estrangin, E, Fauveau, E, Garrait, V, Ledudal, P, Pichon, C, Richier, L, Thebault, A, Touboul, C, Bornarel, D, Chambrin, V, Clech, L, Dubreuil, P, Foix L'helias, L, Picone, O, Schoen, H, Stralka, M, Crenn-Hebert, C, Floch-Tudal, C, Hery, E, Ichou, H, Meier, F, Tournier, V, Walter, S, Chevojon, P, Devidas, A, Granier, M, Khanfar-Boudjemai, M, Malbrunot, C, Nguyen, R, Ollivier, B, Radideau, E, Turpault, I, Jault, T, Barrail, A, Colmant, C, Fourcade, C, Goujard, C, Pallier, C, Peretti, D, Taburet, AM, Bocket, L, D'Angelo, S, Godart, F, Hammou, Y, Houdret, N, Mazingue, F, Thielemans, B, Brochier, C, Cotte, L, Januel, F, Le Thi, T, Gagneux, MC, Bozio, A, Massardier, J, Kebaïli, K, Ben Akli, K, Heller-Roussin, B, Riehl, C, Roos, S, Taccot, F, Winter, C, Arias, J, Brunet-François, C, Dailly, E, Flet, L, Gournay, V, Mechinaud, F, Reliquet, V, Winner, N, Peytavin, G, Bardin, C, Boudjoudi, N, Compagnucci, A, Guerin, C, Krivine, A, Pannier, E, Salmon, D, Treluyer, JM, Firtion, G, Ayral, D, Ciraru-Vigneron, N, Mazeron, MC, Rizzo Badoin, N, Trout, H, Benachi, A, Boissand, C, Bonnet, D, Boucly, S, Chaix, ML, Duvivier, C, Parat, S, Cayol, V, Oucherif, S, Rouzioux, C, Viard, JP, Bonmarchand, M, De Montgolfier, I, Dommergues, M, Fievet, MH, Iguertsira, M, Pauchard, M, Quetin, F, Soulie, C, Tubiana, R, Faye, A, Magnier, S, Bui, E, Carbonne, B, Daguenel Nguyen, A, Harchi, N, Meyohas, MC, Poirier, JM, Rodriguez, J, Hervé, F, Pialloux, G, Dehee, A, Dollfus, C, Tillous Borde, I, Vaudre, G, Wallet, A, Allemon, MC, Bolot, P, Boussairi, A, Chaplain, C, Edrief, S, Ekoukou, D, Ghibaudo, N, Kana, JM, Khuong, MA, Weil, M, Entz-Werle, N, Livolsi, A, Lutz, P, Beretz, L, Cheneau, M, Partisani, ML, Schmitt, MP, Acar, P, Armand, E, Berrebi, A, Guibaud Plo, C, Lavit, M, Nicot, F, Tricoire, J, Ajana, F & 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, vol. 59, no. 9, pp. 5727-5735. https://doi.org/10.1128/AAC.00863-15

@article{faaff25eeb2347d985913fc9456d4245,

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

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.",

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

year = "2015",

month = sep,

day = "1",

doi = "10.1128/AAC.00863-15",

language = "English (US)",

volume = "59",

pages = "5727--5735",

journal = "Antimicrobial agents and chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "9",

}

TY - JOUR

T1 - Population approach to analyze the pharmacokinetics of free and total lopinavir in HIV-infected pregnant women and consequences for dose adjustment

AU - Fauchet, Floris

AU - Treluyer, Jean Marc

AU - Illamola, Silvia M.

AU - Pressiat, Claire

AU - Lui, Gabrielle

AU - Valade, Elodie

AU - Mandelbrot, Laurent

AU - Lechedanec, Jerome

AU - Delmas, Sandrine

AU - Blanche, Stéphane

AU - Warszawski, Josiane

AU - Urien, Saik

AU - Tubiana, Roland

AU - Hirt, Déborah

AU - Ngondi, J.

AU - Chernai, N.

AU - Teglas, J. P.

AU - Laurent, C.

AU - Huyn, P.

AU - Le Chenadec, J.

AU - Delmas, S.

AU - Warszawski, J.

AU - Muret, P.

AU - Baazia, Y.

AU - Jeantils, V.

AU - Lachassine, E.

AU - Rodrigues, A.

AU - Sackho, A.

AU - Sagnet-Pham, I.

AU - Tassi, S.

AU - Breilh, D.

AU - Iriard, X.

AU - Andre, G.

AU - Douard, D.

AU - Reigadas, S.

AU - Roux, D.

AU - Louis, I.

AU - Morlat, P.

AU - Pedebosq, S.

AU - Barre, J.

AU - Estrangin, E.

AU - Fauveau, E.

