Kazuro Ikawa

Clinical Outcomes With Extended or Continuous Versus Short-term Intravenous Infusion of Carbapenems and Piperacillin/Tazobactam: A Systematic Review and Meta-analysis

We sought to study whether the better pharmacokinetic and pharmacodynamic (PK/PD) properties of carbapenems and piperacillin/tazobactam, when the duration of infusion is longer, were associated with lower mortality. PubMed and Scopus were searched for studies reporting on patients treated with extended (≥3 hours) or continuous (24 hours) versus short-term duration (20-60 minutes) infusions of carbapenems or piperacillin/tazobactam. Fourteen studies were included (1229 patients). Mortality was lower among patients receiving extended or continuous infusion of carbapenems or piperacillin/tazobactam compared to those receiving short-term (risk ratio [RR], 0.59; 95% confidence interval [CI], .41-.83). Patients with pneumonia who received extended or continuous infusion had lower mortality than those receiving short-term infusion (RR, 0.50; 95% CI, 0.26-0.96). Data for other specific infections were not available. The available evidence from mainly nonrandomized studies suggests that extended or continuous infusion of carbapenems or piperacillin/tazobactam was associated with lower mortality. Well-designed randomized controlled trials are warranted to confirm these findings before such approaches become widely used.

Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction

The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P<0.01) strong correlation (r=0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the trough concentration was 14.4-35.6 mg/L and the area under the plasma linezolid concentration-time curve for 24h (AUC(24h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2mg/L for trough concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid trough concentration and AUC and that higher drug exposure induced thrombocytopenia.

Pharmacokinetic–pharmacodynamic target attainment analysis of doripenem in infected patients

This study was a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of doripenem. Drug concentration data in plasma (115 samples) and urine (61 samples) from 18 infected patients were concurrently analysed to develop a more accurate population PK model for doripenem. In the final PK model, creatinine clearance (CL(Cr)) was the most significant covariate: CL(r) (L/h)=0.137xCL(Cr); CL(nr) (L/h)=2.49; V(1) (L)=8.29; Q (L/h)=8.10; and V(2) (L)=9.37, where CL(r) and CL(nr) are the renal and non-renal clearances, V(1) and V(2) are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central-peripheral) clearance. Based on the PK model, a Monte Carlo simulation predicted the probabilities of attaining the bactericidal exposure target (40% of the time above the minimum inhibitory concentration (MIC)) in plasma and defined the PK-PD breakpoints (the highest MIC values at which the target attainment probabilities were >or=90%). The breakpoint for 500 mg every 8h (q8h) (1-h infusion) with a CL(Cr) of 80 mL/min (1 microg/mL) corresponded to those for 250 mg q8h with a CL(Cr) of 40 mL/min and 250 mg every 12h with a CL(Cr) of 20 mL/min. Prolonging the infusion time was a more effective strategy than dose escalation to increase the breakpoint. These results provide guidance for constructing a PK-PD-based strategy for dosing guidance for tailoring doripenem regimens.

Quantification of doripenem in human plasma and peritoneal fluid by high-performance liquid chromatography with ultraviolet detection

A simple and rapid HPLC method that includes ultrafiltration to remove plasma and peritoneal fluid protein was developed to determine doripenem concentrations in human plasma and peritoneal fluid. Doripenem was stabilized by immediate mixing of the plasma or peritoneal fluid with 1M 3-morpholinopropanesulfonic acid buffer (pH 7.0) (1:1). Doripenem and an internal standard were detected by measuring their ultraviolet absorbance at 300 nm. The calibration curves for doripenem in human plasma and peritoneal fluid were linear from 0.05 to 100 microg/mL. For plasma, both the intra- and the interday precision were less than 3.41% (CV), and the accuracy was between 97.4 and 101.7% above 0.05 microg/mL. For peritoneal fluid, the intra- and the interday precision were less than 2.98% (CV), and the accuracy was between 94.4 and 103.9% above 0.05 microg/mL. The limit of detection was 0.02 microg/mL in both plasma and peritoneal fluid. The assay has been applied to the therapeutic drug monitoring of doripenem in both plasma and peritoneal fluid.

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.

Pharmacodynamic assessment of doripenem in peritoneal fluid against Gram-negative organisms: use of population pharmacokinetic modeling and Monte Carlo simulation

This study aimed to assess the peritoneal pharmacodynamics of intravenous doripenem using population pharmacokinetic modeling and Monte Carlo simulation. Drug concentrations in peritoneal fluid (PF) and serum from 11 laparotomy patients and MIC distributions against clinical isolates in Japan for 4 Gram-negative organisms were used. The probabilities of attaining the pharmacodynamic target (40% T > MIC) were greater in PF than in serum. To achieve a > or =90% probability of target attainment in PF, 0.25 g tid and 0.5 g tid (0.5-h infusions) had to be sufficient against Escherichia coli, Klebsiella spp., and Enterobacter cloacae; however, 1 g tid (0.5-h infusion) was required against Pseudomonas aeruginosa. Prolonged (4-h) infusion regimens resulted in increase of the target attainment probabilities in PF for P. aeruginosa. These results should help to achieve a better understanding of the peritoneal pharmacodynamics of doripenem while also helping to rationalize and optimize the dosing regimen for intra-abdominal infections.

