Erika Watanabe

Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients

The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC₂₄)/minimum inhibitory concentration (MIC) ratio of ≥100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CLCr) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)=0.0258 × CLCr + 2.03. A strong correlation (r=0.970) was found between AUC₂₄ and trough plasma concentrations (Cmin) [AUC₂₄=18.2 × Cmin + 134.4]. The Cmin value for AUC₂₄=200 (in the case of MIC=2 μg/mL) was estimated to be 3.6 μg/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 μg/mL. A Kaplan-Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target Cmin range was 3.6-8.2 μg/mL. The following formula to achieve a target Cmin in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day)=CL × AUC₂₄=(0.0258 × CLCr + 2.03)×(18.2 × Cmin + 134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued.

Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention.

Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor β-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125–500 μM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.

Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections

Background Teicoplanin is a glycopeptide antibiotic that has been used to treat serious, invasive infections caused by Gram-positive bacteria. The area under the drug concentration–time curve (AUC)/minimum inhibitory concentration (MIC) was identified as a pharmacokinetic–pharmacodynamic (PK–PD) parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes. Although optimized dosing regimens based on PK–PD are needed, a PK–PD analysis of teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) infections has not yet been performed. Thus, this study examined patients with MRSA infections, who were administered with teicoplanin in order to determine the target AUC/MIC ratio. Methods This study retrospectively assessed data obtained as part of our routine therapeutic drug monitoring (TDM) of teicoplanin therapy in 46 patients with MRSA infections at Kagoshima University Hospital. Serum concentrations of teicoplanin were determined using a fluorescence polarization immunoassay system and used for a Bayesian PK estimation to estimate AUC for 24 hours (AUC24). The MIC value for teicoplanin was determined using a standardized agar dilution method. The effects of teicoplanin were evaluated in terms of bacteriological responses by a quantitative assessment. Results The estimated AUC24/MIC ratios with and without bacteriological responses were 926.6±425.2 µg·h/mL (n=34) and 642.2±193.9 µg·h/mL, respectively (n=12; P<0.05). On the basis of a logistic regression analysis, AUC24/MIC ratios of 500 µg·h/mL, 700 µg·h/mL, and 900 µg·h/mL gave probabilities of treatment success of 0.50, 0.72, and 0.87, respectively. Furthermore, using the Kaplan–Meier curve analysis, an AUC24/MIC ratio of ≥900 led to a significantly stronger bacteriological response than an AUC24/MIC ratio of <900. Conclusion These results suggest that an AUC24/MIC ratio of ≥900 µg·h/mL is required to ensure a sufficient bacteriological response.

Linezolid dosage in pediatric patients based on pharmacokinetics and pharmacodynamics

Linezolid pharmacokinetic profile in pediatric patients has not been fully characterized, and the dose needed to achieve a pharmacokinetic-pharmacodynamic (PK-PD) target has yet to be established because its efficacy is associated with the area under the plasma drug concentration-time curve (AUC24)/minimum inhibitory concentration (MIC) ratio. The present study aimed to define the pharmacokinetic parameters of intravenous linezolid in pediatric patients and assess the rationale for the approved dosage recommendations. Linezolid was safe, tolerated well, and clinically effective for treating Gram-positive bacteria in five pediatric patients (3-11 years). The mean values for the volume of distribution and total clearance (CL) in a one-compartment model were estimated to be 0.646 ± 0.239 l/kg and 0.171 ± 0.068 l/h/kg, respectively (mean ± S.D.). Based on this analysis, the AUC24 and trough drug concentration in plasma (C(min)) for linezolid doses were predicted to be 175.4 μg h/ml and 3.4 μg/ml for 30 mg/kg/day, 204.7 μg h/ml and 4.3 μg/ml for 35 mg/kg/day, and 263.2 μg h/ml and 6.2 μg/ml for 45 mg/kg/day, respectively. Taking into account that AUC24 should be ≥ 200 μg h/ml for MIC of 2.0 μg/ml (to achieve an AUC24/MIC ratio of ≥ 100) and C(min) should be approximately 7 μg/ml (to avoid thrombocytopenia), we consider the approved dosage of 30 mg/kg/day to be fundamentally rational, but can be underdosed against bacteria with MIC of 2.0 μg/ml; therefore, a dose of 35-45 mg/kg/day is more appropriate to ensure the efficacy and safety of linezolid in pediatric patients.

Pharmacokinetic/pharmacodynamic evaluation of sulbactam against Acinetobacter baumannii in in vitro and murine thigh and lung infection models

Acinetobacter baumannii is a pathogen that has become globally associated with nosocomial infections. Sulbactam, a potent inhibitor of β-lactamases, was previously shown to be active against A. baumannii strains in vitro and effective against A. baumannii infections. However, a pharmacokinetic/pharmacodynamic (PK/PD) analysis of sulbactam against A. baumannii infections has not yet been performed. This is necessary because optimisation of dosing regimens should be based on PK/PD analysis. Therefore, in vitro and in vivo PK/PD analyses of sulbactam were performed using murine thigh and lung infection models of A. baumannii to evaluate the pharmacokinetics and pharmacodynamics of sulbactam. Sulbactam showed time-dependent bactericidal activity in vitro against A. baumannii. The PK/PD index that best correlated with its in vivo effects was the time that the free drug concentration remained above the minimum inhibitory concentration (fT>MIC) both in the thigh (R(2)=0.95) and lung (R(2)=0.96) infection models. Values of fT>MIC for a static effect and 1, 2 and 3log10 kill, respectively, were 21.0%, 32.9%, 43.6% and 57.3% in the thigh infection model and 20.4%, 24.5%, 29.3% and 37.3% in the lung infection model. Here we report the in vitro and in vivo time-dependent activities of sulbactam against A. baumannii infection and demonstrate that sulbactam was sufficiently bactericidal when an fT>MIC of >60% against A. baumannii thigh infection and >40% against A. baumannii lung infection was achieved.

