Pharmacokinetic/pharmacodynamic modelling of GnRH antagonist degarelix: a comparison of the non-linear mixed-effects programs NONMEM and NLME.
In this paper, the two non-linear mixed-effects programs NONMEM and NLME were compared for their use in population pharmacokinetic/pharmacodynamic (PK/PD) modelling. We have described the first-order conditional estimation (FOCE) method as implemented in NONMEM and the alternating algorithm in NLME proposed by Lindstrom and Bates. The two programs were tested using clinical PK/PD data of a new gonadotropin-releasing hormone (GnRH) antagonist degarelix currently being developed for prostate cancer treatment. The pharmacokinetics of intravenous administered degarelix was analysed using a three compartment model while the pharmacodynamics was analysed using a turnover model with a pool compartment. The results indicated that the two algorithms produce consistent parameter estimates. The bias and precision of the two algorithms were further investigated using a parametric bootstrap procedure which showed that NONMEM produced more accurate results than NLME together with the nlmeODE package for this specific study.
Tornøe
Christoffer W
CW
Experimental Medicine, Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK 2300, Copenhagen S, Denmark. christoffer.tornoe@ferring.com
Agersø
Henrik
H
Nielsen
Henrik A
HA
Madsen
Henrik
H
Jonsson
E Niclas
EN
D000465:Algorithms; D003198:Computer Simulation; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008954:Models, Biological; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology*
D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone