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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 5/2017

01-05-2017 | Original Research Article

A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways

Authors: Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud

Published in: Clinical Pharmacokinetics | Issue 5/2017

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Abstract

Background

Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful.

Methods

A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK). The model was developed in both non-pregnant and pregnant women, and all physiological and enzymatic changes that could impact nevirapine PK were taken into account. Transplacental parameters estimated from ex vivo human placenta perfusion experiments were included in this PBPK model. To validate the model, observed maternal and cord blood concentrations were compared with predicted concentrations, and the impact of fetal clearance on fetal PK was investigated.

Results

By implementing physiological changes, including CYP3A4, 2D6 and 2B6 inductions, we predicted a clearance increase of 21 % in late pregnancy. The PBPK model successfully predicted the disposition for both non-pregnant and pregnant populations. Parameters obtained from the ex vivo experiments allowed the prediction of nevirapine concentrations that matched observed cord blood concentrations. The fetal-to-maternal area under the curve ratio (0–24 h interval) was 0.77, and fetal metabolism had no significant effect on fetal PK.

Conclusions

The PBPK approach is a useful tool for quantifying a priori the drug exposure of metabolized drugs during pregnancy, and can be applied to evaluate alternative dosing regimens to optimize drug therapy. This approach, including ex vivo human placental perfusion parameters, is a promising approach for predicting human fetal exposure.
Literature
1.
Daw JR, Hanley GE, Greyson DL, Morgan SG. Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf. 2011;20(9):895–902.PubMedPubMedCentral
2.
Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol. 2011;205(1):51.e1–51.e8.
3.
Zaki NM, Albarraq AA. Use, attitudes and knowledge of medications among pregnant women: a Saudi study. Saudi Pharm J. 2014;22(5):419–28.CrossRefPubMed
4.
Eyal S, Easterling TR, Carr D, Umans JG, Miodovnik M, Hankins GDV, et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos. 2010;38(5):833–40.CrossRefPubMedPubMedCentral
5.
Gaohua L, Abduljalil K, Jamei M, Johnson TN, Rostami-Hodjegan A. A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4. Br J Clin Pharmacol. 2012;74(5):873–85.CrossRefPubMedPubMedCentral
6.
Ke AB, Nallani SC, Zhao P, Rostami-Hodjegan A, Unadkat JD. A PBPK model to predict disposition of CYP3A-metabolized drugs in pregnant women: verification and discerning the site of CYP3A induction. CPT Pharmacomet Syst Pharmacol. 2012;1(9):e3.CrossRef
7.
Ke AB, Nallani SC, Zhao P, Rostami-Hodjegan A, Unadkat JD. Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19. Br J Clin Pharmacol. 2014;77(3):554–70.CrossRefPubMedPubMedCentral
8.
Ke AB, Nallani SC, Zhao P, Rostami-Hodjegan A, Isoherranen N, Unadkat JD. A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women. Drug Metab Dispos Biol Fate Chem. 2013;41(4):801–13.CrossRefPubMedPubMedCentral
9.
Alqahtani S, Kaddoumi A. Development of physiologically based pharmacokinetic/pharmacodynamic model for indomethacin disposition in pregnancy. PLoS One. 2015;10(10):e0139762.CrossRefPubMedPubMedCentral
10.
Xia B, Heimbach T, Gollen R, Nanavati C, He H. A simplified PBPK modeling approach for prediction of pharmacokinetics of four primarily renally excreted and CYP3A metabolized compounds during pregnancy. AAPS J. 2013;15(4):1012–24.CrossRefPubMedPubMedCentral
