This submission belongs to the 2025 PAGANZ symposium “Pharmacometric approaches in malaria research”
Adherence to medication is critical to the outcome of the treatment. To date, many approaches have been proposed for adherence assessment, such as patient self-reports and pill counts. However, pharmacology-based approaches, with the measurement of drug concentrations, are considered to be the most objective approach for adherence assessment of recent dose events. In the present work, a framework to assess patient adherence has been developed, by utilizing two population pharmacokinetic-based approaches – the percentile and the Bayesian method. Three different dosing strategies were investigated in patients being prescribed a total of 3 doses over 3 days; (1) non-observed therapy, (2) directly observed administration of the first dose, (3) directly observed administration of the first two doses. The percentile approach used population pharmacokinetic-based simulations to derive optimal concentration percentile cut-off values from the distribution of simulated drug concentrations at a specific time. This was done for each adherence scenario and compared to full adherence. The Bayesian approach calculated the posterior probability of each adherence scenario at a given drug concentration. The predictive performance (ie., Youden index, receiver operating characteristic (ROC) curve) of both approaches were highly influenced by sample collection time (early was better) and inter-individual variability (smaller was better). The complexity of the structural model and the half-life had a minimal impact on the predictive performance of these methods. The impact of the assay (limit of quantification) on the predictive performance was relatively small if the fraction of LOQ data was <20%. Overall, the percentile method performed similar or better for adherence predictions compared to the Bayesian approach, with the latter showing slightly better results when investigating the adherence to the last dose only. The percentile approach showed acceptable adherence predictions (area under ROC curve >0.74) when sampling the antimalarial drugs piperaquine at day 7 post-dose and lumefantrine at day 3 post-dose (ie., 12 hours after the last dose). This could be a highly useful approach when evaluating programmatic implementations of preventive and curative antimalarial treatment programs in endemic areas.