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.

Fig. 1

a Anticipation of human dose (AHD), PK/PD, and projections of efficacious dosing regimen often involves multiple steps (see text). The predictions of human PK parameters such as CL, V _ss, F, and a targeted C _ssavg are usually performed once preclinical PK data are available for at least one species. After incorporating PD data from preclinical efficacy models, human PK/PD projections can be performed. Formulation strategies are needed during all steps and are especially critical prior to first in human (FIH) studies. With FIH data, the AHD process can be validated with the frontrunner data and the models can be refined. “Reverse pharmacology” strategies utilize clinical PK/PD data to establish a link and validate preclinical PK/PD models and can aid in the selection of back-up candidates. b Formulation-dependent PK/PD requires the integration of parameters, such as solubility and dosage form with PK and PD parameters. Systemic exposure or bioavailability (F) is controlled by fraction of drug absorbed (F _a), the fraction that escapes gut wall metabolism (F _g), which is often negligible, and the systemic clearance (CL) (2,41). F _a is determined by permeability (P _app), solubility, intestinal efflux, and formulation parameters. CL can be estimated via several methods including allometry, the rule of exponents (13), IVIVE (14,15), or the Wajima et al. method (26). Formulation-dependent PK concentration–time profiles can be determined after input of V _ss, which can be predicted using allometry or mechanistic methods (17,20). PD parameters, e.g., IC₅₀ values can be obtained from preclinical efficacy studies using direct and indirect PD models (46) to generate a formulation-dependent response time-course profile (effect vs. time; PD profiles after Meibohm and Derendorf (40))

Fig. 2

a, b Preclinical dog PK/PD of clinical frontrunner A (a) compared to the backup B (b). Both compounds were administered orally at 1 mg/kg. Measured plasma concentrations (CP) are shown on the left axis, while the PD response is shown on the right. The data were fitted to a direct I _max model using GastroPlus PKPDPlus™. The dog IC₅₀ for backup B was 3.4 ng/mL and was 15 ng/mL for frontrunner A

Fig. 3

a, b Human PK/PD of frontrunner A and the backup candidate, backup B using GastroPlus™ for 50 and 100 mg IR doses. Predicted PK plasma concentrations are shown on the left (a). The solid symbols represent observed clinical PK data after a single dose of 100 mg of frontrunner A. The corresponding simulated PD responses using a direct I _max model are shown on the right (b). The solid vertical line represents the targeted inhibition profile with a desired PD response of 80% inhibition. Fifty milligrams IR of backup B was simulated to yield a PD response of 80% for 24 h, while frontrunner A requires a 100 mg daily IR dose

Fig. 4

a, b Predicted human PK/PD relationship shown as a double-Y plot for compound K after IR dosing. PK plasma concentrations are shown on the left. The PD response is shown on the right. a The PK profile after a 20 mg oral QD dose with low systemic CL (0.83 mL/min/kg) and a solubility of 0.010 mg/mL (“best case scenario”). b PK and PD following a 500 mg oral dose for a moderate systemic CL (7.3 mL/min/kg) and low solubility (worst case scenario)

Fig. 5

Rat observed (solid circles) and predicted (solid line) IV profile after a 2-mg/kg bolus dose for compound R. The r ² was 0.82

Fig. 6

a Human observed (solid circles) vs. predicted (solid line) IV plasma concentration–time profile following a single 75 mg infusion over 25 min for compound R. The r ² value was 0.76. b Human observed and predicted oral plasma concentration–time profiles after a single 75 mg oral SEDDS solution administration of compound R (right). The r ² value was also 0.76

Fig. 7

a Prediction of human profile for frontrunner B (reference) using only rat data. Observed oral plasma concentration profile after an 80 mg QD dose (left axis and solid circles) vs. predicted oral profiles (dotted line). The r ² value was 0.74. The long-dashed line (right axis) represents the projected PD response, assuming that the response is conserved. b Predicted oral plasma concentration–time profile (left axis, dotted line) after 50 mg QD oral dosing for backup C. The long-dashed (right axis) represents the PD response. The targeted PD effect is above 0.55, or 55%