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

Clinical Pharmacokinetics, vol. 62, pp. 1157–1167

Abstract

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.

Authors 8

1. Julie M. Janssen

   The Netherlands Cancer Institute

   Affiliation as printed

   Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

2. David Damoiseaux

   The Netherlands Cancer Institute

   Affiliation as printed

   Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

3. J. G. Coen van Hasselt Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

4. Frédéric Amant

   The Netherlands Cancer Institute · Centrum voor Gynaecologische Oncologie Amsterdam · Amsterdam University Medical Centers · KU Leuven

   Affiliation as printed

   Centre for Gynaecologic Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek/Netherlands Cancer Institute and Amsterdam University Medical Center, Amsterdam, The Netherlands

   Department of Oncology, Catholic University of Leuven, Leuven, Belgium

5. Kristel Van Calsteren

   KU Leuven

   Affiliation as printed

   Department of Development and Regeneration, Obstetrics and Gynaecology, KU Leuven, Leuven, Belgium

6. Jos H. Beijnen

   Utrecht University · The Netherlands Cancer Institute

   Affiliation as printed

   Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

   Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

7. Alwin D. R. Huitema

   Utrecht University · The Netherlands Cancer Institute · University Medical Center Utrecht · Princess Máxima Center

   Affiliation as printed

   Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

   Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht University, Utrecht, The Netherlands

   Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

8. Thomas P. C. Dorlo corresponding

   Uppsala University · The Netherlands Cancer Institute

   Affiliation as printed

   Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. thomas.dorlo@farmaci.uu.se

   Department of Pharmacy, Uppsala University, Uppsala, Sweden. thomas.dorlo@farmaci.uu.se