Population Pharmacokinetics Of Amikacin Research Articles

Population pharmacokinetics of amikacin in suspected cases of neonatal sepsis.

This study aimed to characterize the population pharmacokinetic parameters of intravenously administered amikacin in newborns and assess the effect of sepsis in amikacin exposure. Newborns aged ≥3 days who received at least 1 dose of amikacin during their hospitalization period were eligible for the study. Amikacin was administered intravenously during a 60-min infusion period. Three venous blood samples were taken from each patient during the first 48 h. Population pharmacokinetic parameter estimates were obtained using a population approach with the programme NONMEM. Data from 329 drug assay samples were obtained from 116 newborn patients (postmenstrual age [PMA] 38.3, range 32-42.4 weeks; weight 2.8, range 1.6-3.8 kg). Measured amikacin concentrations ranged from 0.8 to 56.4 mg/L. A 2-compartment model with linear elimination produced a good fit of the data. Estimated parameters for a typical subject (2.8 kg, 38.3 weeks) were clearance (Cl = 0.16 L/h), intercompartmental clearance (Q = 0.15 L/h), volume of distribution of the central compartment (Vc = 0.98 L) and peripheral volume of distribution (Vp = 1.23 L). Total bodyweight, PMA and the presence of sepsis positively influenced Cl. Plasma creatinine concentration and circulatory instability (shock) negatively influenced Cl. Our main results confirm previous findings showing that weight, PMA and renal function are relevant factors influencing newborn amikacin pharmacokinetics. In addition, current results showed that pathophysiological states of critically ill neonates, such as sepsis and shock, were associated with opposite effects in amikacin clearance and should be considered in dose adjustments.

Review on Population Pharmacokinetics of Amikacin in Paediatrics

Amikacin is an aminoglycoside antibiotic with a broad-spectrum bacterial coverage that is frequently utilized both as monotherapy and in combination with other antibiotics for severe bacterial infections in the paediatric population. The narrow therapeutic index of the drug and high inter-individual variabilities in drug exposure results in either drug toxicity or subtherapeutic concentrations. Thus, therapeutic drug monitoring and population pharmacokinetics are pivotal to facilitate the optimal dosage regimens in paediatrics and negate the adverse outcomes. The therapeutic goal is to maintain the target peak and trough concentrations within 30-40mg/l and <5 mg/l respectively. This review aimed to summarize population pharmacokinetic considerations and the pharmacokinetic parameters of amikacin across the paediatric population.

Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis.

Practitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

Population pharmacokinetics of amikacin in a Korean clinical population

This study aimed at investigating the influence of demographic and clinical covariates on the population pharmacokinetics of amikacin in Korean patients from routinely collected therapeutic drug monitoring data. Pharmacokinetics was studied in 305 adult Korean patients who received amikacin 125 - 1,000 mg once-daily or every-other- day. Peak and trough plasma levels of steady state were measured. Patients were randomized into an index dataset (n = 197) and a validation dataset (n = 108). Covariates were selected in a step-wise approach using NONMEM 7 software. The predictive performance of the model was evaluated by the percent prediction error and the percent coverage of 95% population prediction interval. The covariates significantly influencing amikacin pharmacokinetics were creatinine clearance (p < 0.0001) and ward setting (p = 0.0017) for clearance, and body weight (p < 0.0001) and presence of cholecystitis (p = 0.0135) for volume of distribution. The estimates of pharmacokinetic parameters for a typical individual were 2.82 l/h for clearance, and 18.04 l for volume of distribution. Inter-individual variability (CV%) was 31% for clearance. The mean (SD) of percent prediction errors was 2.1 (26.4)% for peak and -121.5 (460.3)% for trough concentrations. Percent coverage of 95% PPIs for peak and trough concentrations were above 80%. The population pharmacokinetic model developed in this study may be used as a basis for finding optimal amikacin dosing in a Korean patient population without a significant bias. Further studies will be needed to validate these results.

Population pharmacokinetics of amikacin in Korean adult patients

Background To determine demographic and clinical covariates that affect amikacin pharmacokinetic parameters in Korean clinical population Methods For 200 Korean adult patients (115 men and 85 women), blood samples were drawn at the trough and peak steady-state plasma concentrations after multiple infusions of the drug. Amikacin concentration was analyzed by Fluorescence Polarization Immunoassay. Using one-compartment model, the clearance and volume of distribution of amikacin and their relevance to various covariates (creatinine clearance, sex, ward (intensive care unit vs general), disease diagnosed) were estimated by a nonlinear mixed effect model using the NONMEM software, with a stepwise addition method for covariate selection. Results Creatinine clearance had the most significant influence on amikacin pharmacokinetics (p << 0.0001 for clearance, p <0.0001 for volume of distribution). In particular, amikacin clearance was significantly influenced by ward (1.37 (1.18–1.56) for intensive care unit, 2.24 (2.09–2.39) for general) and urinary tract infection (UTI) (1.44 (0.85–2.03) for UTI, 2.13 (1.97–2.29) for no UTI), with numbers denoting mean values (95% confidence interval) (L/hr). Conclusions Our results suggest that a pharmacokinetic model incorporating clinically important covariates would be necessary for a nonbiased amikacin dosage individualization in Korean clinical population. Further study would be needed to verify the appropriateness of the model proposed here. Clinical Pharmacology & Therapeutics (2005) 77, P86–P86; doi: 10.1016/j.clpt.2004.12.220

Population Pharmacokinetics of Amikacin in Korean Neonates

Population Pharmacokinetics of Amikacin in Korean Neonates

Population pharmacokinetics of amikacin in patients with haematological malignancies.

