PII-159 - THE NEED FOR EQUITABLE REPRESENTATION IN PHARMACOKINETIC STUDIES TO ENHANCE OPTIMAL DOSING STRATEGIES TO TREAT POVERTY-RELATED DISEASES IN MALNOURISHED CHILDREN.

M. Shin¹, R. Miyakawa¹, S. Nandamuri², R. Savic¹; ¹University of California, San Francisco, ²University of California, San Francisco, University of California, San Diego.

Background: Extrapolation of adult dosing with allometric scaling based on total body weight (TBW) often leads to pediatric underexposure. The effect of malnutrition should also be incorporated in building pediatric population pharmacokinetic (popPK) models, for drugs used to treat poverty-related diseases, like tuberculosis (TB), malaria, and human immunodeficiency virus (HIV). Historically, validation of fat-free mass (FFM) for allometric scaling was done in children aged 4 and older. The best methods for accounting for malnutrition remain uncertain.

Methods: A PubMed search yielded 22 pediatric popPK models on first-line TB drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol). HIV and malaria drugs with the largest number of popPK models were also examined (13 for nevirapine and 9 for piperaquine) (Table 1). Six studies considered malnutrition effects by incorporating weight-for-age Z-score (WAZ) as a covariate for bioavailability or clearance or by using FFM for allometric scaling of clearance.

Results: The largest effect of malnutrition was observed in a pediatric piperaquine popPK model from a post-marketing study (n = 280). A larger piperaquine popPK model with 546 children did not observe this effect. The study mostly included Phase II/III trial populations excluding malnourished children, and the authors acknowledged this limitation. A smaller, yet significant WAZ effect on pyrazinamide clearance attributed malnutrition to reduced pyrazinamide exposure. Older studies were unable to distinguish the effect of malnutrition from other factors, such as HIV co-infection.

Conclusion: Nutritional status effects are often undetected due to the limited inclusion of malnourished children in clinical trials, underscoring the need to include these vulnerable populations in studies. Recent studies have shown the utility of WAZ in assessing the effect of malnutrition on clearance and bioavailability. WAZ, designed to discern both acute and chronic malnutrition in children under the age of 10, could aid in pediatric popPK model development. Implementing an Individual Patient Data Meta-Analysis (IPDMA) with diverse populations reflecting real-world demographics may uncover the impact of factors like malnutrition. This, in turn, may improve dosing and consequently clinical outcomes, especially for malnourished children.