Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma

Abstract

We demonstrated that highly active antiretroviral therapy (HAART) increases the toxic effect of cyclophosphamide, vincristine, doxorubicin (DOX) and prednisone (CHOP) in HIV-patients with non-Hodgkin's lymphoma (NHL). To ascertain the cause of increased toxicity, we investigated the pharmacokinetics of DOX in HIV-patients with NHL treated with CHOP with and without HAART. Complete pharmacokinetics and pharmacodynamic analysis was determined in 19 patients during 38 cycles of chemotherapy: 19 cycles with CHOP and 19 CHOP + HAART in a crossover-designed study. HAART included protease inhibitors indinavir (IDV) in nine patients, saquinavir (SQV) hard gel in six patients and nelfinavir (NFV) in four patients. No significant effects of HAART on pharmacokinetics parameters of DOX were observed. Similarly, no differential effect on DOX pharmacokinetics among IDV, SQV, and NFV was evidenced. Significant associations (P=0.012) were observed between DOX AUC0-infinity (area under the concentration curve) and G3-G4 WHO haematologic toxicity, in patients treated with CHOP alone, but not in those treated with CHOP + HAART (P = not significant). We demonstrated that HAART therapy has no significant effect on DOX pharmacokinetics. DOX AUC appears to be a predictor of toxicity only in patients treated with CHOP alone. Other factors beside DOX plasma levels are detrimental for toxicity after CHOP + HAART. Therefore, pharmacodynamic interactions between HAART and DOX should be considered.