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ABSTRACT: Colistin is increasingly used as a salvage therapy of nosocomial infections caused by multidrug-resistant gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data of colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients.Fifty patients with burns ranging from 4% to 85% of total body surface area treated with colistimethate sodium (CMS) were studied. CMS which is hydrolyzed in vivo to an active metabolite was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a LC/MS/MS system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, ver. 6.2).A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance on the relative fraction of CMS converted into colistin and the presence of edema on the turnover rate constant of CMS converted into colistin. Steady-state 24 h the area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Unlike previous reports in critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter and continuous renal replacement therapy was not a significant covariate for any PK parameters.
Antimicrobial Agents and Chemotherapy 02/2013; · 4.84 Impact Factor
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ABSTRACT: The pharmacokinetic (PK) property of fluconazole might be significantly altered in major burn patients by medical interventions and physiologic changes. In this study, we were to investigate fluconazole PK in burn patients using population approach and to recommend the optimal fluconazole regimen based upon the predicted therapeutic outcome. At steady-state, blood samples for PK analysis were obtained from 60 burn patients receiving daily 100 ∼ 400 mg fluconazole. A mixed-effect modeling was performed and the therapeutic outcome of antifungal therapy was predicted from 10,000 virtual patients using NONMEM (Ver.7.2). Minimum inhibitory concentration (MIC) values were sampled from the MIC distribution at the study site. fAUC/MIC > 25 hr was used as the criterion for therapeutic success. When the same dose was given, plasma concentration of fluconazole was predicted to be lower in burn patients compared to non-burn population because of the large PK parameter (Clearance, Volume of Distribution) estimates and continuous renal replacement therapy (CRRT). This tendency was particularly predominant when the patients were within 30 post-burn days. Thus, conventional fluconazole regimen might not guarantee a successful treatment against Candida spp. in burn patients even when the strain was susceptible. Based upon our findings, 400 mg/day fluconazole is recommended to obtain therapeutic successes in major burn patients.
Antimicrobial Agents and Chemotherapy 12/2012; · 4.84 Impact Factor
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ABSTRACT: We analyzed the pharmacokinetics of C3G on data from twelve subjects, after 2-week multiple dosing of black bean (Phaseolus vulgaris, Cheongjakong-3-ho) seed coat extract, using the mixed effect analysis method (NONMEM, Ver. 6.2), as well as the conventional non-compartmental method. We also examined the safety and tolerability. The PK analysis used plasma concentrations of the C3G on day 1 and 14. There was no observed accumulation of C3G after 2-week multiple dosing of black bean seed coat extract. The typical point estimates of PK were CL (clearance)=3,420 l/h, V (volume)=7,280 L, Ka (absorption constant)=9.94 h(-1), ALAG (lag time)=0.217 h. The black bean seed coat extract was well tolerated and there were no serious adverse events. In this study, we confirmed that a significant amount of C3G was absorbed in human after given the black bean seed coat extract.
Korean Journal of Physiology and Pharmacology 08/2012; 16(4):249-53. · 0.96 Impact Factor
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ABSTRACT: PURPOSE: Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT(1) receptor. The aim of our study was to perform a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of fimasartan to evaluate the effect of food on the mechanistic PK-PD relationship. METHODS: This was a food-drug interaction single-center study involving 24 healthy subjects that was designed as a randomized, open-label, single-dosing, two-way crossover trial. Extensive PK data was obtained on blood samples collected at 0, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, and 24 h post-dosing and five systolic/diastolic blood pressure (BP) measurements made at 0, 4, 8, 12 and 24 h post-dosing and used to construct a mixed effect model (NONMEM, ver. 6.2). RESULTS: A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high-fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37 % when the subjects were given a high-fat diet. CONCLUSIONS: The turnover PK-PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 h after dosing better than the effect compartment or transduction models. To predict the influence of a high-fat diet on the blood pressure-lowering effect of fimasartan in healthy subjects, we simulated changes in BP when fimasartan was given daily for 30 days. The overlapping pattern of simulated BP curves in the fasted versus fed group demonstrated that a high-fat diet would not cause a clinically significant reduction in the BP-lowering effect of fimasartan, despite a significant reduction in bioavailability.
European Journal of Clinical Pharmacology 06/2012; · 2.85 Impact Factor
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ABSTRACT: The aim of this study was to develop a non-linear mixed effect circadian rhythm model of acetylcholinesterase (AChE) activity variation and to evaluate the inhibitory effect of acorn extract (2 g) and galantamine (16 mg), used as positive control, on human AChE in red blood cells (RBC).
This was an open-label, randomized, three-way crossover study involving 12 healthy subjects who received one of the treatments in each study period: no treatment, acorn extract, and galantamine. RBC AChE activity was measured in peripheral blood samples collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16 and 24 h post-dose administration. Non-linear mixed effect modeling was performed using NONMEM (ver. 7.0).
The circadian variation of AChE activity was best described using two mixed effect cosine functions, with periods of 24 and 12 h, respectively. When the inhibitory effect terms were added, the model was significantly improved for both acorn extract and galantamine. In terms of the effect, a 2-g single dose of acorn extract showed AChE inhibition (about 5%) similar to that of a 16-mg single dose of galantamine, in the first 24 h after administration.
Based on the very pronounced inter- and intra-day variation in AChE activity in RBC, we conclude that the model-based approach is essential for the proof of concept and quantitation of AChE inhibition in human subjects.
European Journal of Clinical Pharmacology 12/2011; 68(5):599-605. · 2.85 Impact Factor
