Nguyen T. X. Q.(1), Munafo A. (1), Goggin T. (1)
(1) Serono International S.A, Geneva, Switzerland
Background: Current evidence suggests that endogenous leukaemia inhibitory factor (LIF) – a heavily glycosylated cytokine plays a physiological role in embryo implantation (1,2). Clinical trials with recombinant human leukaemia inhibitory factor (r-hLIF – obtained in E. coli and consequently non glycosylated) are in progress to assess its potential therapeutic role in overcoming embryo implantation failure following IVF (In Vitro Fertilisation) and ET.
Purpose: The purpose of this analysis was to describe the pharmacokinetics of recombinant-hLIF (Emfilermin; AMRAD Corp. Ltd, Australia) in healthy postmenopausal women and in women with recurrent implantation failure (RIF) who undergo IVF and ET.
Methods: Data from the following studies were combined.
Study 1 : was a double-blind, randomised, placebo-controlled, phase I study in twelve healthy oestrogenised postmenopausal women (mean age: 57 ± 5 years). Subjects received 150 µg of Emfilermin or placebo SC twice daily during 7 days. Frequent pharmacokinetic sampling was performed on day 1 and 7.
Study 2 : was a double-blind, randomised, placebo-controlled, proof of concept study in sixty-six young women with RIF justifying IVF and ET (mean age: 33 ± 2 years). Patients received 150 µg of Emfilermin or placebo SC just before ET and twice daily for 7 days. Pharmacokinetic sampling was sparse and was done on Days 1, 4 and 7.
Non-compartmental analysis on serum LIF concentrations was performed using WinNonLin version 4.0. Population pharmacokinetic analysis was performed using NONMEM version V.
Results: Non-compartmental analysis of data of Study 1 showed an apparent terminal half-life at 2.5 h (median value), which was similar on day 1 and day 7. An accumulation ratio of 1.3-1.5 was observed in 4 out of 10 subjects, unexplained by the observed half-life. The reason for this could not be determined.
The subsequent population pharmacokinetic analysis was performed on (assumed) steady-state data only (day 4 and day 7). A one-compartment
disposition model with zero order input was used. The duration of the absorption was 1.1 h. Inter-subject variability on this parameter was negligible. The apparent volume of distribution was 184 L (with a CV of 28%)and devoid of any significant covariate effects. The observed CL/F on Study Day 7 was 31% higher compared to the Study Day 4 (Study Day modelled as a covariate). In addition the systemic clearance in younger women with RIF was reduced by 40% compared to that in older healthy women (which was 61.3 L/h with a CV of 11%). CL/F was also found to be roughly proportional to body weight, with a 2?fold increase in body weight resulting in a 1.9-fold increase in CL/F.
The geometric mean post-hoc estimates of apparent clearance and volume of distribution and their variability were consistent with the population estimates. In healthy subjects, results were fully consistent with those obtained using non-compartmental methods. The residual variability on r-hLIF serum levels was quite low (CV = 17%).
Conclusion: Recombinant –hLIF pharmacokinetics are quite complex. The initial assumption of steady-state is not supported by the results of this analysis, which suggests possible time dependence in the apparent clearance of r-hLIF,higher on Day 7 compared to Day 4. All available pharmacokinetic data will now be combined and analyzed to further characterize this possible phenomenon. The clinical impact of this non-stationarity is however mitigated by the fact that the observation period in this experiment corresponds to the intended duration of treatment (7 days)
in this indication.
References:
1- Laird, S.M., Tuckerman, E.M., Dalton, C.F., Dunphy, B.C., Li, T.C. and Zhang, X. (1997) The production of human leukemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Human Reproduction 12, 569-574.
2- Hambartsoumian, E. (1998) Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. American Journal of Reproductive Immunology 39, 137-143.
Reference: PAGE 12 (2003) Abstr 384 [www.page-meeting.org/?abstract=384]
Poster: poster