BACKGROUND: It is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better @entity1 compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C(max)), area under the plasma concentration-time curve (AUC) and a suitable half-life (t(  )). The C(max) and t(  ) following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V(z)/F), each of which may be predicted and combined to estimate C(max) and t(  ). Allometric scaling is a widely used methodology in the pharmaceutical industry to predict @entity1 pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C(max), V(z)/F and t(  ) after oral drug administration in @entity1 . METHODS: Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C(max) following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as @entity11231 ( @entity11231 ), maximum life-span potential or brain weight (reverse rule of exponents, unbound C(max) approach); and (iii) an indirect approach using allometrically predicted CL/F and V(z)/F and absorption rate constant (k(a)). The k(a) was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in @entity1 (P(eff)), using a Caco-2 permeability assay. The V(z)/F was predicted using allometric scaling with or without @entity11231 correction. The t(  ) was estimated from the allometrically predicted parameters CL/F and V(z)/F. Predictions were deemed adequate when errors were within a 2-fold range. RESULTS: C(max) and t(  ) could be predicted within a 2-fold error range for 59% and 66% of the tested compounds, respectively, using allometrically predicted CL/F and V(z)/F. The best predictions for C(max) were obtained when k(a) values were calculated from the Caco-2 permeability assay. The V(z)/F was predicted within a 2-fold error range for 72% of compounds when @entity11231 correction was applied as the correction factor for scaling. CONCLUSIONS: We conclude that (i) C(max) and t(  ) are best predicted by indirect scaling approaches (using allometrically predicted CL/F and V(z)/F and accounting for k(a) derived from permeability assay); and (ii) the @entity11231 is an important correction factor for the prediction of V(z)/F by using allometric scaling. Furthermore, additional work is warranted to understand the mechanisms governing the processes underlying determination of C(max) so that the empirical approaches can be fine-tuned further.

Towards a better prediction of peak concentration, volume of distribution and half-life after oral drug administration in XXXX , using allometry.

@entity1 :: ('9606', 'Species') :: ['human', 'patient', 'man'] @entity11231 :: ('MESH:C563602', 'Disease') :: ['PPB', 'plasma protein binding']
@entity1 :: (9606,Species) :: ['man']
