© 2004 European Society for Medical Oncology
Original Article |
Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma
1 Experimental and Clinical Pharamcology Unit; 2 Experimental Oncology 1; 3 Division of Medical Oncology A, National Cancer Institute, Aviano, Italy
* Correspondence to: Dr G. Toffoli, Experimental and Clinical Pharmacology, Oncologia Sperimentale I, C.R.O.-National Cancer Institute, via Pedemontana Occidentale, 12, Aviano (PN), Italy. Tel: +39-0434-659612; Fax +39-0434-659659; Email: gtoffoli{at}cro.it
Background: 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.
Methods: 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.
Results: 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–
(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).
Conclusion: 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.
Key words: CHOP, doxorubicin, HAART, HIV, interactions, pharmacokinetics
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