Laura Ibarra Gomez 1
1 Pharma Mar (Madrid, España)
Introduction
Lurbinectedin is a selective inhibitor of oncogenic transcription that has demonstrated significant clinical activity across various adult solid tumors. In adults, the recommended dose of 3.2 mg/m2 administered every three weeks (Q3W) was established based on exposure-response (E-R) modeling. This dose provides a median AUCu of 1400 ng·h/L, maximizing the proportion of patients within the lurbinectedin target exposure range [1]. Given the physiological differences between adult and pediatric populations, a model-informed drug development (MIDD) approach was applied to bridge adult pharmacokinetic (PK) data to a younger population. This analysis provides the quantitative basis for dose selection in a Phase I/II study evaluating lurbinectedin in pediatric participants with previously treated solid tumors and pediatric and young adult participants with recurrent/refractory Ewing sarcoma.
Objective
To apply a model-informed approach to support dose selection in the pediatric population by integrating allometric modeling with established adult PK data and preliminary pediatric data.
Methods
The population pharmacokinetics (PopPK) modeling approach utilized the comprehensive lurbinectedin adult PopPK model, which was previously established using data from nine phase I to III studies. To predict pediatric PK, allometric scaling was applied to clearance (CL) and volume of distribution (V) parameters. Body weight (WT) was used as a covariate, with an exponent of 1.0 for volume parameters and an age-dependent exponent (ranging from 0.75 to 0.9) for the rest of parameters to account for physiological maturation. Simulations were conducted in a virtual population of 1,000 pediatric oncology patients (aged ≥2 to <18 years old), using body surface area (BSA) and WT distributions that reflect real-world distributions.
Results
Population PK analyses using an allometric model and preliminary PK data from the Phase I study demonstrated an age-dependent exposure profile, with younger participants exhibiting higher unbound lurbinectedin exposure (AUCu) at a given dose. In participants aged ≥ 6 to < 18 years, a dose of 3.2 mg/m2 produced AUCu values comparable to those in adults. At this dose, the median AUCu fell within the exposure range associated with an optimal benefit–risk profile. In contrast, the 4.0 mg/m² dose resulted in median AUCu values exceeding the target exposure range. Preliminary clinical PK data from initial cohorts confirmed these findings. Therefore, 3.2 mg/m2 was selected as the recommended dose for participants aged ≥ 6 to < 18 years.
Conclusion
The model-informed approach effectively leveraged adult data and preliminary pediatric data to support dose selection in the pediatric population. Allometric modeling demonstrated that 3.2 mg/m² is the appropriate dose for patients aged ≥ 6 to < 18 years, providing a quantitative justification for dose selection in phase I/II study.
References:
[1] Fernandez-teruel C, Lubomirov R, Fudio S. Exposure-response analyses and clinical utility index to justify the dosage of lurbinectedin in small-cell lung cancer. Poster session presented at: World Conference on Lung Cancer Singapore. 2021 28-31 Jun 2021; Worldwide virtual event
Reference: PAGE 34 (2026) Abstr 11938 [www.page-meeting.org/?abstract=11938]
Poster: Drug/Disease Modelling - Paediatrics