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Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients.

ABSTRACT: Aminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m(2), respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051-1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance.

SUBMITTER: Pai MP

PROVIDER: S-EPMC3165292 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients.

Pai Manjunath P MP Nafziger Anne N AN Bertino Joseph S JS

Antimicrobial agents and chemotherapy 20110613 9

Aminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic k ...[more]

PMID: 21670189

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Project description:The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.).

Dataset Information

Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients.

Publications

Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients.

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