Predicting Oral Clearance in Humans

BackgroundOral 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.MethodsWe 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.ResultsThe 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.ConclusionsOverall, 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.