AU - Garrait, V.

AU - Ledudal, P.

AU - Pichon, C.

AU - Richier, L.

AU - Thebault, A.

AU - Touboul, C.

AU - Bornarel, D.

AU - Chambrin, V.

AU - Clech, L.

AU - Dubreuil, P.

AU - Foix L'helias, L.

AU - Picone, O.

AU - Schoen, H.

AU - Stralka, M.

AU - Crenn-Hebert, C.

AU - Floch-Tudal, C.

AU - Hery, E.

AU - Ichou, H.

AU - Meier, F.

AU - Tournier, V.

AU - Walter, S.

AU - Chevojon, P.

AU - Devidas, A.

AU - Granier, M.

AU - Khanfar-Boudjemai, M.

AU - Malbrunot, C.

AU - Nguyen, R.

AU - Ollivier, B.

AU - Radideau, E.

AU - Turpault, I.

AU - Jault, T.

AU - Barrail, A.

AU - Colmant, C.

AU - Fourcade, C.

AU - Goujard, C.

AU - Pallier, C.

AU - Peretti, D.

AU - Taburet, A. M.

AU - Bocket, L.

AU - D'Angelo, S.

AU - Godart, F.

AU - Hammou, Y.

AU - Houdret, N.

AU - Mazingue, F.

AU - Thielemans, B.

AU - Brochier, C.

AU - Cotte, L.

AU - Januel, F.

AU - Le Thi, T.

AU - Gagneux, M. C.

AU - Bozio, A.

AU - Massardier, J.

AU - Kebaïli, K.

AU - Ben Akli, K.

AU - Heller-Roussin, B.

AU - Riehl, C.

AU - Roos, S.

AU - Taccot, F.

AU - Winter, C.

AU - Arias, J.

AU - Brunet-François, C.

AU - Dailly, E.

AU - Flet, L.

AU - Gournay, V.

AU - Mechinaud, F.

AU - Reliquet, V.

AU - Winner, N.

AU - Peytavin, G.

AU - Bardin, C.

AU - Boudjoudi, N.

AU - Compagnucci, A.

AU - Guerin, C.

AU - Krivine, A.

AU - Pannier, E.

AU - Salmon, D.

AU - Treluyer, J. M.

AU - Firtion, G.

AU - Ayral, D.

AU - Ciraru-Vigneron, N.

AU - Mazeron, M. C.

AU - Rizzo Badoin, N.

AU - Trout, H.

AU - Benachi, A.

AU - Boissand, C.

AU - Bonnet, D.

AU - Boucly, S.

AU - Chaix, M. L.

AU - Duvivier, C.

AU - Parat, S.

AU - Cayol, V.

AU - Oucherif, S.

AU - Rouzioux, C.

AU - Viard, J. P.

AU - Bonmarchand, M.

AU - De Montgolfier, I.

AU - Dommergues, M.

AU - Fievet, M. H.

AU - Iguertsira, M.

AU - Pauchard, M.

AU - Quetin, F.

AU - Soulie, C.

AU - Tubiana, R.

AU - Faye, A.

AU - Magnier, S.

AU - Bui, E.

AU - Carbonne, B.

AU - Daguenel Nguyen, A.

AU - Harchi, N.

AU - Meyohas, M. C.

AU - Poirier, J. M.

AU - Rodriguez, J.

AU - Hervé, F.

AU - Pialloux, G.

AU - Dehee, A.

AU - Dollfus, C.

AU - Tillous Borde, I.

AU - Vaudre, G.

AU - Wallet, A.

AU - Allemon, M. C.

AU - Bolot, P.

AU - Boussairi, A.

AU - Chaplain, C.

AU - Edrief, S.

AU - Ekoukou, D.

AU - Ghibaudo, N.

AU - Kana, J. M.

AU - Khuong, M. A.

AU - Weil, M.

AU - Entz-Werle, N.

AU - Livolsi, A.

AU - Lutz, P.

AU - Beretz, L.

AU - Cheneau, M.

AU - Partisani, M. L.

AU - Schmitt, M. P.

AU - Acar, P.

AU - Armand, E.

AU - Berrebi, A.

AU - Guibaud Plo, C.

AU - Lavit, M.

AU - Nicot, F.

AU - Tricoire, J.

AU - Ajana, F.

AU - Huleux, T.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84940945475&partnerID=8YFLogxK

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U2 - 10.1128/AAC.00863-15

DO - 10.1128/AAC.00863-15

M3 - Article

C2 - 26149996

AN - SCOPUS:84940945475

SN - 0066-4804

VL - 59

SP - 5727

EP - 5735

JO - Antimicrobial agents and chemotherapy

JF - Antimicrobial agents and chemotherapy

IS - 9

ER -

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

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