11.
Pilari S, Preuße C, Huisinga W. Gestational influences on the pharmacokinetics of gestagenic drugs: a combined in silico, in vitro and in vivo analysis. Eur J Pharm Sci. 2011;42(4):318–31.CrossRefPubMed
12.
Gentry PR, Covington TR, Andersen ME, Clewell HJ III. Application of a physiologically based pharmacokinetic model for isopropanol in the derivation of a reference dose and reference concentration. Regul Toxicol Pharmacol. 2002;36(1):51–68.CrossRefPubMed
13.
Luecke RH, Wosilait WD, Pearce BA, Young JF. A computer model and program for xenobiotic disposition during pregnancy. Comput Methods Programs Biomed. 1997;53(3):201–24.CrossRefPubMed
14.
Yoon M, Schroeter JD, Nong A, Taylor MD, Dorman DC, Andersen ME, et al. Physiologically based pharmacokinetic modeling of fetal and neonatal manganese exposure in humans: describing manganese homeostasis during development. Toxicol Sci. 2011;122(2):297–316.CrossRefPubMed
15.
De Sousa Mendes M, Hirt D, Vinot C, Valade E, Lui G, Pressiat C, et al. Prediction of human fetal pharmacokinetics using ex-vivo human placenta perfusion studies and physiologically based models. Br J Clin Pharmacol. 2016;81(4):646–57.CrossRef
16.
Shintaku K, Hori S, Satoh H, Tsukimori K, Nakano H, Fujii T, et al. Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies. Br J Clin Pharmacol. 2012;73(2):248–56.CrossRefPubMedPubMedCentral
17.
Abduljalil K, Furness P, Johnson TN, Rostami-Hodjegan A, Soltani H. Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: a database for parameters required in physiologically based pharmacokinetic modelling. Clin Pharmacokinet. 2012;51(6):365–96.CrossRefPubMed
18.
Ke AB, Rostami-Hodjegan A, Zhao P, Unadkat JD. Pharmacometrics in pregnancy: an unmet need. Annu Rev Pharmacol Toxicol. 2014;54(1):53–69.CrossRefPubMed
19.
Isoherranen N, Thummel KE. Drug metabolism and transport during pregnancy: how does drug disposition change during pregnancy and what are the mechanisms that cause such changes? Drug Metab Dispos. 2013;41(2):256–62.CrossRefPubMedPubMedCentral
20.
Chappuy H, Tréluyer J-M, Jullien V, Dimet J, Rey E, Fouché M, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2004;48(11):4332–6.CrossRefPubMedPubMedCentral
21.
Mirochnick M, Taha T, Kreitchmann R, Nielsen-Saines K, Kumwenda N, Joao E, et al. Pharmacokinetics and safety of tenofovir in HIV-infected women during labor and their infants during the first week of life. J Acquir Immune Defic Syndr. 2014;65(1):33–41.CrossRefPubMedPubMedCentral
22.
Hirt D, Urien S, Rey E, Arrivé E, Ekouévi DK, Coffié P, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2009;53(3):1067–73.CrossRefPubMed
23.
Hirt D, Urien S, Ekouévi DK, Rey E, Arrivé E, Blanche S, et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther. 2009;85(2):182–9.CrossRefPubMed
24.
Myllynen P, Vähäkangas K. Placental transfer and metabolism: an overview of the experimental models utilizing human placental tissue. Toxicol In Vitro. 2013;27(1):507–12.CrossRefPubMed
25.
Prouillac C, Lecoeur S. The role of the placenta in fetal exposure to xenobiotics: importance of membrane transporters and human models for transfer studies. Drug Metab Dispos. 2010;38(10):1623–35.CrossRefPubMed
26.
Price PS, Conolly RB, Chaisson CF, Gross EA, Young JS, Mathis ET, et al. Modeling Interindividual variation in physiological factors used in PBPK models of humans. Crit Rev Toxicol. 2003;33(5):469–503.CrossRefPubMed
27.
Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.CrossRefPubMed
28.
Ibarra M, Vázquez M, Fagiolino P. Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose. J Pharmacokinet Pharmacodyn. 2014;41(4):363–73.CrossRefPubMed
29.
