POPULATION PHARMACOKINETIC MODELING OF A NOVEL ONCE-DAILY LITHIUM CARBONATE EXTENDED RELEASE (XR) BI-LAYER MATRIX FORMULATION TO SUPPORT FORMULATION SWITCHING AND PEDIATRIC DOSING
Author(s)
John A. Bates, PhD1, Rupinder Phull, PhD1, Ripal Gaudana, PhD1, Jogarao Gobburu, PhD2, Michael Tagen, PhD3, Pavan Rathina Muthu Kumar, PharmD3, Joan Korth-Bradley, PharmD, PhD4, Rama Yarasani, PhD1;
1Almatica Pharma LLC, Morristown, NJ, USA, 2University of Maryland School of Pharmacy, Baltimore, MD, USA, 3PumasAI, Dover, DE, USA, 4Vivpro, Landsdale, PA, USA
1Almatica Pharma LLC, Morristown, NJ, USA, 2University of Maryland School of Pharmacy, Baltimore, MD, USA, 3PumasAI, Dover, DE, USA, 4Vivpro, Landsdale, PA, USA
OBJECTIVES: A population pharmacokinetic (popPK) model of lithium carbonate was developed to simulate PK profiles of a novel once-daily (QD) extended-release (XR) formulation in adult and pediatric patients. Objectives included characterization of lithium pharmacokinetics, evaluation of formulation-switching strategies from two-times-daily (BID) extended-release (ER) and three-times-daily (TID) immediate-release (IR) formulations to QD XR dosing, and assessment of dosing strategies in pediatric and adolescent patients aged 7 to <18 years using fixed allometric scaling.
METHODS: A popPK analysis was conducted using lithium concentration data from three Phase 1 studies in healthy adults evaluating lithium QD XR, BID ER, and TID IR formulations. A two-compartment model was developed to characterize lithium exposure and sources of variability across formulations and dosing regimens. Key covariates, including body weight, food status, and circadian rhythm effects on absorption, were incorporated to support clinically relevant comparisons. The final model simulated steady-state exposure, formulation-switching scenarios, and dosing outcomes in virtual adult and pediatric populations under fed conditions.
RESULTS: The model adequately described lithium concentration-time profiles across different formulations, doses, and food states. Simulations showed dose-proportional increases in steady-state exposure with QD XR dosing. Switching from BID ER or TID IR to QD XR at equivalent total daily doses produced minimal changes in AUC, Cmax, and Cmin, with exposures within the expected therapeutic range. Pediatric simulations incorporating allometric scaling predicted higher trough concentrations at higher approved doses, particularly in adolescents at 1800 mg daily, and in children weighing 20 to <30 kg at doses of 1200-1500 mg daily, supporting current weight-based dosing recommendations and maximum dose limits.
CONCLUSIONS: This popPK model supports QD lithium carbonate XR dosing in adults and pediatric patients and predicts negligible changes in systemic exposure when switching from currently available IR or ER formulations to XR formulation at steady state across approved adult dose ranges.
METHODS: A popPK analysis was conducted using lithium concentration data from three Phase 1 studies in healthy adults evaluating lithium QD XR, BID ER, and TID IR formulations. A two-compartment model was developed to characterize lithium exposure and sources of variability across formulations and dosing regimens. Key covariates, including body weight, food status, and circadian rhythm effects on absorption, were incorporated to support clinically relevant comparisons. The final model simulated steady-state exposure, formulation-switching scenarios, and dosing outcomes in virtual adult and pediatric populations under fed conditions.
RESULTS: The model adequately described lithium concentration-time profiles across different formulations, doses, and food states. Simulations showed dose-proportional increases in steady-state exposure with QD XR dosing. Switching from BID ER or TID IR to QD XR at equivalent total daily doses produced minimal changes in AUC, Cmax, and Cmin, with exposures within the expected therapeutic range. Pediatric simulations incorporating allometric scaling predicted higher trough concentrations at higher approved doses, particularly in adolescents at 1800 mg daily, and in children weighing 20 to <30 kg at doses of 1200-1500 mg daily, supporting current weight-based dosing recommendations and maximum dose limits.
CONCLUSIONS: This popPK model supports QD lithium carbonate XR dosing in adults and pediatric patients and predicts negligible changes in systemic exposure when switching from currently available IR or ER formulations to XR formulation at steady state across approved adult dose ranges.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
MSR57
Topic
Methodological & Statistical Research
Disease
SDC: Neurological Disorders