Dissertation > Medicine, health > Neurology and psychiatry > Psychiatry > Child psychiatry

Population Pharmacokinetics of Methylphenidate Hydrochloride Prolonged-Release Tablets and Relationship between Plasma Concentration and Curative Effect in Patients with Attention Deficit/Hyperactivity Disorder

Author WuWeiGe
Tutor WangWenQiang
School Xiamen University
Course Psychiatry and Mental Health
Keywords Attention Deficit/Hyperactivity Disorder MethylphenidateProlonged-Release Tablets Population Pharmacokinetics
CLC R749.94
Type Master's thesis
Year 2014
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AIM1. To establish a population pharmacokinetic (PPK) model for Methylphenidate Hydrochloride Prolonged-Release Tablets(PR-MPH) in patients with Attention Deficit/Hyperactivity Disorder(ADHD). investigate the distribution of the PPK parameters, and provide important parameter for clinical rational treatment.2. Explore the steady-state plasma concentration levels of PR-MPH after multiple dosing, discuss the relationship between levels and clinical efficacy and adverse effects of PR-MPH in patients with ADHD, to guide clinical drug treatment reasonably.METHODSInclude patients with ADHD, according with the diagnostic criteria of international disease diagnosis and classification criteria10th edition (International Classification of Diseases-10. ICD-10) prospectively.1. Serum concentration data (n=165) in elimination phase were collected prospectively from78ADHD patients taking PR-MPH during their routine clinical treatment, measured by LC-MS/MS. Meanwhile, other important clinical data was collected. Analyzed the data using nonlinear mixed-effects model (nonlinear mixed effect model. NONMEM) method, verified the stability and effectiveness of the model with the use the Bootstrap method internally.2. Included40ADHD patients for the study, who never used central nervous system stimulants. Completed dose titration of PR-MPH systematically within3weeks, then continued treatment in the optimal dose for2weeks, divided into groups in accordance with actual dose of the last2weeks. Blood samples were collected8h after taking PR-MPH. in the first, second and third weekend of the test, measured steady-state plasma concentrations of PR-MPH with LC-MS/MS. Clinical efficacy were assessed using the Conners index of hyperactivity in baseline and the first. second and third weekend of the test. Statistical data was analysed with SPSS vl3.0.RESULTS1. First-order absorption and elimination of the one-compartment pharmacokinetic model was used for the base model. Exponential model was utilized for the individual random variation of the clearance rate (CL) and apparent volume of distribution (Vd). the additive model fitting was utilized for the individual’s own variation. Weight (WT) and combined with sodium Valproate (VPA) were the affecting factors of CL. The final model was:CL(L·h-’)=254·(WT/34.7)0663·0.884(if taking sodium VPA, otherwise it equals to1)-EXP(ETA(CL)) in which WT is weight(kg). CL increased with the increasing of WT nonlinearly. CL of patients combined VPA reduced by11.6%. Random variation between individuals of CL was16.06%.2.31patients (77.5%.31/40) completed the final test, assessed the relationship between plasma concentration and efficacy. The patients were divided into two groups.18mg-group (n=21).36mg-group (n=10). according to the optimal dose titration. The steady-state plasma concentrations of the two groups were5.55±0.64μg·L-1,8.56±0.50μg·l-1at the end of the test respectively, and showed a linear correlation (P<0.05) with the dose. The individual differences among concentration were obvious. The overall clinical effective rate was70.97%, the rates of the two groups were similar (P>0.05). Conners index of hyperactivity of the two groups patients were significantly decreased (P<0.05) compared with the baseline. Steady-state plasma concentration and clinical efficacy has a high positive correlation (r=0.82)(P<0.05).in patients of36mg-groups. The clinical efficacy threshold plasma concentration was5.17μg·L-1from the preliminary exploration in this study. The probability of gastrointestinal adverse reactions might increase in higher plasma concentrations.CONCLUSION1. A population pharmacokinetic model was established successfully and proposed to estimate the individual CL for patients taking PR-MPH in terms of patients’characteristics and dosing history, and to establish a prior dosage regimen.2. Treatment for ADHD patients with PR-MPH is effective, steady-state plasma concentration and dose showed linear correlation, the individual differences among concentration were significant. Increasing steady-state plasma concentrations may improve clinical symptoms, but we should pay attention to the monitoring of adverse drug reactions.5.17μg·L-1can be used as an objective indicator to predict clinical efficacy.

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