Combination antiretroviral therapy (cART) component ritonavir significantly alters docetaxel exposure.
OBJECTIVE
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.
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Room 1M52, Baltimore, MD, 21231-1000, USA, mrudek2@jhmi.edu.
Michelle A
MA
Rudek
Cathy Y
CY
Chang
Kenneth
K
Steadman
Michael D
MD
Johnson
Naveen
N
Desai
John F
JF
Deeken
D000480:Alkynes; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D000077143:Docetaxel; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology*; D043823:Taxoids / Q000493:pharmacokinetics* / Q000494:pharmacology
D000480:Alkynes; D000970:Antineoplastic Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D019438:Ritonavir; D007654:Ketoconazole