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PBPK Analysis to Study the Impact of Genetic Polymorphism of NAT2 on Drug-Drug Interaction Potential of Isoniazid

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Abstract

Purpose

Isoniazid (INH) is prescribed both for the prophylaxis as well as the treatment of tuberculosis. It is primarily metabolized through acetylation by a highly polymorphic enzyme, N-acetyl transferase 2 (NAT2), owing to which significant variable systemic drug levels have been reported among slow and rapid acetylators. Furthermore, many drugs, like phenytoin, diazepam, triazolam, etc., are known to show toxic manifestation when co-administered with INH and it happens prominently among slow acetylators. Additionally, it is revealed in in vitro inhibition studies that INH carries noteworthy potential to inhibit CYP2C19 and CYP3A4 enzymes. However, CYP inhibitory effect of INH gets masked by opposite enzyme-inducing effect of rifampicin, when used in combination. Thus, distinct objective of this study was to fill the knowledge gaps related to gene-drug-drug interactions (DDI) potential of INH when given alone for prophylactic purpose.

Methods

Whole body-PBPK models of INH were developed and verified for both slow and fast acetylators. The same were then utilized to carry out prospective DDI studies with CYP2C19 and CYP3A4 substrates in both acetylator types.

Results

The results highlighted likelihood of significant higher blood levels of CYP2C19 and CYP3A4 substrate drugs in subjects receiving INH pre-treatment. It was also re-established that interaction was more likely in slow acetylators, as compared to rapid acetylators.

Conclusion

The novel outcome of the present study is the indication that prescribers should give careful consideration while advising CYP2C19 and CYP3A4 substrate drugs to subjects who are on prophylaxis INH therapy, and are slow to metabolic acetylation.

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ACKNOWLEDGMENTS AND DISCLOSURES

Authors would like to sincerely thank Simcyp (Simcyp division, Certara Inc., Sheffield, UK) and Simulation Plus Inc., (Lancaster, CA, USA) for providing the academic license to our institute, NIPER, SAS Nagar. A special thanks to Dr. Mayur Ladumor (University of Washington, Seattle, USA) for his valuable suggestions. Authors declare no conflict of interest for the present work.

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Authors would like to thanks NIPER, SAS Nagar for providing fellowship to Mr. Ankit Balhara and facilities for carrying out this work.

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Correspondence to Saranjit Singh.

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Balhara, A., Singh, S. PBPK Analysis to Study the Impact of Genetic Polymorphism of NAT2 on Drug-Drug Interaction Potential of Isoniazid. Pharm Res 38, 1485–1496 (2021). https://doi.org/10.1007/s11095-021-03095-9

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