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Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP)

Abstract

Background

Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy.

Objective

With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women.

Methods

PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates.

Results

Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients.

Conclusion

Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

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Acknowledgements

The authors thank Liesbeth Leemans and Katrien Van Tornout for sample collections, and the Research HPC Facility of the Netherlands Cancer Institute for support in the use of computational resources.

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Authors

Corresponding author

Correspondence to Frederic C. H. Amant.

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Funding

Funding for the INCIP registry, sample bioanalysis and sample logistics was provided by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 647047), the Research Foundation-Flanders and the Belgian Cancer Plan, Ministry of Health, Belgium.

Conflicts of Interest

Frédéric Amant is a senior clinical investigator for the Research Fund-Flanders; Kristel Van Calsteren received a clinical research fund from the University Hospitals Leuven; Thomas Dorlo was personally supported by a Dutch Research Council (NWO)/ZonMw Veni grant; Michael J. Halaska was supported by the Charles University research project Progres Q28 and Q34; and Jos Beijnen is a part-time employee, patent holder (partly) and stock holder (indirectly) of Modra Pharmaceuticals BV, a spin-out company developing oral taxane formulations and therapies, which is not related to the submitted work. Julie M. Janssen, Robert Fruscio, Petronella Ottevanger, Carolien P. Schröder, Ingrid Boere, Petronella O. Witteveen, Rebecca C. Painter, Ruud Bekkers, Vit Drochytek and Alwin D.R. Huitema have no conflicts of interest to declare.

Ethics approval

The data used in this study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by institutional review boards and independent ethics committees at participating 137 institutions.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

All individual participants signed informed consent regarding publishing their data.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Author contributions

JJ, TD and AH performed the analysis, data interpretation and writing of the manuscript. KVC and FA designed the study, included patients, contributed to the writing of the manuscript, and provided financial support. MH, RF, PO, CS, IB, PW, RP, RB and VD included patients and contributed to the writing of the manuscript. JB contributed to drug analysis and writing of the manuscript.

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Janssen, J.M., Van Calsteren, K., Dorlo, T.P.C. et al. Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP). Clin Pharmacokinet 60, 775–784 (2021). https://doi.org/10.1007/s40262-020-00961-4

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  • DOI: https://doi.org/10.1007/s40262-020-00961-4