Effects of cytokines on antiviral pharmacokinetics: an alternative approach to assessment of drug interactions using bioequivalence guidelines

Abstract

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.

Ribavirin and interferon alfa‐2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions

“…However because of the wide confidence intervals, more subtle pharmacokinetic interactions might not be detected in this study. These findings are consistent with a recent study which showed that IFN did not alter the AUC or C max of the nucleoside analog reverse transcriptase inhibitor didanosine [ 14]. These findings also suggest that the mechanism for the enhanced antiviral activity of combined IFN and ribavirin compared with either drug alone is not due to an alteration of the pharmacokinetics of one or both compounds as a result of a drug interaction.…”

Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping

“…The same equations also detected CYP3A induction with rifampin and Ginkgo biloba extract, as a lack of equivalence was observed. Midazolam CL ORAL utilizing a partial AUC 0-4 and/or AUC [1][2][3][4] can be used to assess real-time, in vivo CYP3A induction with rifampin and Ginkgo biloba extract.…”

“…Equivalence was concluded if the 90% CI of the LS-GMR was within 0.8-1.25. This statistical method is used to assess equivalence in drug-drug interaction studies and to evaluate bioequivalence for drugs utilizing a truncated AUC approach [3,31,32].…”

“…Pharmacokinetic parameters commonly used to estimate CYP3A activity include midazolam apparent oral clearance (CL ORAL ) and area under the concentration time curve (AUC) [2]. To determine if there is a significant pharmacokinetic difference between baseline and test conditions, equivalence testing is performed [3,4], with such differences assumed to reflect CYP3A inhibition or induction/ activation.…”

Limitations of S-Warfarin Truncated Area Under the Concentration-Time Curve to Predict Cytochrome P450 2c9 Activity

“…In brief, genomic DNA was isolated from whole blood using a QIAamp blood kit (Qiagen Inc., Valencia, CA). This statistical method is used to assess equivalence in drug-drug interaction studies and to evaluate bioequivalence for drugs utilizing a truncated AUC approach [19,20,30]. Wild-type-derived fragments were cut into 115+75 bp, while CYP2C9*2 fragments remained uncut.…”