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.

Antoni van Leeuwenhoek Netherlands Cancer Institute and Amsterdam Amsterdam University Medical Centers Amsterdam The Netherlands

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

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

Department of Gynaecology and Obstetrics Amsterdam University Medical Centres University of Amsterdam Amsterdam The Netherlands

Department of Medical Oncology Erasmus MC Cancer Institute Erasmus University Medical Center Rotterdam The Netherlands

Department of Medical Oncology Radboudumc Nijmegen The Netherlands

Department of Medical Oncology University Medical Center Groningen Groningen The Netherlands

Department of Medical Oncology University Medical Center Utrecht Utrecht The Netherlands

Department of Medicine and Surgery Clinic of Obstetrics and Gynecology San Gerardo Hospital University of Milan Bicocca Monza Italy

Department of Obstetrics and Gynaecology 3rd Medical Faculty University Hospital Kralovske Vinohrady Charles University Prague Czech Republic

Department of Obstetrics and Gynecology Catherina Cancer Institute Catharina Hospital Eindhoven Eindhoven The Netherlands

Department of Oncology Catholic University of Leuven Leuven Belgium

Department of Pharmacy and Pharmacology Antoni van Leeuwenhoek Netherlands Cancer Institute Amsterdam The Netherlands

GROW School for Oncology and Developmental Biology Maastricht University Maastricht The Netherlands

Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands

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$a Janssen, Julie M $u Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/Netherlands Cancer Institute, Amsterdam, The Netherlands

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$a 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) / $c JM. Janssen, K. Van Calsteren, TPC. Dorlo, MJ. Halaska, R. Fruscio, P. Ottevanger, CP. Schröder, I. Boere, PO. Witteveen, RC. Painter, R. Bekkers, V. Drochytek, JH. Beijnen, ADR. Huitema, FCH. Amant

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$a 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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$a Van Calsteren, Kristel $u Department of Development and Regeneration, Obstetrics and Gynaecology, KU Leuven, Leuven, Belgium

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$a Dorlo, Thomas P C $u Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/Netherlands Cancer Institute, Amsterdam, The Netherlands

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$a Halaska, Michael J $u Department of Obstetrics and Gynaecology, 3rd Medical Faculty, University Hospital Kralovske Vinohrady, Charles University, Prague, Czech Republic

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$a Fruscio, Robert $u Department of Medicine and Surgery, Clinic of Obstetrics and Gynecology, San Gerardo Hospital, University of Milan-Bicocca, Monza, Italy

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$a Ottevanger, Petronella $u Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands

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$a Schröder, Carolien P $u Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands

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$a Boere, Ingrid $u Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

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$a Drochytek, Vit $u Department of Obstetrics and Gynaecology, 3rd Medical Faculty, University Hospital Kralovske Vinohrady, Charles University, Prague, Czech Republic

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$a Beijnen, Jos H $u Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/Netherlands Cancer Institute, Amsterdam, The Netherlands $u Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

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$a Huitema, Alwin D R $u Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/Netherlands Cancer Institute, Amsterdam, The Netherlands $u Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

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$a Amant, Frederic C H $u Department of Oncology, Catholic University of Leuven, Leuven, Belgium. f.amant@nki.nl $u Antoni van Leeuwenhoek/Netherlands Cancer Institute and Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands. f.amant@nki.nl

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