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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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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Dacarbazine
Pharmacokinetics
5-(3-methyl-1-triazeno)imidazole-4-carboxamide
Aminoimidazole Carboxamide
Pregnancy
Postpartum Period
Metabolites
Hodgkin Disease
Area Under Curve
Cytochrome P-450 CYP1A2
Vinblastine
Bleomycin
Prodrugs
Metabolism
Doxorubicin
High Pressure Liquid Chromatography
5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide
Pharmaceutical Preparations
4-aminoimidazole

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., ... 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

Pharmacokinetics of dacarbazine (DTIC) in pregnancy. / Kantrowitz-Gordon, Ira; Hays, Karen; Kayode, Olumide; Kumar, Aditya R.; Kaplan, Henry G.; Reid, Joel M; Safgren, Stephanie L.; Ames, Matthew M.; Easterling, Thomas R.; Hebert, Mary F.

In: Cancer Chemotherapy and Pharmacology, 05.01.2018, p. 1-6.

Research output: Contribution to journalArticle

Kantrowitz-Gordon, I, Hays, K, Kayode, O, Kumar, AR, Kaplan, HG, Reid, JM, Safgren, SL, Ames, MM, Easterling, TR & Hebert, MF 2018, 'Pharmacokinetics of dacarbazine (DTIC) in pregnancy', Cancer Chemotherapy and Pharmacology, pp. 1-6. https://doi.org/10.1007/s00280-017-3511-6
Kantrowitz-Gordon, Ira ; Hays, Karen ; Kayode, Olumide ; Kumar, Aditya R. ; Kaplan, Henry G. ; Reid, Joel M ; Safgren, Stephanie L. ; Ames, Matthew M. ; Easterling, Thomas R. ; Hebert, Mary F. / Pharmacokinetics of dacarbazine (DTIC) in pregnancy. In: Cancer Chemotherapy and Pharmacology. 2018 ; pp. 1-6.
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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.",
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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.

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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.

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