Predicting oral clearance in humans: how close can we get with allometry?
BACKGROUND
Oral clearance (CL/F) is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. Throughout the pharmaceutical industry, many drugs are administered via the oral route; however, there are only a handful of published scaling studies for the prediction of oral pharmacokinetic parameters.


METHODS
We evaluated the predictive performances of four different allometric approaches -- simple allometry (SA), the rule of exponents, the unbound CL/F approach, and the unbound fraction corrected intercept method (FCIM) -- for the prediction of human CL/F and the oral area under the plasma concentration-time curve (AUC). Twenty-four compounds developed at Johnson and Johnson Pharmaceutical Research and Development, covering a wide range of physicochemical and pharmacokinetic properties, were selected. The CL/F was predicted using these approaches, and the oral AUC was then estimated using the predicted CL/F.


RESULTS
The results of this study indicated that the most successful predictions of CL/F and the oral AUC were obtained using the unbound CL/F approach in combination with the maximum lifespan potential or the brain weight as correction factors based on the rule of exponents. We also observed that the unbound CL/F approach gave better predictions when the exponent of SA was between 0.5 and 1.2. However, the FCIM seemed to be the method of choice when the exponent of SA was <0.50 or >1.2.


CONCLUSIONS
Overall, we were able to predict CL/F and the oral AUC within 2-fold of the observed value for 79% and 83% of the compounds, respectively, by selecting the allometric approaches based on the exponents of SA.
Sinha
Vikash K
VK
ADME-TOX Department, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium.
De Buck
Stefan S
SS
Fenu
Luca A
LA
Smit
Johan W
JW
Nijsen
Marjoleen
M
Gilissen
Ron A H J
RA
Van Peer
Achiel
A
Lavrijsen
Karel
K
Mackie
Claire E
CE
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D049628:Body Size; D001835:Body Weight; D003627:Data Interpretation, Statistical; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000882:Haplorhini; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
D004364:Pharmaceutical Preparations