TY - JOUR
T1 - Pharmacokinetics of dacarbazine (DTIC) in pregnancy
AU - Kantrowitz-Gordon, Ira
AU - Hays, Karen
AU - Kayode, Olumide
AU - Kumar, Aditya R.
AU - Kaplan, Henry G.
AU - Reid, Joel M.
AU - Safgren, Stephanie L.
AU - Ames, Matthew M.
AU - Easterling, Thomas R.
AU - Hebert, Mary F.
N1 - Funding Information:
Conflict of interest Dr. Hebert received a research grant from the Eu-nice Kennedy Shriver National Institute of Child Health (Grant Number U10HD047892) and the study was conducted in the University of Washington Clinical Research Unit which is supported by a grant from the National Institutes of Health, National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program (CTSA) (Grant Number UL1TR000423).
Funding Information:
Acknowledgements This work was supported in part by grant number U10HD047892 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and UL1TR000423 from the National Institutes of Health, National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program (CTSA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.
Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Purpose: The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1). Methods: Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin’s lymphoma. Drug concentrations were measured by HPLC. Results: In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin’s lymphoma. Conclusions: Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin’s lymphoma.
AB - Purpose: The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1). Methods: Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin’s lymphoma. Drug concentrations were measured by HPLC. Results: In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin’s lymphoma. Conclusions: Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin’s lymphoma.
KW - Dacarbazine
KW - Metabolites
KW - Pharmacokinetics
KW - Pregnancy
UR - http://www.scopus.com/inward/record.url?scp=85040064936&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040064936&partnerID=8YFLogxK
U2 - 10.1007/s00280-017-3511-6
DO - 10.1007/s00280-017-3511-6
M3 - Article
C2 - 29305638
AN - SCOPUS:85040064936
VL - 81
SP - 455
EP - 460
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 3
ER -