Mechanistic PBPK Modelling to Predict the Advantage of the Salt Form of a Drug When Dosed with Acid Reducing Agents

Abstract

Acid reducing agents (ARAs) reduce the dissolution rate of weakly basic drugs in the stomach potentially leading to lower bioavailability. Formulating the API as a rapidly dissolving salt is one strategy employed to reduce the impact of ARAs on dissolution of such drugs. In the present work, a model drug was selected with an immediate release formulation of the free base dosed in both the absence and presence of the ARA famotidine. In the latter case, bioavailability is restricted and several salt formulations were investigated. To simulate these drug products a mechanistic physiologically based pharmacokinetic (PBPK) model was built using the Simcyp Simulator, which illustrates the advantage of formulating an API as a salt compared to the free base form. The simulations use a mechanistic salt model utilising knowledge of the solubility product which was applied to predict the salt advantage. The developed PBPK model exemplifies that it can be critical to account for the surface pH and solubility when modelling the dissolution of low pKa bases and their salts in the gastric environment. In particular, the mechanistic salt model can be used to aid in screening and salt form selection where the aim is to mitigate effects of ARAs.

Integrating In Vitro Biopharmaceutics into Physiologically Based Biopharmaceutic Model (PBBM) to Predict Food Effect of BCS IV Zwitterionic Drug (GSK3640254)

“…In previously published works, SIVA was used to estimate the LogK M:W values and predicted the experimental solubilities with high accuracy in biorelevant media of different versions across a range of compounds, such as ritonavir [ 21 ], ketoconazole [ 22 , 23 ], flurbiprofen [ 24 ], dipyridamole [ 23 ], itraconazole [ 23 ] and in a model ampholyte drug that behaves as a weak base within the physiological pH range in the GI tract [ 25 ]. In all these cases, the solubility was measured for each fasted and fed biorelevant media only at the typical average pH values of FaSSIF and FeSSIF media or with small difference between versions (e.g., Level II FaSSIF V1 (pH = 6.5) vs. Level II FaSSIF V3 (pH = 6.7)).…”

Application of a Physiologically Based Pharmacokinetic Approach to Predict Theophylline Pharmacokinetics Using Virtual Non-Pregnant, Pregnant, Fetal, Breast-Feeding, and Neonatal Populations

“…After oral administration of theophylline in adult subjects, the bioavailability is ~100% from uncoated tablet and liquid formulations ( 19 ). When tablets were used in the clinical study the solid formulation option was chosen for the PBPK model with dissolution being described using a diffusion layer model ( 20 ) with an intrinsic solubility value for theophylline being calculated from the melting point and lipophilicity of the drug [273°C; ( 21 )] ( 22 ). The distribution of theophylline into the tissues was described using a full-body PBPK model with tissue partition coefficients (Kps) being predicted according to Rodgers and Rowland ( 23 ) with a global tissue scalar of 1.2 to recover reported data after an intravenous dose ( 24 ).…”

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 ].…”