Pharmacokinetics of dacarbazine (DTIC) in pregnancy

Ira Kantrowitz-Gordon, Karen Hays, Olumide Kayode, Aditya R. Kumar, Henry G. Kaplan, Joel M Reid, Stephanie L. Safgren, Matthew M. Ames, Thomas R. Easterling, Mary F. Hebert

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalCancer Chemotherapy and Pharmacology
DOIs
StateAccepted/In press - Jan 5 2018

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Keywords

  • Dacarbazine
  • Metabolites
  • Pharmacokinetics
  • Pregnancy

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Kantrowitz-Gordon, I., Hays, K., Kayode, O., Kumar, A. R., Kaplan, H. G., Reid, J. M., Safgren, S. L., Ames, M. M., Easterling, T. R., & Hebert, M. F. (Accepted/In press). Pharmacokinetics of dacarbazine (DTIC) in pregnancy. Cancer Chemotherapy and Pharmacology, 1-6. https://doi.org/10.1007/s00280-017-3511-6