Population Pharmacokinetics of Onercept in Healthy Subjects

Abstract

To develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of onercept (recombinant human tumour necrosis factor [TNF] receptor-1) in healthy subjects. Onercept pharmacokinetics data were obtained from 48 healthy male and female subjects (four phase I studies). In study A, 12 subjects received increasing single intravenous doses of onercept either 5 and 50mg or 15 and 150mg. In study B, 12 subjects received single intravenous, subcutaneous and intramuscular doses of onercept 50mg. Study C investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 50mg every 48 hours in 12 subjects. Study D investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 100mg and 150mg over 2 weeks in 12 subjects. Nonlinear mixed-effects modelling software NONMEM was used to build a base model, while the final model was determined after selection of the covariates. The disposition of onercept was described using a two-compartment model with two absorption processes (a first-order followed by a zero-order) and included a constant baseline, accounting for the endogenous TNF receptor-1 levels. Slow absorption of onercept following subcutaneous and intramuscular administration was observed and suggested that absorption was the rate-limiting process. The population mean (coefficient of variation %) values for clearance, absorption rate constant, volume of distribution of the central compartment, bioavailability of onercept and baseline TNF receptor-1 levels were 4.03 L/h (13.3%), 0.04 h-1 (29.1%), 4.42L (6.2%), 0.90 (23.8%) and 1.68 microg/L (20.4%), respectively. The only significant covariates were found to be dose (which affected clearance), and day (which affected absorption rate constant); however, the effects were small (10-15%) and are unlikely to be of any clinical relevance. The proposed population pharmacokinetic model characterises well the overall pharmacokinetic profile of onercept after intramuscular, subcutaneous and intravenous administration in healthy subjects. The pharmacokinetics of onercept showed modest intersubject variability.