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A Prospective Clinical Study Characterizing the Influence of Morbid Obesity on the Pharmacokinetics of Gentamicin: Towards Individualized Dosing in Obese Patients.

ABSTRACT: BACKGROUND AND OBJECTIVE:Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. Although the prevalence of obesity is increasing dramatically, there is no consensus on how to adjust the dose in obese individuals. In this prospective clinical study, we study the pharmacokinetics of gentamicin in morbidly obese and non-obese individuals to develop a dosing algorithm that results in adequate drug exposure across body weights. METHODS:Morbidly obese subjects undergoing bariatric surgery and non-obese healthy volunteers received one intravenous dose of gentamicin (obese: 5 mg/kg based on lean body weight, non-obese: 5 mg/kg based on total body weight [TBW]) with subsequent 24-h sampling. All individuals had a normal renal function. Statistical analysis, modelling and Monte Carlo simulations were performed using R version 3.4.4 and NONMEM® version 7.3. RESULTS:A two-compartment model best described the data. TBW was the best predictor for both clearance [CL = 0.089 × (TBW/70)0.73] and central volume of distribution [Vc = 11.9 × (TBW/70)1.25] (both p < 0.001). Simulations showed how gentamicin exposure changes across the weight range with currently used dosing algorithms and illustrated that using a nomogram based on a 'dose weight' [70 × (TBW/70)0.73] will lead to similar exposure across the entire population. CONCLUSIONS:In this study in morbidly obese and non-obese individuals ranging from 53 to 221 kg we identified body weight as an important determinant for both gentamicin CL and Vc. Using a body weight-based dosing algorithm, optimized exposure across the entire population can be achieved, thereby potentially improving efficacy and safety of gentamicin in the obese and morbidly obese population. TRIAL REGISTRATION:Registered in the Dutch Trial Registry (NTR6058).

SUBMITTER: Smit C

PROVIDER: S-EPMC6768900 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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A Prospective Clinical Study Characterizing the Influence of Morbid Obesity on the Pharmacokinetics of Gentamicin: Towards Individualized Dosing in Obese Patients.

Smit Cornelis C Wasmann Roeland E RE Goulooze Sebastiaan C SC Hazebroek Eric J EJ Van Dongen Eric P A EPA Burgers Desiree M T DMT Mouton Johan W JW Brüggemann Roger J M RJM Knibbe Catherijne A J CAJ

Clinical pharmacokinetics 20191001 10

<h4>Background and objective</h4>Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. Although the prevalence of obesity is increasing dramatically, there is no consensus on how to adjust the dose in obese individuals. In this prospective clinical study, we study the pharmacokinetics of gentamicin in morbidly obese and non-obese individuals to develop a dosing algorithm that results in adequate drug exposure across body weights.<h4>Methods</h4>Morbidly obese s ...[more]

PMID: 31016671

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Project description:IMPORTANCE:Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown. OBJECTIVE:To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children. EVIDENCE REVIEW:We searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ?18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and nonobese children. We explored the association between drug physicochemical properties and clearance and volume of distribution. FINDINGS:Twenty studies met the inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range, 1-112) and ages ranged from newborn to 29 years (1 study described pharmacokinetics in children and adults together). Dosing schema varied and were either a fixed dose (6 [29%]) or based on body weight (10 [48%]) and body surface area (4 [19%]). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11 of 17) of the studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and nonobese children for 38% (5 of 13) of the drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity. CONCLUSIONS AND RELEVANCE:Consensus is lacking on the most appropriate weight-based dosing strategy for obese children. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.

