Integration of Precipitation Kinetics From an In Vitro, Multicompartment Transfer System and Mechanistic Oral Absorption Modeling for Pharmacokinetic Prediction of Weakly Basic Drugs

Abstract

Solubility, dissolution, and precipitation in the gastrointestinal tract can be critical for the oral bioavailability of weakly basic drugs. To understand the dissolution and precipitation during the transfer out of the stomach into the intestine, a multicompartment transfer system was developed by modifying a conventional dissolution system. This transfer system included gastric, intestinal, sink and supersaturation, and reservoir compartments. Simulated gastric fluid and fasted state simulated intestinal fluid were used in the gastric and intestinal compartment, respectively, to mimic fasted condition. The new transfer system was evaluated based on 2 model weak bases, dipyridamole and ketoconazole. Traditional 2-stage dissolution using 250 mL of simulated gastric fluid media, followed by 250 mL of fasted state simulated intestinal fluid, was used as a reference methodology to compare dissolution and precipitation results. An in silico model was built using R software suite to simulate the in vitro time-dependent dissolution and precipitation process when formulations were tested using the transfer system. The precipitation rate estimated from the in vitro data was then used as the input for absorption and pharmacokinetic predictions using GastroPlus. The resultant simulated plasma concentration profiles were generally in good agreement with the observed clinical data, supporting the translatability of the transfer system in vitro precipitation kinetics to in vivo.

Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib

“…This work also illustrates the value of in vitro studies to understand and quantify the impact of formulation on the dissolution and precipitation of weak bases. Generation of in vitro data predictive of in vivo precipitation is challenging with many different methods employed, and coupling with PBPK requires further evaluation to increase confidence in translation (42), although there is good progress being made (43,44). This work for entrectinib used an approach developed by Jakubiak et al (21), and the complete lack of precipitation seen when using biorelevant conditions gave confidence that very slow in vivo precipitation was appropriate for GastroPlus™ modelling.…”

Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration

“…Various methods have been proposed to address these issues, including both in vitro assays [ 22 , 23 ] and mathematical predictions [ 24 , 25 , 26 ]. Consequently, the precipitation process has been considered in the dissolution models integrated within PBBM software [ 27 , 28 , 29 , 30 ].…”

The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development

“…However, these data are sometimes difficult to obtain due to the limited information or lack of knowledge, particularly concerning special populations such as paediatrics, geriatrics, pregnant women and various disease populations (6). There has been a number of examples illustrating the use of in house designed PBPK models, including both relatively simple and more complex models (7)(8)(9)(10)(11). However, nowadays it is more common to use commercially available software packages such as GastroPlus™ (https://www.simulationsplus.com/software/gastroplus/), Simcyp™ PBPK Simulator (https://www.certara.com/software/simcyp-pbpk/) and PK-Sim ® (http://www.systems-biology.com/products/PK-Sim/).…”