Population pharmacokinetic–pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function: Dosing considerations for Acinetobacter baumannii infections

UNLABELLED This study aimed to perform a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of sulbactam against Acinetobacter baumannii in patients with impaired renal function. The PK data (188 plasma samples and 27 urine samples) were modeled simultaneously. The mean population parameters were CLr (l/h) = 0.0792 × CLcr (ml/min), CLnr (l/h) = 2.35, Vc (l) = 12.2, Q (l/h) = 4.68 and Vp (l) = 4.44, where CLr and CLnr are the renal and non-renal clearances, Vc and Vp are the distribution volumes of the central and peripheral compartments and Q is intercompartmental clearance. The creatinine clearance (CLcr) was the most significant covariate. The determined MIC of sulbactam against A. baumannii clinical isolates (n = 27) was 0.75-6.0 μg/ml with MIC50 and MIC90 of 1 and 4 μg/ml, respectively. For sulbactam regimens, a Monte Carlo simulation estimated the probabilities of attaining the bactericidal target (60% of the time above the MIC) and determined the PK-PD breakpoints (the highest MICs at which the probabilities were 90% or more). In a patient with a CLcr of 15 ml/min, a regimen of 1 g twice daily achieved a 90% or more probability against the A. baumannii isolate population; however, 2 g four times daily was needed for a 90% or more probability in a patient with a CLcr of 90 ml/min. The results of the PK-PD target attainment analysis are useful when choosing the sulbactam regimen based on the CLcr of the patient and the susceptibility of A. baumannii. REGISTRATION NUMBER UMIN000007356.

Therapeutic drug monitoring of voriconazole in Japanese patients: analysis based on clinical practice data

The aim of this study was to investigate whether routine therapeutic drug monitoring (TDM) of voriconazole (VRCZ) reduced discontinuation due to hepatotoxicity. Hepatotoxicity was observed in 15 (51.7%) out of 29 patients. The percentages of patients who developed hepatotoxicity within 4 days and 1 week were 26.7 and 46.7%, respectively. The drug trough concentrations in patients with and without hepatotoxicity were 5.55 ± 2.73 and 2.36 ± 1.67 μg/ml (P < 0.01, the two-sided Students t-test), respectively. Trough concentrations reached the target of 1–5 μg/ml in patients with gradual dose reductions based on TDM, and, consequently, liver enzyme levels returned to the original levels before the VRCZ treatment. All patients eventually continued effective VRCZ therapy despite its hepatotoxicity. Thus, dose adjustments by TDM to achieve the target trough concentrations is useful in order to avoid hepatotoxicity and enable continued effective VRCZ therapy for Japanese patients with invasive fungal infections.

Pharmacokinetics of Prophylactic Ampicillin-Sulbactam and Dosing Optimization in Patients Undergoing Cardiovascular Surgery with Cardiopulmonary Bypass.

UNLABELLED Antibiotic concentrations must be maintained at an adequate level throughout cardiovascular surgery to prevent surgical site infection. This study aimed to determine the most appropriate timing for intraoperative repeated dosing of ampicillin-sulbactam, a commonly used antibiotic prophylaxis regimen, to maintain adequate concentrations throughout the course of cardiovascular surgery with cardiopulmonary bypass (CPB). The total plasma concentrations of ampicillin were monitored in 8 patients after ampicillin (1 g)-sulbactam (0.5 g) administration via initial intravenous infusion and subsequent CPB priming. Pharmacokinetic parameters were estimated and used to predict the free plasma concentrations of ampicillin. The mean values for the volume of distribution, elimination rate constant, elimination half-life, and total clearance of ampicillin were 15.8±4.1 L, 0.505±0.186 h(-1), 1.52±0.47 h, and 7.72±2.72 L/h, respectively. When ampicillin (1 g)-sulbactam (0.5 g) was intravenously administered every 3, 4, 6, and 12 h after the start of CPB, the predicted free trough plasma concentrations of ampicillin were 15.20, 8.25, 2.74, and 0.13 µg/mL, respectively. Therefore, an every-6-h regimen was needed to maintain the free ampicillin concentration at more than 2 µg/mL during cardiovascular surgery with CPB. We suggest that the dose and dosing interval for ampicillin-sulbactam should be adjusted to optimize the efficacy and safety of treatment, according to the minimum inhibitory concentrations for methicillin-sensitive Staphylococcus aureus isolates at each institution. REGISTRATION NUMBER UMIN000007356.