Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data

Abstract

Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and "developable" dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the "anticipation" of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for "AHD" demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via "reverse pharmacology strategies" that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

“…Physiologically based models which integrate anatomical and physiological parameters of gastrointestinal tracts in preclinical species and humans, along with physicochemical drug product formulation properties, have been used to predict absorption and disposition (18)(19)(20)(21)(22)(23)(24)(30)(31)(32). These approaches have been applied during formulation development; yet their practical application in the prediction of human food effects has not been described extensively.…”

“…These approaches have been applied during formulation development; yet their practical application in the prediction of human food effects has not been described extensively. Heimbach et al reported the practical application of preclinical and clinical PK/PD modeling by integrating in vitro and preclinical in vivo data for the anticipation of human doses (30). Here, we used a similar strategy to predict potential food effect outcomes that can be conducted by both DMPK and formulation scientists.…”

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

“…Heimbach et al (29) further improved the four-step approach by incorporating formulation and biopharmaceutical parameters (e.g., Biopharmaceutics Classification System), which made it possible to project the PK/PD profiles of drugs with various dosage forms and properties. They also demonstrated that the human PK/PD profile could be projected using animal data from a single species.…”

“…(MABELs) (25), pharmacokinetic prediction (5,24,26,27), pharmacokinetic/pharmacodynamic (PK/PD) simulation (16,28,29), and similar drug comparison (5,24). Advances in PK and PK/PD modeling and simulation have increased the use of these approaches (5).…”

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

“…The importance of human PK and efficacious dose projections has been recognized 9. An approach toward rational prediction of efficacious human doses, eventually using physiologically based modeling for human PK prediction in the absence of observed clinical drug exposure, has been presented in the literature 10. In this approach, the preclinical exposure–response is characterized, together with an adjustment for interspecies differences in potency between animals and humans.…”