title: Population pharmacokinetics and exposure-response of albinterferon alfa-2b.
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 h(-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.
authors.affiliation: Metrum Research Group LLC, Tariffville, CT, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Riggs
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Bergsma
authors.forename: James A
authors.initials: JA
authors.lastname: Rogers
authors.forename: Marc R
authors.initials: MR
authors.lastname: Gastonguay
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.forename: Cecil
authors.initials: C
authors.lastname: Chen
authors.forename: Matt
authors.initials: M
authors.lastname: Devalaraja
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Corey
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Stein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000418:Albumins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000418:Albumins; D000998:Antiviral Agents; D016898:Interferon-alpha; D012254:Ribavirin; C531108:albinterferon alfa-2b