首页|Evaluating the impact of acid-reducing agents on drug absorption using biorelevant in vitro tools and PBPK modeling-case example dipyridamole

Evaluating the impact of acid-reducing agents on drug absorption using biorelevant in vitro tools and PBPK modeling-case example dipyridamole

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  • NSTL
  • Elsevier
Background: In vitro and in silico methods have become an essential tool in assessing metabolic drug-drug in-teractions (DDI) and avoiding reduced efficacy and increased side-effects. Another important type of DDI is the impact of acid-reducing agent (ARA) co-therapy on drug pharmacokinetics due to changes in gastric pH, espe-cially for poorly soluble weakly basic drugs. Methods: One-stage, two-stage and transfer dissolution experiments with dipyridamole tablets using novel bio-relevant media representing the ARA effect were conducted and the results were coupled with a PBPK model. Clinical pharmacokinetic data were compared with the simulations from the PBPK model and with output from TIM-1 experiments, an evolved in vitro system which aims to simulate the physiology in the upper GI tract. Results: Two-stage and transfer experiments confirmed that these in vitro set-ups tend to overestimate the extent of dipyridamole precipitation occurring in the intestines in vivo. Consequently, data from one-stage dissolution testing under elevated gastric pH conditions were used as an input for PBPK modeling of the ARA/dipyridamole interaction. Using media representing the ARA effect in conjunction with the PBPK model, the ARA effect observed in vivo was successfully bracketed. As an alternative, the TIM-1 system with gastric pH values adjusted to simulate ARA pre-treatment can be used to forecast the ARA effect on dipyridamole pharmacokinetics. Conclusion: Drug-drug interactions of dipyridamole with ARA were simulated well with a combination of dissolution experiments using biorelevant media representing the gastric environment after an ARA treatment together with the PBPK model. Adjustment of the TIM-1 model to reflect ARA-related changes in gastric pH was also successful in forecasting the interaction. Further testing of both approaches for predicting ARA-related DDIs using a wider range of drugs should be conducted to verify their utility for this purpose.

Acid-reducing agentProton pump inhibitorH2 receptor antagonistPhysiologically based pharmacokinetic (PBPK)modelingDissolutionTransfer experimentDipyridamole

Segregur, Domagoj、Barker, Richard、Mann, James、Moir, Andrea、Karlsson, Eva M.、Turner, David B.、Arora, Sumit、Dressman, Jennifer

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Goethe Univ Frankfurt, Inst Pharmaceut Technol, D-60438 Frankfurt, Germany

AstraZeneca, New Modal & Parenteral Dev, Pharmaceut Technol & Dev, Operat, Macclesfield, Cheshire

AstraZeneca, Operat, Pharmaceut Technol & Dev, Oral Prod Dev, Macclesfield, Cheshire, England

AstraZeneca, Operat, Pharmaceut Technol & Dev, Oral Prod Dev, Gothenburg, Sweden

Certara UK Ltd, Simcyp Div, Sheffield, S Yorkshire, England

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2021

10.1016/j.ejps.2021.105750

European journal of pharmaceutical sciences

European journal of pharmaceutical sciences

ISTP
ISSN：0928-0987
年,卷(期)：2021.160
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