TY - JOUR
T1 - 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)
AU - Janssen, J.M.
AU - Van Calsteren, K.
AU - Dorlo, T.P.C.
AU - Halaska, M.J.
AU - Fruscio, R.
AU - Ottevanger, P.
AU - Schroder, C.P.
AU - Boere, I.
AU - Witteveen, P.O.
AU - Painter, R.C.
AU - Bekkers, R.
AU - Drochytek, V.
AU - Beijnen, J.H.
AU - Huitema, A.D.R.
AU - Amant, F.C.H.
N1 - Funding Information:
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.
Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2021, Springer Nature Switzerland AG.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - cyclophosphamide
KW - missing data
KW - model
KW - parameters
KW - ritonavir
KW - CYCLOPHOSPHAMIDE
KW - MISSING DATA
KW - MODEL
KW - PARAMETERS
KW - RITONAVIR
U2 - 10.1007/s40262-020-00961-4
DO - 10.1007/s40262-020-00961-4
M3 - Article
C2 - 33506375
SN - 0312-5963
VL - 60
SP - 775
EP - 784
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 6
ER -