Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
POPULATION PHARMACOKINETICS AND EXPOSURE-RESPONSE OF ALBINTERFERON ALFA-2B
M. Riggs1*, T. Bergsma1, J. Rogers1, M. Gastonguay1, G. Subramanian2, C. Chen2, M. Devalaraja2, A. Corey2
1Metrum Research Group LLC, Tariffville, CT, 2Human Genome Sciences, Inc., Rockville, MD, USA. *email@example.com
Background and aims: Albinterferon alfa-2b (albIFN) is a long-acting interferon for the treatment of chronic hepatitis C. Population pharmacokinetics (PK) for albIFN was determined, and efficacy/safety exposure-response relationships were assessed.
Methods: PK and exposure-response were evaluated from five phase 2 and 3 studies in which subcutaneous albIFN doses (900-1800 µg q2wk or q4wk) were administered for 24 (genotype 2/3) or 48 (genotype 1) weeks. Sustained virologic response (SVR) exposure-response was modeled using logistic regression. Incidence of adverse events (AE) was tabulated vs exposure quartiles.
Results: PK parameter estimates included a first-order absorption constant (0.0148 h-1), apparent clearance (38.9 mL/h), and apparent volume of distribution (11.6 L), equating to an elimination half-life of ~200 h; interindividual variances (CV%) were 21%, 34%, and 24%, respectively. Residual variance estimates were 1.51 ng/mL (standard deviation) and 27% (CV%). Body weight was the only explanatory covariate; exposures would be ~30% greater and lower for 50- and 125-kg patients, respectively, relative to a 75-kg patient. PK did not differ for subgroups based on fibrosis score, steatosis, opioid dependence/drug use, or insulin resistance. Steady state would be attained after the 3rd q2wk dose, with 40% accumulation. Important predictors of SVR included baseline viral load and fibrosis score (both genotypes), as well as black race (genotype 1). There was no relationship between average serum albIFN concentration (Cavg) and SVR. Most AEs had similar incidence rates across exposure quartiles. For some AEs with higher incidence in the upper exposure quartile, exposure-response was not evident across the lower quartiles. Reductions in hemoglobin and neutrophil counts were higher in the upper exposure quartile, with evidence of a dose-response relationship. Median Cavg and Cmax for 900 µg q2wk were within the second quartile, with 12% and 6% of the individual Cavg and Cmax, respectively, within the fourth quartile.
Conclusions: The PK of albIFN was described by a one-compartment model with first-order absorption. The most meaningful explanatory covariate for exposure differences was weight. SVR was minimally related to exposure. Treatment with albIFN 900 µg q2wk targeted the lower exposure quartiles in which no exposure-response was observed.