Prediction of modified release pharmacokinetics and pharmacodynamics from in vitro, immediate release, and intravenous data

Abstract

The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlus (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration-time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs' bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.

Fig. 1

Simulated and experimental Cp–time profiles of adinazolam modeled with a two-compartmental PK model: a i.v. infusion administration and b IR p.o. administration

Fig. 2

Optimized in vivo release profile and simulated and experimental Cp–time profiles of adinazolam modeled with two-compartmental PK model after p.o. administration of SR formulations: a complete Cp–time profiles and b initial 5 h of the Cp–time profiles

Fig. 3

Pharmacodynamic effect (sedation score) after : a 20 and 40 mg dose of IR p.o. administration and b 60 mg IR and SR p.o. administration. The 20- and 40-mg IR p.o. doses were used to fit the PK/PD model; the 60-mg IR and SR p.o. doses were predicted using the fitted PK/PD model

Fig. 4

Predicted Cp–time and PD effect-time profiles for two 20-mg adinazolam formulations with different release rates: a drug release over 20 h, b drug release over 10 h

Fig. 5

Simulated and experimental Cp–time profiles of metoprolol modeled with PBPK model: a i.v. infusion administration and b colonic perfusion and IR p.o. administration

Fig. 6

Simulated and experimental Cp–time profiles : a with corresponding in vitro release profiles and b used to represent in vivo release from a fast-releasing metoprolol formulation

Fig. 7

Simulated and experimental Cp–time profiles : a corresponding in vitro release profiles and b measured using Apparatus I at pH 6.8 and 150 rpm for slow- and moderate-releasing formulations

Fig. 8

Simulated and experimental Cp–time profiles from colonic perfusion : a slow-releasing MR formulation and b simulated using the incomplete release hypothesis and low colon absorption hypothesis