Daniel Moj (1), André Schäftlein (1), Nina Hanke (1), Wiebke Braun (2), Manfred James Müller (2), Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany, (2) Institute of Human Nutrition and Food Science, Christian-Albrechts University, Kiel, Germany
Objectives: The body composition of the human population is constantly changing and recent changes were taken into account by the novel “Kiel reference man”. We investigated the differences between the “old” ICRP and the “new” Kiel reference man on pharmacokinetic (PK) parameters determined in PBPK simulations.
Methods: The Kiel reference man is based on a healthy Caucasian population (n=208, 105 males, 103 females) aged from 18 to 78 years with a BMI from 16.8-35.0 kg/m2. In addition to age, height and weight, the masses of brain, fat, heart, kidney, liver, muscle and spleen have been measured. The Kiel reference man has been implemented in PK-Sim 5.3.2 and used for simulation of concentration-time profiles after single oral doses of clarithromycin, midazolam, paracetamol and theophylline. The AUC, Cmax and half-life of the simulated concentration-time profiles were compared to simulations using the ICRP reference man.
Results: The recently established Kiel reference man is taller, heavier and has a higher BMI value than the ICRP reference man, but shows e.g. a smaller liver size. PBPK simulation and analysis revealed that the changes in biometry have significant impact on descriptive pharmacokinetic parameters of clarithromycin, midazolam, paracetamol and theophylline. The AUC0-24 of the investigated drugs increased by approximately 30% in the Kiel reference population compared to the ICRP population. Cmax and half-life increased by 7% and 20% respectively, except for midazolam where the half-life declined by 4%.
Conclusions: The Kiel reference man has been established and successfully used for PBPK simulations. The taller and heavier Kiel reference man shows a significant increase in AUC0-24, Cmax and half-life of various compounds. This analysis demonstrates that an update of the ICRP reference man, which is intensively used in PBPK modeling, is necessary.
References:
[1] ICRP, 2002. Basic Anatomical and Physiological Data for Use in Radiological Protection Reference Values. ICRP Publication 89. Ann. ICRP (2002) 32(3-4).
[2] Later W, Bosy-Westphal A, Kossel E, Glüer CC, Heller M, Müller MJ. Is the 1975 Reference Man still a suitable reference? Eur J Clin Nutr (2010) 64(10): 1035-42.
Reference: PAGE 24 () Abstr 3371 [www.page-meeting.org/?abstract=3371]
Poster: Drug/Disease modeling - Absorption & PBPK