Jen-Hao (Eric) Wu 1,2, Emma Bernsen 1, Francisco Sirvent 1, Andrew Brandon 3, Shelby Barnett 3, Gareth Veal 3, Michel Zwaan 1,2, Alwin Huitema 1,4,5
1 Princess Máxima Center for Pediatric Oncology (Utrecht, the Netherlands), 2 Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital (Rotterdam, the Netherlands), 3 Centre For Cancer, Translational And Clinical Research Institute, Newcastle University (Newcastle upon Tyne, United Kingdom), 4 Department of Pharmacy & Pharmacology, Netherlands Cancer Institute (Amsterdam, the Netherlands), 5 Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University (Utrecht, the Netherlands)
Introduction
Etoposide is an antineoplastic podophyllotoxin derivative that inhibits topoisomerase II, resulting in irreversible DNA strand breaks and cell apoptosis [1,2]. It is an essential component of multi-drug combination therapies for various pediatric malignancies [2–5]. Pediatric etoposide dosing strategies are largely extrapolated from adult pharmacokinetic (PK) data, while previous studies reported no significant differences in etoposide PK between children and adults after adjustment for body size [6–9], patients ≤1 year of age were underrepresented in these analyses. Therefore, leaving the pharmacokinetics of etoposide in this vulnerable population insufficiently characterized [6–8]. The PK of etoposide in infants remains unclear and potential PK differences between infants and older children needs to be investigated. As part of the “Pharmacokinetics of cytostatic agents in children’s oncology study” (PINOCCHIO study , protocol ID NL63037.078.18), we developed a population PK model of etoposide in a combined infant and pediatric oncology population. The objectives of this study were: i) to characterize the PK of etoposide across a wide pediatric age range, including infants; ii) to identify covariates that explain PK variability, with emphasis on maturation and developmental factors; and iii) to conduct model-based simulations evaluating current dosing strategies and the potential need for dose adjustments in infants.
Methods
Our dataset comprised three pediatric cohorts: (i) the PINOCCHIO study conducted at the Princess Máxima Centrum; (ii) a multi-center study conducted across 20 centers in the United Kingdom (UK); (iii) a multi-center therapeutic drug monitoring programs in the UK. Both UK datasets were led by Newcastle University. Patients received etoposide at doses ranging from 3.3 to 5 mg/kg or 100 to 275 mg/m² for multiple days, as 30-minute, 1-hour, 2-hour, or 24-hour infusions. Per patient, generally 4–8 PK samples were collected at pre-dose and at 0-1, 1-3, 3-5, 6-8 and 20-24 hours after the end of infusion. The UK patients underwent PK sampling during infusion and sampled across multiple administrations. While PINOCCHIO study patients were sampled during a single administration. The basis of model development were structural models as mentioned in a recent review on pediatric PK of cytotoxic agents [9]. Pre-specified covariates, including maturation [10,11], kidney and liver function on clearance (CL) and age on central volume of distribution (Vc), were examined. PopPK model-based simulations following common etoposide dosages were performed across pediatric ages. PopPK analysis was performed using NONMEM version 7.5.0.
Results
In total, we analyzed 1041 Etoposide PK samples from 243 pediatric patients, including 6 neonates (<28 days) and 65 infants (≥1 month - ≤1 year). Etoposide PK was well-described by a two-compartment model with fixed exponents allometric scaling (normalized to 70kg) and a maturation effect on Vc. The estimated typical value (RSE) of CL was 2.45 L/h (2.30%); Vc was 7.72 L (6.90%); the intercompartmental clearances (Q) were 1.39 L/h (22.8%), with the peripheral volume (V2) 4.84 L (7.50%), respectively. Body weight was incorporated using fixed allometric exponents of 0.75 for clearances and 1.00 for volumes. A postnatal maturation function was identified on Vc, characterized by a 2.66-fold higher (30.4%) etoposide central volume of distribution in neonates at birth compared with adults, and this excess volume decays by 50% every 0.386 years (34.2%). Simulations demonstrated comparable exposure (AUC₀-₂₄) across pediatric age groups following administration of 100 mg/m². The simulated median AUC₀-₂₄ were 81.7, 79.6, 83.1, 77.3, and 73.2 h*mg/L for patients aged 0-1, <1-2, <2-9, <9-<18, 18-20 years, respectively.
Conclusion
Etoposide PK was well characterized by a two-compartment model with fixed allometric scaling and a postnatal maturation effect on central volume of distribution. The inclusion of a substantial number of infants enabled a robust evaluation of developmental influences. The pediatric popPK model indicates that age-related changes primarily affect distribution of etoposide rather than clearance, aligning with the absence of maturation on clearance demonstrated in previous PK studies [7]. The maturation on distribution could be explained by the body composition difference between neonates and infants [12,13]. Model-based simulations over clinical range of 100-200 mg/m² indicated a consistent exposure across age strata, supporting the current body surface area based dosing. This analysis provides quantitative evidence and support for current pediatric etoposide dosing practices use in infants, an underrepresented population in previous PK investigations.
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Reference: PAGE 34 (2026) Abstr 12148 [www.page-meeting.org/?abstract=12148]
Poster: Drug/Disease Modelling - Paediatrics