Pregnancy-Associated Changes in Pharmacokinetics and their Clinical Implications

Purpose To critically review pregnancy-induced pharmacokinetic changes and their clinical application. Methods Structured review of Pubmed, MBASE and published books. Results For many drugs, advanced pregnancy is associated with lower maternal serum concentrations. As most drug concentrations are not measured routinely, such changes are not evident to the clinician. Moreover, even for drug concentrations measured clinically, one cannot interpret lower total drug levels as evidence of lower fraction of free drug, which is the pharmacologically-active component, due to lower protein binding of many drugs in late pregnancy. Higher fractions of free drug will lead to higher rate of hepatic metabolism, especially for high extraction medications, leading to lower total drug concentrations.. Pregnancy-induced larger volume of distribution will lead to lower peak of drugs and hence may impact the achievement therapeutic levels. To further complicate matters, the adherence of many women decreases during pregnancy, mostly due to fears of adverse fetal effects. These dynamic and complex processes make changes in recommendations for dose schedule very challenging and in many cases not practical. Conclusions Indeed, there are presently no pregnancy-targeted dose schedules, similar to existing dose changes, for example, in renal failure. Similar to the recent increased attention given to pharmacokinetic changes in pregnancy, well designed studies should compare dose-effect relationships in women receiving medications in different stages of pregnancy, to women receiving the same drug before, and/or after pregnancy. Whenever possible, women with chronic conditions can serve as their own controls and decrease the uncertainty created by inter-patient variability. Measuring drug effects in parallel to drug concentrations, will allow pharmacokinetic-pharmacodynamic modelling, leading to evidence-based decisions regarding changes in dose schedules during gestation.