Riska P, Lamson M, MacGregor T, Sabo J, Hattox S, Pav J, et al. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos Biol Fate Chem. 1999;27(8):895–901.PubMed
30.
Fan-Havard P, Liu Z, Chou M, Ling Y, Barrail-Tran A, Haas DW, et al. Pharmacokinetics of phase i nevirapine metabolites following a single dose and at steady state. Antimicrob Agents Chemother. 2013;57(5):2154–60.CrossRefPubMedPubMedCentral
31.
Lamson M, MacGregor T, Riska P, Erickson D, Maxfield P, Rowland L, et al. Nevirapine induces both CYP3A4 and CYP2B6 metabolic pathways. Clin Pharmacol Ther. 1999;65(2):137.CrossRef
32.
Lamson MJ, Sabo JP, MacGregor TR, Pav JW, Rowland L, Hawi A, et al. Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers. Biopharm Drug Dispos. 1999;20(6):285–91.CrossRefPubMed
33.
Schneider H, Panigel M, Dancis J. Transfer across the perfused human placenta of antipyrine, sodium and leucine. Am J Obstet Gynecol. 1972;114(6):822–8.CrossRefPubMed
34.
Forestier F, de Renty P, Peytavin G, Dohin E, Farinotti R, Mandelbrot L. Maternal-fetal transfer of saquinavir studied in the ex vivo placental perfusion model. Am J Obstet Gynecol. 2001;185(1):178–81.CrossRefPubMed
35.
Vinot C, Gavard L, Treluyer JM, Manceau S, Courbon E, Scherrmann JM, et al. Placental transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of ABC transporter expression. Antimicrob Agents Chemother. 2013;57(3):1415–20.CrossRefPubMedPubMedCentral
36.
Kiserud T, Ebbing C, Kessler J, Rasmussen S. Fetal cardiac output, distribution to the placenta and impact of placental compromise. Ultrasound Obstet Gynecol. 2006;28(2):126–36.CrossRefPubMed
37.
Heller M, Burd L. Review of ethanol dispersion, distribution, and elimination from the fetal compartment. Birt Defects Res A Clin Mol Teratol. 2014;100(4):277–83.CrossRef
38.
Underwood MA, Gilbert WM, Sherman MP. Amniotic fluid: not just fetal urine anymore. J Perinatol. 2005;25(5):341–8.CrossRefPubMed
39.
Beall MH, van den Wijngaard JPHM, van Gemert MJC, Ross MG. Amniotic fluid water dynamics. Placenta. 2007;28(8–9):816–23.CrossRefPubMed
40.
Gilbert WM, Newman PS, Eby-Wilkens E, Brace RA. Technetium Tc 99m rapidly crosses the ovine placenta and intramembranous pathway. Am J Obstet Gynecol. 1996;175(6):1557–62.CrossRefPubMed
41.
Benaboud S, Ekouévi DK, Urien S, Rey E, Arrivé E, Blanche S, et al. Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2011;55(1):331–7.CrossRefPubMed
42.
Capparelli EV, Aweeka F, Hitti J, Stek A, Hu C, Burchett SK, PACTG 1026S Study Team, PACTG P1022 Study Team, et al. Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med. 2008;9(4):214–20.CrossRefPubMedPubMedCentral
43.
Shintaku K, Arima Y, Dan Y, Takeda T, Kogushi K, Tsujimoto M, et al. Kinetic analysis of the transport of salicylic acid, a nonsteroidal anti-inflammatory drug, across human placenta. Drug Metab Dispos. 2007;35(5):772–8.CrossRefPubMed
44.
Yeh RF, Rezk NL, Kashuba ADM, Dumond JB, Tappouni HL, Tien H-C, et al. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob Agents Chemother. 2009;53(6):2367–74.CrossRefPubMedPubMedCentral
45.
Gingelmaier A, Kurowski M, Kästner R, Eberle J, Mylonas I, Belohradsky BH, et al. Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery. AIDS Lond Engl. 2006;20(13):1737–43.CrossRef
46.
Capparelli EV, Englund JA, Connor JD, Spector SA, McKinney RE, Palumbo P, et al. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. J Clin Pharmacol. 2003;43(2):133–40.CrossRefPubMed
47.
Ivanovic J, Nicastri E, Anceschi MM, Ascenzi P, Signore F, Pisani G, Pregnancy and Newborn Clinical Outcome Group in HIV Infection (PANCOH), et al. Transplacental transfer of antiretroviral drugs and newborn birth weight in HIV-infected pregnant women. Curr HIV Res. 2009;7(6):620–5.CrossRefPubMed
48.
