Utility of a single adjusting compartment: a novel methodology for whole body physiologically-based pharmacokinetic modelling.
BACKGROUND
There are various methods for predicting human pharmacokinetics. Among these, a whole body physiologically-based pharmacokinetic (WBPBPK) model is useful because it gives a mechanistic description. However, WBPBPK models cannot predict human pharmacokinetics with enough precision. This study was conducted to elucidate the primary reason for poor predictions by WBPBPK models, and to enable better predictions to be made without reliance on complex concepts.


METHODS
The primary reasons for poor predictions of human pharmacokinetics were investigated using a generic WBPBPK model that incorporated a single adjusting compartment (SAC), a virtual organ compartment with physiological parameters that can be adjusted arbitrarily. The blood flow rate, organ volume, and the steady state tissue-plasma partition coefficient of a SAC were calculated to fit simulated to observed pharmacokinetics in the rat. The adjusted SAC parameters were fixed and scaled up to the human using a newly developed equation. Using the scaled-up SAC parameters, human pharmacokinetics were simulated and each pharmacokinetic parameter was calculated. These simulated parameters were compared to the observed data. Simulations were performed to confirm the relationship between the precision of prediction and the number of tissue compartments, including a SAC.


RESULTS
Increasing the number of tissue compartments led to an improvement of the average-fold error (AFE) of total body clearances (CL tot) and half-lives (T 1/2) calculated from the simulated human blood concentrations of 14 drugs. The presence of a SAC also improved the AFE values of a ten-organ model from 6.74 to 1.56 in CL tot, and from 4.74 to 1.48 in T 1/2. Moreover, the within-2-fold errors were improved in all models; incorporating a SAC gave results from 0 to 79% in CL tot, and from 14 to 93% in T 1/2 of the ten-organ model.


CONCLUSIONS
By using a SAC in this study, we were able to show that poor prediction resulted mainly from such physiological factors as organ blood flow rate and organ volume, which were not satisfactorily accounted for in previous WBPBPK models. The SAC also improved precision in the prediction of human pharmacokinetics. This finding showed that the methodology of our study may be useful for functionally reinforcing a WBPBPK model.
Ando
Hirotaka
H
Discovery Research Laboratories, Kyorin Pharmaceutical Co, Ltd, Tochigi, Japan. hirotaka.andou@mb.kyorin-pharm.co.jp
Izawa
Shigeru
S
Hori
Wataru
W
Nakagawa
Ippei
I
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001693:Biological Transport, Active / Q000502:physiology; D001798:Blood Proteins / Q000493:pharmacokinetics; D001825:Body Fluid Compartments / Q000502:physiology*; D003198:Computer Simulation; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D051381:Rats; D014018:Tissue Distribution / Q000502:physiology
D001798:Blood Proteins; D004364:Pharmaceutical Preparations