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

Gehang Ju,1– 3 Xin Liu,4 Yeheng Peng,4 Wenyu Yang,4 Nuo Xu,4 Qingfeng He,4 Chenchen Zhang,5 Lulu Chen,3,6 Nan Yang,3,6,7 Gufen Zhang,3,6,7 Chao Li,3,6,7 Pan Su,8 Xiao Zhu,4 Dongsheng Ouyang1– 3,6 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Institute of Clinical Pharmacology, Central South University, Changsha, People’s Republic of China; 3Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, People’s Republic of China; 4Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 5School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 6Changsha Duxact Biotech Co., Ltd., Changsha, People’s Republic of China; 7Phamark Data Technology Co., Ltd., Changsha, People’s Republic of China; 8Hunan Chest Hospital, Changsha, People’s Republic of ChinaCorrespondence: Dongsheng Ouyang, Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Lutian Road 28, Changsha, People’s Republic of China, Tel +86 0731 84805380, Email [email protected] Xiao Zhu, Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Jinke Road 3728, Shanghai, People’s Republic of China, Tel +86 21 51980025, Email [email protected]: 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.Keywords: isoniazid, optimal sampling design, population pharmacokinetics, stochastic simulation and estimation