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Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents.

ABSTRACT: In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents.Overweight (BMI for age ? 85(th) percentile) and obese (BMI for age ? 95(th) percentile) adolescents undergoing surgery received 2 or 3?mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8?h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2.Nineteen overweight and obese patients with a mean body weight of 102.7?kg (62-149.8?kg), a mean BMI of 36.1?kg?m(-2) (24.8-55?kg?m(-2)), and a mean age of 15.9?years (range 12.5-18.9?years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66?l?min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154?l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ).The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.

SUBMITTER: van Rongen A

PROVIDER: S-EPMC4631191 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents.

van Rongen Anne A Vaughns Janelle D JD Moorthy Ganesh S GS Barrett Jeffrey S JS Knibbe Catherijne A J CA van den Anker Johannes N JN

British journal of clinical pharmacology 20150910 5

<h4>Aim</h4>In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents.<h4>Methods</h4>Overweight (BMI for age ≥ 85(th) percentile) and obese (BMI for age ≥ 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Populat ...[more]

PMID: 26044579

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Project description:Background and objectivesCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.MethodsData from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.ResultsCariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.ConclusionsPopulation pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.

Dataset Information

Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents.

Publications

Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents.

Similar Datasets

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