PII-103 - REGISTERED DIGOXIN DOSES FOR CHILDREN DO NOT LEAD TO OPTIMAL EXPOSURE: A PBPK STUDY.

M. de Hoop-Sommen¹, J. van der Heijden¹, J. Freriksen¹, R. Greupink¹, S. de Wildt^1,2; ¹Radboud University Medical Center, Nijmegen, The Netherlands, ²Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Digoxin is registered for use in all age groups and commonly prescribed. The drug has a narrow therapeutic window (0.8 - 2 ng/mL) and clinical observations indicate that under- or overdosing occurs frequently in pediatric patients. Therefore, we aimed to develop optimized dosing guidelines, using a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach.

Methods: A PBPK model was built in Simcyp (v20), by coupling an existing digoxin compound model to a physiology model, to predict digoxin pharmacokinetics (PK) in different age groups. We first verified PBPK model performance using PK data from four adult and four pediatric studies. Then, virtual pediatric trials were conducted with on-label dosing strategies to study PK.

Results: PBPK model performance was considered adequate for predicting PK in adults (i.e. ratio of predicted-to-observed PK parameters within 2-fold). In pediatrics, PK predictions were less accurate. However, as pediatric PK data were scarce and quality was sometimes questionable, model performance was considered acceptable. Virtual trials showed that plasma levels above 2 ng/mL are expected in preterm neonates after administration of the on-label loading dose. A once-daily, not a twice-daily, maintenance dose in infants and children resulted in subtherapeutic levels ( < 0.8 ng/mL). Simulations of PK in adolescents showed adequate plasma levels with the registered dose.

Conclusion: Our pragmatic PBPK approach showed that the registered digoxin doses do not lead to optimal exposure, supporting clinical observations of under- and overdosing in pediatric patients. Simulations suggest that the loading dose should be decreased for preterm neonates and that a twice-daily maintenance dose leads to adequate exposure in all pediatric age groups.