Optimized Sampling Strategies for Isoniazid in East Asian Pediatric Populations Using Population Pharmacokinetics-Informed Approaches.

OBJECTIVE

Isoniazid exposure in vivo is significantly affected by NAT2 genotypes and has ethnic differences. To optimize the sampling strategy for isoniazid in East Asian pediatric populations. We employed a model-informed optimization approach based on INH population pharmacokinetic (PopPK) models.

METHODS

We selected PopPK models for children and East Asian adults and optimized the sampling strategy using PopED (Population Experimental Design), a method that helps identify the most efficient sampling points for maximizing parameter estimation accuracy. Virtual patients with varying NAT2 phenotypes were created, and real-world pediatric scenarios were evaluated using questionnaire data, sampling windows, and stochastic simulations.

RESULTS

From eight analyzed models (four for East Asian adults and four for non-East Asian pediatrics), we simplified two over-parameterized models using lumping without loss of performance. The optimized clinical sampling strategy involved collecting samples at 0.25 [0-0.5], 1.5 [1-2], 6 [3-8], 12 [9-14], and 24 [22-24] hours post-dose. Simulation verification showed that re-estimated major PK parameters had acceptable relative biases and relative standard error (<30%).

CONCLUSION

Traditional adult sampling strategies are inadequate for East Asian pediatric populations. A tailored strategy involving up to five samples can accurately estimate INH PopPK parameters and should be considered for clinical implementation to optimize treatment and reduce patient sampling burden.