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Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

ABSTRACT: Merck KGaA observed slight differences in the dissolution of Concor^® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).

SUBMITTER: Macwan JS

PROVIDER: S-EPMC8213417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:PurposeThe aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.MethodsSamples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch.ResultsThe disintegration time (R 2?=?0.86) and API dissolved after 15 min (R 2?=?0.96) linearly correlates with the effective refractive index, n eff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of n eff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, ? eff, we observed a better correlation with dissolution after 20 min (R 2?=?0.96) and a weaker correlation with disintegration (R 2?=?0.83) compared to n eff.ConclusionThe measurements of n eff and ? eff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.

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Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

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