Sophie Glatt (1), Quyen T. X. Nguyen (2); Arnaud Ythier (2) & Alain Munafo (2)
(1) EMF Consulting France Aix en Provence, France; (2)Serono International SA, Geneva, Switzerland.
AIMS: To characterise the pharmacokinetics of Onercept (recombinant human Tumor Necrosis Factor Binding Protein), r-hTBP-1, a soluble glycoprotein corresponding to the extracellular portion of the human TNF receptor type I (p55) using population pharmacokinetics and deconvolution techniques. METHODS: Rich data were available from healthy subjects who received Onercept. Three randomised studies were conducted in healthy subjects (12 subjects in each study) and aimed at safety, pharmacokinetics and pharmacodynamics in different settings. In the placebo-controlled study 1, subjects received increasing intravenous doses of Onercept at 5, 15, 50, and 150 mg. In study 2, absorption and bioavailability of Onercept were investigated in a Latin square, crossover design after single intravenous (IV), subcutaneous (SC) and intramuscular (IM) doses of 50 mg of Onercept. In both studies, the washout period between injections was 14 days. Study 3 investigated TBP-1 steady-state pharmacokinetics following 50 mg Onercept injected SC 6 times 48 hours apart. Serum concentrations of TBP-1 were measured by immunoassay using the Quantikineä Human’s TNFRI ELISA kit manufactured by R&D Systems. The assay was validated with a detection limit of 3 pg/mL. Concentration-time pooled data were analysed by a population approach using NONMEM. RESULTS: The disposition could be described using a two-compartment model with two absorption processes: a zero order followed by a first order. The bioavailability after both extravascular routes was similar (ca.80%). The estimated value of first order absorption rate constant (ka) was 0.04 h-1, which corresponded to the value determined by deconvolution analysis. The population estimates of the clearance and the volume of distribution were 3.6 L/h and 5.2 L. The apparent terminal half-life was estimated about 23 h. CONCLUSION: The proposed model well characterizes the overall pharmacokinetics profile of TBP-1 after IM, SC and IV administration of Onercept. Slow absorption following SC and IM dosing was observed, and suggests flip-flop pharmacokinetics, i.e. absorption rate controlling the terminal phase. The final estimate of Vc is close to the plasma volume. The population analysis indicates that the variability in CL is moderate.
Reference: PAGE 10 () Abstr 194 [www.page-meeting.org/?abstract=194]
Poster: poster