Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models

被引:24
作者
Abduljalil, Khaled [1 ]
Ning, Jia [1 ]
Pansari, Amita [1 ]
Pan, Xian [1 ]
Jamei, Masoud [1 ]
机构
[1] Certara UK Ltd, Simcyp Div, Level 2 Acero,1 Concourse Way, Sheffield S1 2BJ, S Yorkshire, England
关键词
FETAL URINE PRODUCTION; UMBILICAL-CORD BLOOD; SERUM; HOURS; PLACENTAL-TRANSFER; RENAL CLEARANCE; AMNIOTIC-FLUID; PREMATURE RUPTURE; WOMEN; ANTIBIOTICS; ABSORPTION;
D O I
10.1124/dmd.121.000711
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Concerns over maternal and fetal drug exposures highlight the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmaco-kinetic (PBPK) modeling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiologic changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters deter-mined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared with the observed data. Fully bottom-up fetoplacental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in nonpregnant subjects and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed pharmacokinetic data reported in nine maternal (five fetoplacental) studies for cefuroxime, 10 maternal (five fetoplacental) studies for cefazolin, and six maternal (two fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calcu-late placental permeability, facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively used for maternal-fetal risk assessment after maternally administered drugs or unintended exposure to environmental toxicants. SIGNIFICANCE STATEMENT This study investigates the performance of an integrated maternal-placental-fetal PBPK model to predict maternal and fetal tissue exposure of renally eliminated antibiotics that cross the placenta through a passive diffusion mechanism. The transplacental perme-ability clearance was predicted from the drug physicochemical properties. Results demonstrate that the PBPK approach can facili-tate the prediction of maternal and fetal drug exposure simulta-neously at any gestational age to support its use in the maternal-fetal exposure assessments. Downloaded from dmd.aspetjournals.org at
引用
收藏
页码:386 / 400
页数:15
相关论文
共 83 条
[1]   Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Cardiac Output and Its Distribution to Different Organs during Development [J].
Abduljalil, Khaled ;
Pan, Xian ;
Clayton, Ruth ;
Johnson, Trevor N. ;
Jamei, Masoud .
CLINICAL PHARMACOKINETICS, 2021, 60 (06) :741-757
[2]   Drug dosing during pregnancy-opportunities for physiologically based pharmacokinetic models [J].
Abduljalil, Khaled ;
Badhan, Raj K. Singh .
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2020, 47 (04) :319-340
[3]   Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Blood Components and Binding Proteins [J].
Abduljalil, Khaled ;
Jamei, Masoud ;
Johnson, Trevor N. .
CLINICAL PHARMACOKINETICS, 2020, 59 (05) :629-642
[4]   Fetal Physiologically-Based Pharmacokinetic Models: Systems Information on Fetal Biometry and Gross Composition [J].
Abduljalil, Khaled ;
Johnson, Trevor N. ;
Rostami-Hodjegan, Amin .
CLINICAL PHARMACOKINETICS, 2018, 57 (09) :1149-1171
[5]   Fetal Physiologically Based Pharmacokinetic Models: Systems Information on the Growth and Composition of Fetal Organs [J].
Abduljalil, Khaled ;
Jamei, Masoud ;
Johnson, Trevor N. .
CLINICAL PHARMACOKINETICS, 2019, 58 (02) :235-262
[6]   Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal PregnancyA Database for Parameters Required in Physiologically Based Pharmacokinetic Modelling [J].
Khaled Abduljalil ;
Penny Furness ;
Trevor N. Johnson ;
Amin Rostami-Hodjegan ;
Hora Soltani .
Clinical Pharmacokinetics, 2012, 51 (6) :365-396
[7]   PHARMACOKINETICS OF AMOXICILLIN AND FLUCLOXACILLIN FOLLOWING THE SIMULTANEOUS INTRAVENOUS ADMINISTRATION OF 4-G AND 1-G, RESPECTIVELY [J].
ADAM, D ;
KOEPPE, P ;
HEILMANN, HD .
INFECTION, 1983, 11 (03) :150-154
[8]   The Role of Megalin in the Transport of Gentamicin Across BeWo Cells, an In Vitro Model of the Human Placenta [J].
Akour, Amal A. ;
Kennedy, Mary Jayne ;
Gerk, Phillip M. .
AAPS JOURNAL, 2015, 17 (05) :1193-1199
[9]   Cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy [J].
Allegaert, Karel ;
van Mieghem, Tim ;
Verbesselt, Rene ;
de Hoon, Jan ;
Rayyan, Maissa ;
Devlieger, Roland ;
Deprest, Jan ;
Anderson, Brian J. .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2009, 200 (02) :170.e1-170.e7
[10]   Efficacy of perioperative cefuroxime as a prophylactic antibiotic in women requiring caesarean section: A systematic review [J].
Alrammaal, Hanadi H. ;
Batchelor, Hannah K. ;
Morris, R. Katie ;
Chong, Hsu R. .
EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, 2019, 242 :71-78