Population Pharmacokinetics of onercept in healthy subjects.
Sophie Glatt, Mauro Buraglio, Eliane Fuseau
Emf-consulting and Serono
Purpose: To develop a population pharmacokinetic (POPPK) model and to determine the covariates affecting the pharmacokinetics of onercept (recombinant human tumour necrosis factor binding protein-1) in healthy subjects.
Methods: Onercept PK data were obtained from 36 healthy male and female subjects (3 phase I studies). In study 1, 12 subjects received increasing single intravenous doses of 5, 15, 50, and 150 mg onercept. In study 2, 12 subjects received single intravenous (IV), subcutaneous (SC) and intramuscular (IM) doses of 50 mg onercept. Study 3 investigated the pharmacokinetics of onercept following repeat SC administration of 6 doses of 50 mg every 48h in 12 subjects.
NONMEM was used to build a base model while the final model was determined after the covariates selection.
Results: The disposition of onercept could be described using a two- compartment model with two absorption processes: a first order followed by a zero order. Slow absorption following SC and IM dosing was observed and suggested that the absorption was the rate limiting process. The population mean (CV%) values for clearance (CL), absorption rate constant (KA), duration of the zero order process (D) and bioavailability (F) were 3.86 L/h (4.4%), 0.0427 h-1 (4.1%), 46.5 h (0.4%) and 0.812 (5.7%), respectively. The population analysis indicates that the variability in CL is moderate. The final estimate of the volume of distribution of the central compartment (Vc) was close to the plasma volume.
The only significant covariate was found to be the sex, which affected the absorption lag time (on the duration of the zero order process) and suggested 25% longer values in male subjects.
Conclusion: The proposed model characterizes well the overall pharmacokinetics profile of onercept after IM, SC and IV administration. The pharmacokinetics of onercept showed limited intersubject variability and appeared not to be affected by the covariates tested, which included demographic parameters and laboratory values. The apparently longer absorption lag time observed in male subjects cannot be explained physiologically, is unlikely to have any clinical relevance and is more likely an artifact of the analysis.