Identifying Dose-Relevant Covariates With SCOUT: A Case Study of Lorlatinib

Molecularly targeted therapeutics, such as lorlatinib, are typically initiated at fixed starting doses with subsequent tolerability-guided modifications, although substantial interindividual variability in pharmacokinetics and drug exposure may influence both efficacy and safety outcomes. Therefore, identifying patient factors associated with individualized dose requirements is an important step toward precision dosing. The aim of this study was to apply the Systematic Covariate Observational Uncovering Technique (SCOUT) framework to explore patient characteristics that may be associated with the individualized optimal dose of lorlatinib. A previously published population pharmacokinetic model was used to estimate individual pharmacokinetic parameters and individualized optimal doses, targeting a trough concentration of 150 ng/mL 3 weeks after treatment initiation. Associations between the estimated optimal dose and patient covariates were examined through exploratory visualization and quantified using multivariate linear regression with Lindeman-Merenda-Gold relative importance analysis. Individualized optimal doses, successfully estimated in all 330 patients, exhibited a wide distribution (mean ± SD: 194 ± 134 mg/day). The exploratory analyses suggested that older age, female sex, and greater renal impairment were associated with lower estimated optimal doses, with sex explaining the largest proportion of the variance. By reframing the covariate analysis around the dose rather than pharmacokinetic parameters, this study provides a clinically interpretable perspective on interindividual variability in dosing requirements. Although exploratory and hypothesis-generating, this study lays a quantitative foundation for future evaluations of precision dosing strategies for lorlatinib.