Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs.
In clinical development stages, an a priori assessment of the sensitivity of the pharmacokinetic behavior with respect to physiological and anthropometric properties of human (sub-) populations is desirable. A physiology-based pharmacokinetic (PBPK) population model was developed that makes use of known distributions of physiological and anthropometric properties obtained from the literature for realistic populations. As input parameters, the simulation model requires race, gender, age, and two parameters out of body weight, height and body mass index. From this data, the parameters relevant for PBPK modeling such as organ volumes and blood flows are determined for each virtual individual. The resulting parameters were compared to those derived using a previously published model (P(3)M). Mean organ weights and blood flows were highly correlated between the two models, despite the different methods used to generate these parameters. The inter-individual variability differed greatly especially for organs with a log-normal weight distribution (such as fat and spleen). Two exemplary population pharmacokinetic simulations using ciprofloxacin and paclitaxel as model drugs showed good correlation to observed variability. A sensitivity analysis demonstrated that the physiological differences in the virtual individuals and intrinsic clearance variability were equally influential to the pharmacokinetic variability but were not additive. In conclusion, the new population model is well suited to assess the influence of individual physiological variability on the pharmacokinetics of drugs. It is expected that this new tool can be beneficially applied in the planning of clinical studies.
Willmann
Stefan
S
Bayer Technology Services GmbH, Process Technology/Systems Biology, Building E41, D-51368 Leverkusen, Germany. Stefan.Willmann@Bayertechnology.com
Höhn
Karsten
K
Edginton
Andrea
A
Sevestre
Michael
M
Solodenko
Juri
J
Weiss
Wolfgang
W
Lippert
Jörg
J
Schmitt
Walter
W
D000328:Adult; D000367:Age Factors; D000465:Algorithms; D001827:Body Height / Q000502:physiology*; D015992:Body Mass Index; D001835:Body Weight / Q000502:physiology*; D002939:Ciprofloxacin / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D011159:Population Surveillance; D044469:Racial Groups; D012016:Reference Values; D012039:Regional Blood Flow / Q000502:physiology*; D015203:Reproducibility of Results; D012737:Sex Factors; D014584:User-Computer Interface
D002939:Ciprofloxacin; D017239:Paclitaxel