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 combination with interleukin-2 and didanosine in combination with alpha interferon. In each study, drug interactions were evaluated by using both a standard method (Student's t test) and bioequivalence testing. Serial blood samples were collected from human immunodeficiency virus-infected patients prior to and during cytokine therapy for determination of nucleoside analog concentrations. Concentrations were fit separately to a two-compartment model by using the iterative two-stage approach to population analysis. No alterations in area under the curve or oral clearance were observed for either drug during combination therapy. In general, there was good agreement between statistical methods for determining if antiviral pharmacokinetic parameters were altered by concomitant cytokine therapy. However, large individual changes in the maximum concentration of zidovudine in serum were detected by bioequivalence testing but no difference was found by Student's t test. For didanosine, significant but clinically irrelevant decreases determined by standard hypothesis testing were seen for both the volume of the central compartment (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. Bioequivalence 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.
Piscitelli
S C
SC
Department of Pharmacy, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. spisc@nih.gov
Amatea
M A
MA
Vogel
S
S
Bechtel
C
C
Metcalf
J A
JA
Kovacs
J A
JA
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000592:standards*; D016207:Cytokines / Q000494:pharmacology* / Q000592:standards*; D016049:Didanosine / Q000493:pharmacokinetics / Q000592:standards; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000592:standards; D007376:Interleukin-2 / Q000494:pharmacology / Q000592:standards; D008297:Male; D012015:Reference Standards; D012016:Reference Values; D013810:Therapeutic Equivalency; D015215:Zidovudine / Q000493:pharmacokinetics / Q000592:standards
D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D007376:Interleukin-2; D015215:Zidovudine; D016049:Didanosine