Project description:BackgroundMitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of mitotane, and the optimization and individualization of mitotane treatment, is desirable for patients.ObjectivesThis study aims to develop a population PK (PopPK) model to characterize and predict the PK profiles of mitotane in patients with ACC, as well as to explore the effect of genetic variation on mitotane clearance. Ultimately, we aimed to facilitate mitotane dose optimization and individualization for patients with ACC.MethodsMitotane concentration and dosing data were collected retrospectively from the medical records of patients with ACC taking mitotane orally and participating in the Dutch Adrenal Network. PopPK modelling analysis was performed using NONMEM (version 7.4.1). Genotypes of drug enzymes and transporters, patient demographic information, and clinical characteristics were investigated as covariates. Subsequently, simulations were performed for optimizing treatment regimens.ResultsA two-compartment model with first-order absorption and elimination best described the PK data of mitotane collected from 48 patients. Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%. Fat amount (i.e. body weight - LBW) was found to significantly affect the central distribution volume. Simulation results indicated that determining the starting dose using the developed model is beneficial in terms of shortening the period to reach the therapeutic target and limit the risk of toxicity. A regimen that can effectively maintain mitotane concentration within 14-20 mg/L was established.ConclusionsA two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required.

Project description:Background: Postexercise hypotension (PEH) is a common physiological phenomenon occurring immediately after endurance training (ET), resistance training (RT), and ET plus RT, also termed concurrent training (CT); however, there is little knowledge about the interindividual and magnitude response of PEH in morbidly obese patients. Aim: The aims of this study were (1) to investigate the effect of CT order (ET + RT vs. RT + ET) on the blood pressure responses; 2) characterize these responses in responders and nonresponders, and 3) identify potential baseline outcomes for predicting blood pressure decreases as responders. Methods: A quasi-experimental study developed in sedentary morbidly obese men and women (age 43.6 ± 11.3 years; body mass index [BMI] ≥40 kg/m2) was assigned to a CT group of ET plus RT (ET + RT; n = 19; BMI 47.8 ± 16.7) or RT plus ET order group (RT + ET; n = 17; BMI 43.0 ± 8.0). Subjects of both groups received eight exercise sessions over four weeks. Primary outcomes include systolic (SBP), diastolic (DBP), mean arterial pressure [MAP], heart rate at rest [HR], and pulse pressure [PP] measurements before and after 10 min post-exercise. Secondary outcomes were other anthropometric, body composition, metabolic, and physical fitness parameters. Using the delta ∆SBP reduction, quartile categorization (Q) in "high" (Rs: quartile 4), "moderate" (MRs: quartile 3), "low" (LRs: quartile 2), and "nonresponders" (NRs: quartile 1) was reported. Results: Significant pre-post changes were observed in ET + RT in session 2 for SBP (131.6 vs. 123.4 mmHg, p = 0.050) and session 4 (131.1 vs. 125.2 mmHg, p = 0.0002), while the RT + ET group showed significant reductions in session 4 (134.2 vs. 125.3 mmHg, p < 0.001). No significant differences were detected in the sum of the eight sessions for SBP (∑∆SBP) between ET + RT vs. RT + ET (-5.7 vs. -4.3 mmHg, p = 0.552). Interindividual analyses revealed significant differences among frequencies comparing Q1 "NRs" (n = 8; 22.2%), Q2 "LRs" (n = 8; 22.2%), Q3 "MRs" (n = 9; 25.0%), and Q4 "HRs" (n = 11; 30.5%), p < 0.0001. Quartile comparisons showed significant differences in SBP changes (p = 0.035). Linear regression analyses revealed significant association between ∑∆SBP with body fat % (β -3.826, R 2 0.211 [21.1%], p = 0.031), skeletal muscle mass [β -2.150, R 2 0.125 (12.5%), p = 0.023], fasting glucose [β 1.273, R 2 0.078 (7.8%), p = 0.003], triglycerides [β 0.210, R 2 0.014 (1.4%), p = 0.008], and the 6-min walking test [β 0.183, R 2 0.038 (3.8%), p = 0.044]. Conclusion: The CT order of ET + RT and RT + ET promote a similar 'magnitude' in the postexercise hypotensive effects during the eight sessions of both CT orders in 4 weeks of training duration, revealing "nonresponders" and 'high' responders that can be predicted from body composition, metabolic, and physical fitness outcomes.

Dataset Information

A Prospective Clinical Study Characterizing the Influence of Morbid Obesity on the Pharmacokinetics of Gentamicin: Towards Individualized Dosing in Obese Patients.

Publications

A Prospective Clinical Study Characterizing the Influence of Morbid Obesity on the Pharmacokinetics of Gentamicin: Towards Individualized Dosing in Obese Patients.

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