An exploratory analysis of the performance of methylphenidate regimens based on a PKPD model of dopamine and norepinephrine transporter occupancy.

Methylphenidate (MPH) is a psychostimulant which inhibits the uptake of dopamine and norepinephrine transporters, DAT and NET, and is mostly used to treat Attention Deficit/Hyperactivity Disorder. The current dose optimization is done through titration, a cumbersome approach for patients. To assess the therapeutic performance of MPH regimens, we introduce an in silico framework composed of (i) a population pharmacokinetic model of MPH, (ii) a pharmacodynamic (PD) model of DAT and NET occupancy, (iii) a therapeutic box delimited by time and DAT occupancy, and (iv) a performance score computation. DAT occupancy data was digitized (n = 152) and described with Emax models. NET occupancy was described with a KPD model. We used this integrative framework to simulate the performance of extended-release (18-99 mg) and tid MPH regimens (25-40 mg). Early blood samples of MPH seem to lead to higher DAT occupancy, consistent with an acute tolerance observed in clinical rating scales. An Emax model with a time-dependent tolerance was fitted to available data to assess the observed clockwise hysteresis. Peak performance is observed at 63 mg. While our analysis does not deny the existence of an acute tolerance, data precision in terms of formulation and sampling times does not allow a definite confirmation of this phenomenon. This work justifies the need for a more systematic collection of DAT and NET occupancy data to further investigate the presence of acute tolerance and assess the impact of low MPH doses on its efficacy.

Trapezoid bioequivalence: A rational bioavailability evaluation approach on account of the pharmaceutical-driven balance of population average and variability.

Among the current approaches for the analysis of bioequivalence, the average bioequivalence (ABE) is limited only to the mean bioavailability, whereas the population bioequivalence (PBE) criterion aggregates both mean and variance in a general comparison formula. However, a rational bioequivalence criterion capable of judging specific drug considerations is always still preferred. As an alternative approach, we introduce an aggregate criterion, namely, the trapezoid bioequivalence (TBE), which includes the consideration of both mean and variance of the bioavailability and adapted weighting of a drug's therapeutic properties. We first applied our method to specific simulated scenarios to compare the strengths and weaknesses of current bioequivalence approaches and demonstrate the improvements brought by TBE. As well, the impact of sample size and variability on ABE, PBE, and TBE are assessed using a population pharmacokinetic model of methylphenidate. Our results indicate that TBE inherits the advantages of both ABE and PBE while greatly reducing their inadequacies. Through simulations with population pharmacokinetic models of specific scenarios, we confirm that (1) TBE does not encounter the overly permissiveness issue of PBE, (2) TBE respects the hierarchy to ABE (TBE => ABE), and (3) TBE assesses bioequivalence with a restriction on σ T 2 - σ R 2 without an increase to type 2 errors. The clinically inspired simulations demonstrate TBE's superiority in a realistic context and its potential usefulness in practice. Moreover, the parameter choice in TBE may be adapted according to the specific context of a drug's pharmacological and pharmacodynamic properties.

Consideration of height-based tobramycin dosing regimens for the treatment of adult cystic fibrosis pulmonary exacerbations.

AIMS: Some population pharmacokinetic models have been developed using height to explain some of the interindividual variability in tobramycin pharmacokinetics in cystic fibrosis patients. However, their predictive performance when extrapolated to other clinical centres is unclear. Therefore, the aim of this study was to externally evaluate the predictability of tobramycin population pharmacokinetic models with an independent dataset and perform simulations using previously recommended height-based dosing regimens. METHODS: A literature search was conducted through the PubMed database to identify relevant population pharmacokinetic models. Tobramycin plasma concentration data from April 2014 to November 2019 were retrospectively collected from the Institut universitaire de cardiologie et de pneumologie de Québec, Canada. External evaluations were performed using NONMEM® v7.5 and RStudio® v1.3.1073. Monte Carlo simulations were performed to evaluate the probability of target attainment of Cmax /MIC ratios for several dosing regimens. RESULTS: The validation dataset included 27 patients and 143 concentration samples. Three models were evaluated. Only the ones by Crass et al. and Alghanem et al. performed satisfactorily in terms of prediction-based diagnostics with MDPE values of -3.4% and 29.3% and MDAPE values of 19.0 and 29.5%, respectively. In simulation-based evaluations, both pcVPC and NPDE showed no evidence of model misspecification. Our simulations suggest that patients treated with a once-daily dose of 3.4 mg/cm should produce peak and trough levels consistent with current guidelines. CONCLUSION: Our results show that the models by Crass et al. and Alghanem et al. are appropriate for simulation-based applications to aid individualized dosing in our population and that height-based dosing regimens could be considered in cystic fibrosis patients.

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.