EFFECTS OF CYTOKINES ON ANTIVIRAL PHARMACOKINETICS - AN ALTERNATIVE APPROACH TO ASSESSMENT OF DRUG-INTERACTIONS USING BIOEQUIVALENCE GUIDELINES

The effects of cytokines on the pharmacokinetics of nucleoside analogs were evaluated in two separate studies using zidovudine in combinatio n with interleukin-2 and didanosine in combination with alpha interfer on. In each study, drug interactions were evaluated by using both a st andard method (Student's t test) and bioequivalence testing. Serial bl ood samples were collected from human immunodeficiency virus-infected patients prior to and during cytokine therapy for determination of nuc leoside analog concentrations. Concentrations were fit separately to a two-compartment model by using the iterative two-stage approach to po pulation analysis. No alterations in area under the curve or oral clea rance were observed for either drug during combination therapy. In gen eral, there was good agreement between statistical methods for determi ning if antiviral pharmacokinetic parameters were altered by concomita nt cytokine therapy. However, large individual changes in the maximum concentration of zidovudine in serum were detected by bioequivalence t esting but no difference was found by Student's t test. For didanosine , significant but clinically irrelevant decreases determined by standa rd hypothesis testing were seen for both the volume of the central com partment (1.91 to 1.86 liters) and the absorption rate constant (0.79 to 0.73 h(-1)) in the presence of alpha interferon. No interaction was noted for these parameters by using bioequivalence guidelines. Bioequ ivalence testing may provide an alternative approach to assessment of drug interactions. Interleukin-2 and alpha interferon do not alter the pharmacokinetics of zidovudine and didanosine, respectively.