Betts S, Björkhem-Bergman L, Rane A, Ekström L. Expression of CYP3A4 and CYP3A7 in human foetal tissues and its correlation with nuclear receptors. Basic Clin Pharmacol Toxicol. 2015;117(4):261–6.PubMed
49.
Fanni D, Fanos V, Ambu R, Lai F, Gerosa C, Pampaloni P, et al. Overlapping between CYP3A4 and CYP3A7 expression in the fetal human liver during development. J Matern Fetal Neonatal Med. 2015;28(11):1291–5.CrossRef
50.
Shuster DL, Risler LJ, Prasad B, Calamia JC, Voellinger JL, Kelly EJ, et al. Identification of CYP3A7 for glyburide metabolism in human fetal livers. Biochem Pharmacol. 2014;92(4):690–700.CrossRefPubMedPubMedCentral
51.
Vyhlidal CA, Pearce RE, Gaedigk R, Calamia JC, Shuster DL, Thummel KE, et al. Variability in expression of CYP3A5 in human fetal liver. Drug Metab Dispos Biol Fate Chem. 2015;43(8):1286–93.CrossRefPubMed
52.
Tracy TS, Venkataramanan R, Glover DD, Caritis SN, National Institute for Child Health and Human Development Network of Maternal-Fetal-Medicine Units. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol. 2005;192(2):633–9.CrossRefPubMed
53.
Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004;43(8):487–514.CrossRefPubMed
54.
Cramer YS, Rosenkranz SL, Hall SD, Szczech LA, Amorosa V, Gupta SK. Hemodialysis does not significantly affect the pharmacokinetics of nevirapine in HIV-1-infected persons requiring hemodialysis: results from ACTG A5177. J Acquir Immune Defic Syndr. 2010;54(4):e7–9.CrossRefPubMedPubMedCentral
55.
Erickson DA, Mather G, Trager WF, Levy RH, Keirns JJ. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos. 1999;27(12):1488–95.PubMed
56.
Smith GCS, Cameron AD. Estimating human fetal blood volume on the basis of gestational age and fetal abdominal circumference. BJOG Int J Obstet Gynaecol. 2002;109(6):721–2.CrossRef
57.
Zanardo V, Gabrieli C, de Luca F, Trevisanuto D, De Santis M, Scambia G, et al. Head-to-body delivery by ‘two-step’ approach: effect on cord blood hematocrit. J Matern Fetal Neonatal Med. 2013;26(12):1234–8.CrossRefPubMed
58.
Chang Y-H, Yang S-H, Wang T-F, Lin T-Y, Yang K-L, Chen S-H. Complete blood count reference values of cord blood in Taiwan and the influence of gender and delivery route on them. Pediatr Neonatol. 2011;52(3):155–60.CrossRefPubMed
59.
Eskola M, Juutistenaho S, Aranko K, Sainio S, Kekomäki R. Association of cord blood platelet count and volume with hemoglobin in healthy term infants. J Perinatol. 2010;31(4):258–62.CrossRefPubMed
60.
Arant BS Jr. Developmental patterns of renal functional maturation compared in the human neonate. J Pediatr. 1978;92(5):705–12.CrossRefPubMed
61.
Moltó J, Valle M, Miranda C, Cedeño S, Miranda J, Santos JR, et al. Once- or twice-daily dosing of nevirapine in HIV-infected adults: a population pharmacokinetics approach. J Antimicrob Chemother. 2008;62(4):784–92.CrossRefPubMed
62.
Peters AM, Perry L, Hooker CA, Howard B, Neilly MDJ, Seshadri N, Sobnack R, Irwin A, Snelling H, Gruning T, Patel NH, Lawson RS, Shabo G, Williams N, Dave S, Barnfield MC. Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling. Nephrol Dial Transplant. 2012;27(4):1429–37.CrossRefPubMed
63.
Clapp JF, Stepanchak W, Tomaselli J, Kortan M, Faneslow S. Portal vein blood flow—Effects of pregnancy, gravity, and exercise. Am J Obstet Gynecol. 2000;183(1):167–72.PubMed
Metadata
Title
A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways
Authors
Maïlys De Sousa Mendes
Gabrielle Lui
Yi Zheng
Claire Pressiat
Deborah Hirt
Elodie Valade
Naïm Bouazza
Frantz Foissac
Stephane Blanche
Jean-Marc Treluyer
Saik Urien
Sihem Benaboud
Publication date
01-05-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 5/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0457-5

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