Combination antiretroviral therapy (cART) component ritonavir significantly alters docetaxel exposure

Michelle Rudek-Renaut, Cathy Y. Chang, Kenneth Steadman, Michael D. Johnson, Naveen Desai, John F. Deeken

Research output: Contribution to journalArticle

Abstract

Purpose: Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations. Methods: Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression. Results: Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure. Conclusions: Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.

Original languageEnglish (US)
Pages (from-to)729-736
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume73
Issue number4
DOIs
StatePublished - 2014

Fingerprint

docetaxel
Ritonavir
efavirenz
Gene expression
Drug interactions
Ketoconazole
Therapeutics
Drug Interactions
Gene Expression
Liver
Antineoplastic Agents
Dexamethasone
Area Under Curve
Neoplasms
Tissue
Cytochrome P-450 CYP3A
Pharmacokinetics
Chemotherapy
Complementary Therapies

Keywords

  • Antiretrovirals
  • Docetaxel
  • Drug interaction
  • HIV
  • Pharmacokinetics

ASJC Scopus subject areas

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

Cite this

Combination antiretroviral therapy (cART) component ritonavir significantly alters docetaxel exposure. / Rudek-Renaut, Michelle; Chang, Cathy Y.; Steadman, Kenneth; Johnson, Michael D.; Desai, Naveen; Deeken, John F.

In: Cancer Chemotherapy and Pharmacology, Vol. 73, No. 4, 2014, p. 729-736.

Research output: Contribution to journalArticle

Rudek-Renaut, Michelle ; Chang, Cathy Y. ; Steadman, Kenneth ; Johnson, Michael D. ; Desai, Naveen ; Deeken, John F. / Combination antiretroviral therapy (cART) component ritonavir significantly alters docetaxel exposure. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 73, No. 4. pp. 729-736.
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abstract = "Purpose: Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations. Methods: Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression. Results: Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure. Conclusions: Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.",
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AU - Rudek-Renaut, Michelle

AU - Chang, Cathy Y.

AU - Steadman, Kenneth

AU - Johnson, Michael D.

AU - Desai, Naveen

AU - Deeken, John F.

PY - 2014

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N2 - Purpose: Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations. Methods: Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression. Results: Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure. Conclusions: Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.

AB - Purpose: Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations. Methods: Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression. Results: Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure. Conclusions: Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.

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