Journal Article

Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs

van Hasselt, J. G. C., Damoiseaux, D., Huitema, A. D. R., Beijnen, J. H., Dorlo, T. P. C., Amant, F. C. H., Janssen, J. M., van Calsteren, K.

2023

Overview

Background and Objective As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. Methods Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. Results The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. Conclusion By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Antineoplastic Agents - pharmacokinetics / Cancer therapies / Child / Cytotoxicity / Docetaxel - therapeutic use / Doxorubicin / Drug dosages / Enzymes / Epirubicin - pharmacokinetics / Epirubicin - therapeutic use / Female / Gestational age / Glycoproteins / Humans / Internal Medicine / Medicine / Medicine & Public Health / Models, Biological / Neoplasms - drug therapy / Original / Original Research Article / Paclitaxel - pharmacokinetics / Patients / Pharmacokinetics / Pharmacology/Toxicology / Pharmacotherapy / Physiology / Plasma / Pregnancy / Proteins / Womens health