Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel.
BACKGROUND
Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments.


METHODS
A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients.


RESULTS
The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21, respectively, with adequate precision [relative standard error (RSE) <37%]. For doxorubicin, no gestational effect could be estimated on clearance (CL). For epirubicin, docetaxel and paclitaxel, a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%).


CONCLUSIONS
Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy.
Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
J G C
JGC
van Hasselt
Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
K
K
van Calsteren
Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
L
L
Heyns
Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
S
S
Han
Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
M
M
Mhallem Gziri
Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmaceutical Sciences, Division of Clinical Pharmacology and Pharmacoepidemiology, Faculty of Science, Utrecht University, JE Utrecht, The Netherlands.
J H M
JHM
Schellens
Department of Pharmacy, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmaceutical Sciences, Division of Clinical Pharmacology and Pharmacoepidemiology, Faculty of Science, Utrecht University, JE Utrecht, The Netherlands.
J H
JH
Beijnen
Department of Pharmacy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
A D R
ADR
Huitema
Gynecologic Oncology University Hospitals Leuven; Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. Electronic address: frederic.amant@uzleuven.be.
F
F
Amant
D000328:Adult; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011247:Pregnancy; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D004317:Doxorubicin; D017239:Paclitaxel
anticancer drugs; chemotherapeutics; modeling; pharmacokinetics; pregnancy