A PHYSIOLOGICALLY-BASED PHARMACOKINETIC COMPUTER-MODEL FOR HUMAN-PREGNANCY

A physiologically based pharmacokinetic (PBPK) model for human pregnan cy must incorporate many factors that are not usually encountered in P BPK models of mature animals. Models for pregnancy must include the la rge changes that take place in the mother, the placenta and the embryo /fetus over the period of pregnancy. The embryo/fetal weight change wa s modeled using the Gompertz equation for growth which gave a good fit to extensive pooled weight data of the human embryo/fetus from 25 to 300 days of gestation. This equation is based on a growth rate that is proportional to the total weight of the organism with the proportiona lity factor decreasing exponentially with time. Allometric equations, which are widely used to relate organ weights, blood flow rates and ot her attributes of mature animals to total weight, were adapted to corr elate fetal organ weights with total fetal weight. Allometric relation ships were also developed for plasma flow rates and other organ-relate d parameters. The computer model, written in FORTRAN 77, included 27 c ompartments for the mother and 16 for the fetus; it also accommodates two substances allowing representation of a parent compound and a meta bolite (or a second drug or environmental substance). Although this mo del is large, the inherent sparsity in the equations allow it to be so lved numerically in a reasonable time on currently available, reasonab ly priced desktop computers. A nonlinear regression routine is include d to fit key model parameters to experimental data. Concentrations of chemicals administered and measured in the mother may be simulated in both maternal and fetal organs at any day(s) between 25 days and 300 d ays of gestation. Allometric relationships are also utilized to adopt this human model for use with data obtained from animal experiments. ( C) 1994 Wiley-Liss, Inc.