Safety analysis of liposomal amphotericin B in adult patients: anaemia, thrombocytopenia, nephrotoxicity, hepatotoxicity and hypokalaemia.

Liposomal amphotericin B (L-AmB), which was developed to reduce side effects, has been shown to have a better safety profile than both the deoxycholate and lipid complex forms of amphotericin B; however, the frequency of major side effects is still unclear. Thus, the aim of the present study was to assess retrospectively the frequency of L-AmB-induced anaemia, thrombocytopenia, nephrotoxicity, hepatotoxicity and hypokalaemia as well as the relationship between daily dose of L-AmB and these side effects. A low red blood cell (RBC) count (post-/pre-treatment) and anaemia were observed in 7 and 10 of 21 adult patients, respectively. Thrombocytopenia was observed in 11 of 19 adult patients. Doses of L-AmB that are estimated to cause side effects of a low RBC count, anaemia and thrombocytopenia with 50% probability are 4.0, 3.3 and 3.0mg/kg/day, respectively. Nephrotoxicity was observed in 6 of 22 patients. Variations of total bilirubin, γ-glutamyl transpeptidase, aspartate aminotransferase and alanine aminotransferase used as indices of hepatotoxicity were observed in 6, 7, 8 and 8 of 22 patients, respectively. Hypokalaemia was observed in 4 of 9 patients; however, nephrotoxicity, hepatotoxicity and hypokalaemia were not caused in a dose-dependent manner. In conclusion, the present analyses showed that L-AmB dose-dependently induced anaemia and thrombocytopenia in adult patients. It is important to pay attention to causing anaemia and thrombocytopenia when patients are receiving L-AmB at doses of >3.3mg/kg/day and >3.0mg/kg/day, respectively.

Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

Objective:  This study aimed to develop a population pharmacokinetic model for high‐dose methotrexate (MTX), specifically focusing on the drug urinary excretion process.

Development of breakpoints of carbapenems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in peritoneal fluid.

This study aimed to develop breakpoints of carbapenems for intraabdominal infections, based on pharmacokinetics (PK) and pharmacodynamics (PD) at the target site. Imipenem, meropenem, and doripenem were each administered to 8–11 patients before abdominal surgery, and venous blood and peritoneal fluid samples were obtained. The drug concentrations in plasma and peritoneal fluid were determined and analyzed using population pharmacokinetic modeling. Using the pharmacokinetic model parameters, a Monte Carlo simulation was performed to estimate the probabilities of attaining the bacteriostatic and bactericidal targets (20% and 40% of the time above the minimum inhibitory concentration [MIC], respectively) in peritoneal fluid. The bacteriostatic and bactericidal breakpoints were defined as the highest MIC values at which the bacteriostatic and bactericidal probabilities in peritoneal fluid were 80% or more. The breakpoints for the minimum and maximum approved dosages of each drug were identical for imipenem, meropenem, and doripenem, and some of these values varied with dosing interval and infusion time. Site-specific PK-PD-based breakpoints are proposed here for the first time, and should help us to select appropriate carbapenem regimens for intraabdominal infections.

Lafutidine, a newly developed antiulcer drug, elevates postprandial intragastric pH and increases plasma calcitonin gene-related peptide and somatostatin concentrations in humans: comparisons with famotidine.

Lafutidine, a newly developed histamine H2-receptor antagonist, inhibits daytime (i.e., postprandial) as well as nighttime gastric acid secretion in clinical studies. It also has gastroprotective activity that particularly affects mucosal blood flow in rats. This study focused on the efficacy of lafutidine on plasma concentrations of gastrointestinal peptides in humans. Six healthy male volunteers aged 23–32 years without Helicobacter pylori infection were orally administered either 10 mg lafutidine, 20 mg famotidine, or water only (control) 30 min after a standard meal (650 kcal). Plasma concentrations of lafutidine and famotidine were highest from 90 to 150 min after administration. Intragastric pH was elevated after both lafutidine and famotidine compared with the control. Plasma concentrations of calcitonin gene-related peptide (CGRP) and somatostatin were significantly increased after lafutidine at 60 and 90 min. We concluded that lafutidine increases plasma concentrations of CGRP and somatostatin in humans, which may result in inhibition of postprandial acid secretion and gastroprotective activity.