The aim of this study was to analyse the pharmacokinetic behaviour of amikacin in patients with haematological malignancies using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 207 haematology patients divided into two groups: one for computing the population model (n = 134) and the other for validation (n = 73). A one-compartment model was used and the following covariates were tested for their influence on clearance and volume of distribution: age, gender, weight, parenteral nutrition, creatinine clearance, stage of antineoplastic treatment (induction, consolidation, intensification), number of weeks postchemotherapy, clinical diagnosis, Eastern Cooperative Oncology Group score, neutropenia, hypoalbuminaemia, concomitant medication (vancomycin and/or amphotericin B), overhydration, and autologous or allogenic bone marrow transplant. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in these patients. Apart from bodyweight and renal function, acute myeloblastic leukaemia and hypoalbuminaemia proved to be the most important covariates explaining the interindividual variability in amikacin pharmacokinetics in patients with haematological malignancies. The predictive performance of this population model for amikacin serum concentrations seems suitable for clinical purposes.

Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models.

The population pharmacokinetics of amikacin, in neonates, was investigated using the nonlinear mixed effects model (NONMEM). One hundred and six steady-state amikacin serum levels were obtained from 53 black neonates with a mean gestational age of 35.1 weeks and mean age at the start of treatment of 3.1 days. A one-compartment model was used to fit the data. The final models for clearance (CL) and volume of distribution (V) were: CL(l.h(-1)) = 0.031WT(1.45) x P and V(l) = 0.316WT(1.44) where WT = birth weight (kg) and P = 1.28 for girls and 1.0 for boys. Inclusion of other fixed effect parameters in the model did not significantly improve the fit of the data. The inter-individual variability for CL and V were 18% and 13%. respectively. Intra-individual variability was 29%. Mean (95% CI) values of CL, V and half-life were 0.048 (0.045, 0.051) l.h(-1).kg(-1), 0.434 (0.414, 0.453) l.kg(-1) and 6.4 (6.2, 6.6) h respectively. Birth weight was an important determinant of both CL and V and, in this data set, gender was also found to influence CL. Mean population pharmacokinetic values were within the range of those previously derived for other neonatal populations using traditional methods.

Influence of Clinical Diagnosis in the Population Pharmacokinetics of Amikacin in Intensive Care Unit Patients

The aim of the present study was to analyse the pharmacokinetic behaviour of amikacin in intensive care unit (ICU) patients using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 158 medical ICU patients divided into two groups: one for computing the population model (n = 120) and the other for validation (n = 38). A 1-compartment model was used and the following covariates were tested for their influence on clearance (CL) and volume of distribution (Vd): age, gender, weight, parenteral nutrition, creatinine clearance, duration of therapy and clinical diagnosis. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in this patient population. In this study, the final population model accounting for amikacin pharmacokinetics in ICU patients was: CL = 0.93 CL(CR) (1 + 0.22 Trauma), Vd = 0.39 TBW (1 + 0.24 Sepsis), where CL(CR) and TBW corresponded to the patients' creatinine clearance and total bodyweight, respectively. The 'Trauma' and 'Sepsis' variables referred to the clinical diagnosis of the patients. This model was subsequently used to predict amikacin serum levels obtained in the validation population by a priori and Bayesian methods. The predictive performance was adequate for clinical purposes, pointing to the feasibility of our population model to provide reference values for a priori prediction as well as the Bayesian approach for individualisation of amikacin therapy in ICU patients.

Population pharmacokinetics of amikacin in intensive care unit patients studied by NPEM algorithm.

The population pharmacokinetics of amikacin was studied in 40 intensive care unit patients (212 plasma concentrations) by NPEM algorithm using a one-compartment model. The population was best characterized by the following pharmacokinetic parameters: renal clearance relative to creatinine clearance (Cs = 0.96 +/- 0.33), and either the total volume of distribution (Vd = 23.9 +/- 7.0 l) or the volume of distribution relative to body weight (Vs = 0.36 +/- 0.10 l.kg-1. The volume of distribution was increased with respect to the usual value of 0.25 l.kg-1. The statistical distribution of these pharmacokinetic parameters was approximately gaussian, with no significant correlation between volume of distribution and clearance. The medians and standard deviations of Cs and Vs were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 29 patients by the bayesian method, with two blood samples per patient. For each patient, the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 h with no significant bias and good precision (2.9 mg.l-1 for peaks and 0.5 mg.l-1 for troughs). This study confirms the ability of the NPEM algorithm to provide reference population values for use in bayesian monitoring of aminoglycoside therapy.