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


CONCLUSIONS
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.
Toffoli
G
G
Experimental and Clinical Pharamcology Unit, National Cancer Institute, Aviano, Italy. gtoffoli@cro.it
Corona
G
G
Cattarossi
G
G
Boiocchi
M
M
Di Gennaro
G
G
Tirelli
U
U
Vaccher
E
E
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D018592:Cross-Over Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000188:drug therapy* / Q000821:virology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage; D014750:Vincristine / Q000008:administration & dosage
D000903:Antibiotics, Antineoplastic; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone