Population pharmacokinetics and exposure-response of albinterferon alfa-2b

Matthew M. Riggs, Timothy T. Bergsma, James A. Rogers, Marc R. Gastonguay, G. Mani Subramanian, Cecil Chen, Matt Devalaraja, Alfred E. Corey, Haiying Sun, Jing Yu, Daniel S. Stein

Research output: Contribution to journalArticle

Abstract

Albinterferon alfa-2b (albIFN) has been studied for treatment of chronic hepatitis C virus (HCV). A population pharmacokinetics model was developed using nonlinear mixed-effects modeling. Efficacy/safety exposure-response relationships were assessed for subcutaneous albIFN doses (900-1800 μg once every 2 or 4 weeks) administered for either 24 weeks (HCV genotypes 2/3) or 48 weeks (genotype 1), plus daily oral ribavirin. Sustained virologic response (SVR) exposure-response was modeled using logistic regression. Adverse event incidence was tabulated versus exposure quartiles. First-order absorption rate constant (0.0148 hü'1), apparent clearance (38.9 mL/h), and apparent volume of distribution (11.6 L) had interindividual variances (coefficient of variation) of 21%, 34%, and 24%, respectively. Residual variance estimates were 27% (coefficient of variation) and 1.51 ng/mL (standard deviation). For the only explanatory covariate-body weight-exposure decreased as weight increased. Important SVR predictors included baseline HCV RNA, fibrosis score, and black race (genotype 1); SVR was minimally related to exposure. Most adverse events had similar incidence rates across exposure quartiles. Some adverse events had a higher incidence in the upper exposure quartile without evidence of exposure-response across the lower quartiles. Given the lack of consistent efficacy/safety exposure-response relationships, further investigation is necessary to optimize albIFN dosing.

Original languageEnglish (US)
Pages (from-to)475-486
Number of pages12
JournalJournal of clinical pharmacology
Volume52
Issue number4
DOIs
StatePublished - Apr 1 2012

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Keywords

  • albIFN
  • albinterferon alfa-2b
  • chronic hepatitis C virus
  • exposure-response
  • population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Riggs, M. M., Bergsma, T. T., Rogers, J. A., Gastonguay, M. R., Subramanian, G. M., Chen, C., Devalaraja, M., Corey, A. E., Sun, H., Yu, J., & Stein, D. S. (2012). Population pharmacokinetics and exposure-response of albinterferon alfa-2b. Journal of clinical pharmacology, 52(4), 475-486. https://doi.org/10.1177/0091270011399576