Dong-Seok Yim

Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients

BACKGROUND Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species. However, despite its potential advantages, the occurrence of unpredictable toxicities might be critical in immunocompromised patients. The aim of this study was to analyze risk factors for voriconazole-related severe adverse events (SAEs). METHODS This prospective observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009. RESULTS Of the 25 patients enrolled, eight (32%) showed voriconazole-related SAEs, which included hepatotoxicities (n=5), cardiac tachyarrhythmias (n=2), and neurotoxicity (n=1). Sex, age, underlying hematological malignancies, voriconazole dose, the co-administration of a proton pump inhibitor, and CYP2C19 genotype were not found to be related to the occurrence of SAEs. However, trough plasma concentrations of voriconazole were found to be significantly higher in the patients with an SAE: median 6.32 mg/l (interquartile range (IQR) 2.86-9.71 mg/l) vs. median 2.15 mg/l (IQR 0.92-4.00 mg/l); p=0.011. Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l (sensitivity 62.5% and specificity 94.1%). Furthermore, multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE. CONCLUSIONS This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.

Efficacies of Vancomycin, Arbekacin, and Gentamicin Alone or in Combination against Methicillin-Resistant Staphylococcus aureus in an In Vitro Infective Endocarditis Model

ABSTRACT We adopted an in vitro infective endocarditis model (IVIEM) to compare the efficacy of vancomycin (VAN), arbekacin (ABK), and gentamicin (GEN) alone or in combination. Using two strains of clinically isolated methicillin-resistant Staphylococcus aureus, one GEN susceptible (GS171) and one GEN resistant (GR153), fibrin clots were prepared and suspended in the IVIEM. Antibiotics were given as boluses every 6 h (q6h), q12h, or q24h or by continuous infusion with VAN, q12h or q24h with ABK, and q8h or q24h with GEN. For combination treatment, VAN q12h plus ABK q24h and VAN q12h plus GEN q24h were given. Fibrin clots were removed from each model at 0, 8, 24, 32, 48, and 72 h, and the bacterial densities were determined. The number of colonies within the fibrin clot was significantly decreased in all study groups compared with control groups (P < 0.001). When VAN and ABK were administered alone, the number of colonies was significantly lower in GS171 than in GR153 by 8 h after administration (P = 0.02) and was lowest in GS171 when ABK was administered q12h (P = 0.01). At 72 h, ABK or VAN alone produced equivalent bacterial reductions regardless of dosing frequency and GEN resistance. In GR153, VAN plus ABK showed an additive effect till 24 h, although VAN plus GEN showed indifference. Our data suggest that ABK could be used as an alternative to VAN in GEN-resistant staphylococcal endocarditis. An additive effect was seen when VAN and ABK were used together in GEN-resistant strains until 24 h; however, further studies are warranted for the clinical application of this combination.

A population pharmacokinetic-pharmacodynamic model for simvastatin that predicts low-density lipoprotein-cholesterol reduction in patients with primary hyperlipidaemia.

Simvastatin (SV), a HMG-CoA reductase inhibitor, is widely used for the treatment of hyperlipidaemia. The objectives of the present study were to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for simvastatin and to evaluate its usefulness in predicting the dose-response relationship of simvastatin in patients with hyperlipidaemia. The data were obtained from a drug-drug interaction study to assess the effect of aspirin on the PK of simvastatin. Twenty-seven healthy volunteers were given simvastatin 40 mg daily for 14 days in whom aspirin 100 mg q.d. was co-administered after day 8. Full PK studies were performed on days 1, 7 and 14 in addition to trough sampling on days 5, 6, 12 and 13. Low-density lipoprotein-cholesterol (LDL-C) levels were also measured serially. Then, a population PK-PD model for simvastatin and its active metabolite, simvastatin acid (SVA), was developed using mixed effect methods (NONMEM Ver. 6.2). A simple linear PK model with parent and metabolite compartments provided the best fit for the 2647 concentrations of simvastatin and simvastatin acid, and a turnover model was used to describe the change in LDL-C levels. The dose-response curve simulated from the final model and those obtained from the literature overlapped very closely. No influence of aspirin was observed in PK or PD. A simple PK-PD model developed using only 2-week study data from fewer than 30 healthy volunteers successfully predicted the dose-response relationship of simvastatin in patients when compared with published data.

Population Pharmacokinetic Analysis of Colistin in Burn Patients

ABSTRACT Colistin is increasingly used as a salvage therapy for nosocomial infections caused by multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data for 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 who had been 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 liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, v. 6.2). A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance for the relative fraction of CMS converted into colistin and the presence of edema for the turnover rate constant of CMS converted into colistin. A steady-state 24-h 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. Relative to previous studies with 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.

A Novel Placement Method of the Bravo Wireless pH Monitoring Capsule for Measuring Intragastric pH

Purpose The delivery system of the Bravo capsule was designed for placement on the esophagus. We evaluated the feasibility of our novel placement method of the Bravo capsule using a clip to monitor intragastric pH and to compare the accuracy of the Bravo wireless system to the traditionally used Slimline catheter-Mark III Digitrapper pH monitoring system. Methods The Bravo capsule was placed by clip or conventional delivery system using suction on the gastric wall in 20 fasted subjects. A separate group of ten healthy volunteers underwent simultaneous intragastric pH monitoring for comparison of the two systems with meals. Results Early dislodgment rate of the capsules was lower when placed using clipping (20%) than using conventional delivery system (70%) within 48 h after placement. We observed prominent movement of one catheter in the stomach during the study. Post-test calibration drifts of the catheters at pH 7.01 were significantly greater than those of the Bravo capsules (P = 0.02). Conclusion Our novel clipping method of the Bravo pH capsule placement provided accurate monitoring of intragastric pH with merits of tolerability, acid stability, and fixing position.

