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      Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents : Pharmacokinetics of midazolam in obese adolescents

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          Abstract

          <div class="section"> <a class="named-anchor" id="d13784737e237"> <!-- named anchor --> </a> <h5 class="section-title" id="d13784737e238">Aim</h5> <p id="d13784737e240">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. </p> </div><div class="section"> <a class="named-anchor" id="d13784737e242"> <!-- named anchor --> </a> <h5 class="section-title" id="d13784737e243">Methods</h5> <p id="d13784737e245">Overweight (BMI for age ≥ 85 <sup>th</sup> percentile) and obese (BMI for age ≥ 95 <sup>th</sup> 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 <span style="font-variant: small-caps">nonmem</span> 7.2. </p> </div><div class="section"> <a class="named-anchor" id="d13784737e256"> <!-- named anchor --> </a> <h5 class="section-title" id="d13784737e257">Results</h5> <p id="d13784737e259">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 <sup>−2</sup> (24.8–55 kg m <sup>−2</sup>), 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 <sup>−1</sup> (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight ( <i>P</i> &lt; 0.001). The increase in peripheral volume could be explained by excess body weight (WT <sub>excess</sub>) instead of body weight related to growth (WT <sub>for age and length</sub>). </p> </div><div class="section"> <a class="named-anchor" id="d13784737e280"> <!-- named anchor --> </a> <h5 class="section-title" id="d13784737e281">Conclusions</h5> <p id="d13784737e283">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. </p> </div>

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          Most cited references17

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          Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models.

          Informative diagnostic tools are vital to the development of useful mixed-effects models. The Visual Predictive Check (VPC) is a popular tool for evaluating the performance of population PK and PKPD models. Ideally, a VPC will diagnose both the fixed and random effects in a mixed-effects model. In many cases, this can be done by comparing different percentiles of the observed data to percentiles of simulated data, generally grouped together within bins of an independent variable. However, the diagnostic value of a VPC can be hampered by binning across a large variability in dose and/or influential covariates. VPCs can also be misleading if applied to data following adaptive designs such as dose adjustments. The prediction-corrected VPC (pcVPC) offers a solution to these problems while retaining the visual interpretation of the traditional VPC. In a pcVPC, the variability coming from binning across independent variables is removed by normalizing the observed and simulated dependent variable based on the typical population prediction for the median independent variable in the bin. The principal benefit with the pcVPC has been explored by application to both simulated and real examples of PK and PKPD models. The investigated examples demonstrate that pcVPCs have an enhanced ability to diagnose model misspecification especially with respect to random effects models in a range of situations. The pcVPC was in contrast to traditional VPCs shown to be readily applicable to data from studies with a priori and/or a posteriori dose adaptations.
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            Impact of obesity on drug metabolism and elimination in adults and children.

            The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown. In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes. This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N-acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults. Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.
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              Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the "cocktail" approach.

              Phenotyping for drug metabolizing enzymes and transporters is used to assess quantitatively the effect of an intervention (e.g., drug therapy, diet) or a condition (e.g., genetic polymorphism, disease) on their activity. Appropriate selection of test drug and metric is essential to obtain results applicable for other substrates of the respective enzyme/transporter. The following phenotyping metrics are recommended based on the level of validation and on practicability: CYP1A2, paraxanthine/caffeine in plasma 6 h after 150 mg caffeine; CYP2C9, tolbutamide plasma concentration 24 h after 125 mg tolbutamide; CYP2C19, urinary excretion of 4'-OH-mephenytoin 0-12 h after 50 mg mephenytoin; CYP2D6, urinary molar ratio debrisoquine/4-OH-debrisoquine 0-8 h after 10 mg debrisoquine; and CYP3A4, plasma clearance of midazolam after 2 mg midazolam (all drugs given orally).
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                Author and article information

                Journal
                British Journal of Clinical Pharmacology
                Br J Clin Pharmacol
                Wiley-Blackwell
                03065251
                November 2015
                November 10 2015
                : 80
                : 5
                : 1185-1196
                Article
                10.1111/bcp.12693
                4631191
                26044579
                c4ba55be-5fea-429c-9d26-6fbc681718ec
                © 2015

                http://doi.wiley.com/10.1002/tdm_license_1.1

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