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Using Tiny-TIM Dissolution and In Silico Simulation to Accelerate Oral Product Development of a BCS Class II Compound

Abstract

Though oral drug delivery is the most preferred route of administration, there is high drug pharmacokinetic variability associated with the oral route. Change in drug substance particle size distribution, formulation composition, or manufacturing process may impact the dissolution and, hence, the systemic drug absorption in biopharmaceutics classification system class II compounds. In the present research, using a Boehringer Ingelheim investigational drug substance as the model compound, the tiny-TIM in vitro data and in silico pharmacokinetic model were used to establish in vitro–in vivo correlation and to predict the oral bioavailability. The level C in vitro–in vivo correlation between in vivo AUC and in vitro amount dissolved in both fasted and fed states could be established. Furthermore, level A in vitro–in vivo correlation was established between in vivo fraction absorbed and bioaccessibility from tiny-TIM dissolution in both fasted and fed states. Prediction of positive food effect from tiny-TIM dissolution was consistent with conclusion from clinical studies. Such predictive models developed using the minimum clinical data and the in vitro tiny-TIM data have the potential to reduce the animal and human experiments and to expedite the overall drug development process.

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Authors and Affiliations

Authors

Contributions

Laibin Luo: data collection and writing with reviewing and editing

Naveen K. Thakral: conceptualization, writing, compiling, reviewing, and editing

Li Li: data collection

Robert Schwabe: data collection and reviewing

Shirlynn Chen: reviewing and editing

Corresponding authors

Correspondence to Laibin Luo or Naveen K. Thakral.

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The authors declare no competing interests.

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Luo, L., Thakral, N.K., Schwabe, R. et al. Using Tiny-TIM Dissolution and In Silico Simulation to Accelerate Oral Product Development of a BCS Class II Compound. AAPS PharmSciTech 23, 185 (2022). https://doi.org/10.1208/s12249-022-02343-4

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  • DOI: https://doi.org/10.1208/s12249-022-02343-4

Keywords

  • Predictive modeling
  • Tiny-TIM
  • Dissolution
  • IVIVC
  • Pharmacokinetics
  • Oral bioavailability
  • BCS class II