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

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 (20mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10mg/kg p.o. ×4d), efavirenz (25mg/kg p.o. ×4d), ketoconazole (50mg/kg p.o.), or ritonavir (12.5mg/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.

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

“…The reason for the difference with ritonavir may be due to the assumption that the fraction of dose escaping gut wall metabolism was 100 % [19], whereas both the hepatocyte data and the SimCYP™ data assumed that the bioavailability was 100 % [19, 31]. The dose of ritonavir was previously shown not to induce or inhibit Cyp3a11 or Abcb1a in mouse liver, which would be consistent with the low-dose regimens commonly utilized in cART [27]. …”

“…Dexamethasone was administered at a dose of 10 mg/kg, while efavirenz was administered at a dose of 25 mg/kg. Ketoconazole and ritonavir were administered by oral gavage at a dose of 50 mg/kg and 12.5 mg/kg, respectively, at approximately 1 h prior to erlotinib administration to ensure adequate CYP3A4 inhibition [27]. Blood samples were collected by cardiac puncture from three mice per time point into syringes coated with heparin as a function of time following erlotinib administration and centrifuged immediately to obtain plasma.…”

Drug Interactions in the Treatment of Malignancy in HIV-Infected Patients

“…For example, erlotinib exposure in human hepatocytes increased 4.2-fold when co-administered with ritonavir and decreased 3-fold with efavirenz [23]. On the other hand, docetaxel exposure in mice increased 6.9-fold with ritonavir co-administration, but was unaffected by efavirenz [29].…”

Diagnósticos de enfermagem e seus componentes em pacientes com a síndrome da imunodeficiência adquirida

“…(12) It is noteworthy that the presentation of fatigue in these patients is probably a result of these cellular changes, particularly the decrease in red blood cells, which contributes to the condition of anemia and dyspnea and weakness symptoms felt by the individual. (13)(14)(15)(16)(17) Based on the patients with AIDS interviewed, the study showed that 12.5% (n=66) presented malnutrition, justified by diarrhea, loss of appetite, fever, and malabsorption of nutrients. It is also important to point out that the HIV has mechanisms that affect specifically the nutritional status of individuals by increasing the energy demand and interfering in the absorption and metabolism of the nutrients.…”