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Utility of physiologically based absorption modeling in implementing Quality by Design in drug development.

ABSTRACT: To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance. Physiologically based absorption models are potentially useful tools; yet, their utility of QbD implementation has not been discussed or explored much in the literature. We simulated pharmacokinetics (PK) of carbamazepine (CBZ) after administration of four oral formulations, immediate-release (IR) suspension, IR tablet, extended-release (XR) tablet and capsule, under fasted and fed conditions and presented a general diagram of a modeling and simulation strategy integrated with pharmaceutical development. We obtained PK parameters and absorption scale factors (ASFs) by deconvolution of the PK data for IR suspension under fasted condition. The model was validated for other PK profiles of IR formulations and used to predict PK for XR formulations. We explored three key areas where a modeling and simulation approach impacts QbD. First, the model was used to help identify optimal in vitro dissolution conditions for XR formulations. Second, identification of critical formulations variables was illustrated by a parameter sensitivity analysis of mean particle radius for the IR tablet that showed a PK shift with decreased particle radius, C (max) was increased and T (max) was decreased. Finally, virtual trial simulations allowed incorporation of inter-subject variability in the model. Virtual bioequivalence studies performed for two test formulations suggested that an in vitro dissolution test may be a more sensitive discriminative method than in vivo PK studies. In summary, a well-validated predictive model is a potentially useful tool for QbD implementation in drug development.

SUBMITTER: Zhang X

PROVIDER: S-EPMC3032086 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other

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Utility of physiologically based absorption modeling in implementing Quality by Design in drug development.

Zhang Xinyuan X Lionberger Robert A RA Davit Barbara M BM Yu Lawrence X LX

The AAPS journal 20110105 1

To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance. Physiologically based absorption models are potentially useful tools; yet, their utility of QbD implementation has not been discussed or explored much in the literature. We simulated pharmacokinetics (PK) of carbamazepine (CBZ) after administration of four oral formulations, immediate-release (IR) suspension, IR tablet, extended-release (XR) tablet and capsul ...[more]

PMID: 21207216

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Project description:Colon absorption is a key determinant for the successful development of modified-release (MR) formulations, and the risk that colon absorption may limit the in vivo performance of an MR product can be assessed early by various in vitro tests or by preclinical in vivo regional absorption studies in dogs. Mechanistic physiologically based biopharmaceutics modeling (PBBM) is becoming increasingly accepted to predict in vivo performance and guide formulation development; however, no evaluation of the ability to predict colon absorption has been performed. The purpose of this study was to investigate if regional and colon absorption of drugs in dogs could be predicted with sufficient accuracy using PBBM to enable the replacement of in vivo dog studies in the early assessment of colon absorption limitation risks. This was done by predicting the regional and colon absorption and plasma exposure of 14 drugs after administration to the dog colon according to an a priori approach using the in silico absorption models GI-Sim and GastroPlus. Predictive performance was primarily assessed by comparing observed and predicted plasma concentration-time profiles, AUC0-t, and the relative bioavailability in the colon (Frel,colon) as compared to an oral/duodenal reference. Trends in dependency of prediction performance on predicted fraction absorbed, permeability, and solubility/dissolution rate were also investigated. For GI-Sim, the absolute average fold error (AAFE) values for AUC0-t and Frel,colon were within a 2-fold prediction error for both solutions (1.88 and 1.51, respectively) and suspensions (1.58 and 1.99, respectively). For GastroPlus, the AAFE values for AUC0-t and Frel,colon were outside the set 2-fold prediction error limit for accurate predictions for both solutions (3.63 and 2.98, respectively) and suspensions (2.94 and 2.09, respectively). No trends for over- or underprediction were observed for GI-Sim, whereas GastroPlus showed a slight trend for underprediction of both AUC0-t and Frel,colon for compounds with low permeability. In addition, regional differences in the plasma profiles were qualitatively predicted in the majority of cases for both software. Despite the differences in prediction performance, both models can be considered to predict regional differences in absorption as well as AUC0-t and Frel,colon with acceptable accuracy in an early development setting. The results of this study indicate that it is acceptable to replace in vivo regional absorption studies in dogs with the evaluated models as a method for the early assessment of the risk for colon absorption limitation of MR drug product candidates.

Dataset Information

Utility of physiologically based absorption modeling in implementing Quality by Design in drug development.

Publications

Utility of physiologically based absorption modeling in implementing Quality by Design in drug development.

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