A Quantitative Comparison Approach for Methylphenidate Drug Regimens in Attention-Deficit/Hyperactivity Disorder Treatment

Objective: Different methylphenidate (MPH) formulations, immediate release (IR) or extended release (ER), have been developed to treat Attention-Deficit/Hyperactivity Disorder (ADHD). A better use of these formulations, with a proper choice of their timing, dosage, and combination, can help to attain optimal therapeutic effect while maintaining a good quality of life. In this study, we aim at presenting a quantitative comparison approach to help identify drug regimens that provide best therapeutic performances and respect patients' specific needs. Methods: Using pharmacokinetic (PK) models of various MPH formulations constructed with data in hand and a formerly developed performance metric for MPH regimens, we proposed a statistical integral strategy for regimen comparison, which comprises a sequential, a relative, and a probability-over-threshold method. The first is hierarchical in nature and sequentially compares the regimen performance, the total daily dose, and the administration frequency. The second compares two regimens by quantifying their similarity. The third computes the probability of an incremental regimen performance over a specified threshold. The first two comparison approaches are used for naive patients, whereas the third one is for patients under treatment. Results: PK models of one compartment effectively describe both the IR and ER data. Applied to three frequent MPH clinical situations, the three-methods strategy is able to distinguish the regimens proposed for each. A combined regimen of IR and ER taken at the same time performs better than a single ER dose. Conclusion: The proposed statistical strategy is able to differentiate ADHD regimens in various clinically relevant situations, and adapt the use of MPH drugs to a patient's daily routine. Since it does not compare fixed doses and formulations but rather any MPH regimen, our approach generalizes the current context of bioequivalence study and provides an accessible computational tool for objectively selecting MPH regimens.