Population pharmacokinetic analysis of piperacillin in burn patients.

ABSTRACT Piperacillin in combination with tazobactam, a β-lactamase inhibitor, is a commonly used intravenous antibiotic for the empirical treatment of infection in intensive care patients, including burn patients. The purpose of this study was to develop a population pharmacokinetic (PK) model for piperacillin in burn patients and to predict the probability of target attainment (PTA) using MICs and concentrations simulated from the PK model. Fifty burn patients treated with piperacillin-tazobactam were enrolled. Piperacillin-tazobactam was administered via infusion for approximately 30 min at a dose of 4.5 g (4 g piperacillin and 0.5 g tazobactam) every 8 h. Blood samples were collected just prior to and at 1, 2, 3, 4, and 6 h after the end of the infusion at steady state. The population PK model of piperacillin was developed using NONMEM. A two-compartment first-order elimination PK model was finally chosen. The covariates included were creatinine clearance (CLCR), day after burn injury (DAI), and sepsis. The final PK parameters were clearance (liters/h) (equal to 16.6 × [CLCR/132] + DAI × [−0.0874]), central volume (liters) (equal to 25.3 + 14.8 × sepsis [0 for the absence or 1 for the presence of sepsis]), peripheral volume (liters) (equal to 16.1), and intercompartmental clearance (liters/h) (equal to 0.636). The clearance and volume of piperacillin were higher than those reported in patients without burns, and the terminal half-life and PTA decreased with the increased CLCR. Our PK model suggests that higher daily doses or longer durations of infusion of piperacillin should be considered, especially for burn patients with a CLCR of ≥160 ml/min.

Population Pharmacokinetic Analysis of Fluconazole To Predict Therapeutic Outcome in Burn Patients with Candida Infection

ABSTRACT The pharmacokinetic (PK) property of fluconazole might be significantly altered in major burn patients by medical interventions and physiologic changes. In this study, our aims were to investigate fluconazole PK in burn patients using a 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 between 100 and ∼400 mg fluconazole daily. A mixed-effect modeling was performed and the therapeutic outcome of antifungal therapy was predicted for 10,000 virtual patients using NONMEM (version 7.2). MIC values were sampled from the MIC distribution at the study site. An area under the free drug concentration-time curve (fAUC)/MIC measurement of >25 h was used as the criterion for therapeutic success. When the same dose was given, the plasma concentration of fluconazole was predicted to be lower in burn patients compared to the nonburn 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 postburn days. Based upon our findings, 400 mg/day fluconazole is recommended to obtain therapeutic successes in major burn patients.

Simulation of the AUC Changes after Generic Substitution in Patients

To address the debate on the safety of generic substitution quantitatively, the author compared the change in AUC in virtual patients who were simulated for several different scenarios of generic substitution. In four scenarios of original (branded) to generic and generic to generic substitution, 5,000 virtual patients were simulated per scenario using the programming software R. The mean population AUC of generics ranged from 90-110% (scenarios A and B) and 80-123.5% (scenarios C and D) of the AUC of the original. Those patients who had an AUC change (ratio) as a result of drug substitution of less than 0.67 or greater than 1.5 were considered to be in potential danger due to the substitution. We found that less than 6% of patients fell outside of the cutoff range of 0.67-1.5 as a result of original to generic substitution. However, in the case of generic to generic substitution, the proportion was as high as 9-12%. This alerts us to the potential danger of generic substitution, especially for drugs with narrow therapeutic indices.

Population Pharmacokinetic/Pharmacodynamic Modeling of Clopidogrel in Korean Healthy Volunteers and Stroke Patients

Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of clopidogrel was developed from pooled data from healthy volunteers (n = 44) and stroke patients (n = 35). The PK modeling used plasma concentrations of the clopidogrel metabolite (SR26334), and the PD modeling used platelet aggregation. The models were developed using NONMEM and evaluated via visual predictive check (VPC). Data were analyzed by 2‐compartment modeling with Erlangs absorption and first‐order elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were ktr (identical transfer rate constant) = 5.97 h−1, ke (elimination rate constant) = 0.126 h−1, kd (distribution rate constant) = 0.212 h−1, V2 (volume of central compartment) = 21.0 L, and V3 (volume of peripheral compartment) = 38.8 L. The typical point estimates of PD were kin (input rate) = 27.9 h−1, Emax (maximum effect on input rate) = 0.292 h−1, EC50 (median effective concentration) = 0.00629 ng/mL, and BASE (predose aggregation) = 66.7%. The final model was used to estimate individual parameters using patient data and showed good predictions using VPC.

Population pharmacokinetics of intravenous itraconazole in patients with persistent neutropenic fever

Purpose:  Empirical use of intravenous (IV) itraconazole (ITZ) for febrile neutropenic patients has recently been introduced in Korea. This study was designed to investigate the population pharmacokinetics (PK) of IV‐ITZ.