Noriyasu Fukuoka

Pharmacokinetics of prophylactic micafungin in very-low-birth-weight infants.

We evaluated the use of micafungin as a prophylaxis in very-low-birth-weight infants. Micafungin was first administered to 25 very-low-birth-weight infants 12 to 24 hours after birth at a dose of 1 mg/kg/d. the apparent volume of distribution, the apparent elimination rate constant, the elimination half-life, and the total body clearance (mean ± SD) were 0.76 ± 0.28 L/kg, 0.12 ± 0.041 1/h, 6.7 ± 2.2 h, and 0.089 ± 0.047 L/kg/h, respectively.

Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation.

Elevated thrombin-antithrombin complex (TAT) or decreased serum albumin levels suggest heightened vascular permeability in disseminated intravascular coagulation (DIC). In such a situation, plasma antithrombin III (AT-III) may decrease because of the leakage. We thus examined whether AT-III activity before and after administration of an AT-III agent changed depending on plasma TAT and/or serum albumin levels in 20 consecutive patients with DIC. We also analyzed the pharmacokinetics for AT-III using a two-compartment model. Serum albumin levels before AT-III administration correlated with preadministered and postadministered AT-III activity, but TAT levels did not. Regardless of TAT levels, AT-III trough activity on the third day increased significantly. In patients with albumin levels of 2.5 g/dL or less, AT-III trough levels on the third day were significantly lower than those with higher levels of albumin. The half-life of the distribution phase for AT-III agent in the patients was shortened to less than one third the value reported in congenital AT-III deficiency, suggesting increased vascular permeability in the acute state patients here. The distribution volume of the agent increased remarkably compared with the previous control. We report here for the first time that in critical patients with DIC, plasma AT-III levels before and after AT-III administration could be predicted by preadministered serum albumin levels, but not by TAT. These findings could be explained by the pharmacokinetic profile, increased vascular permeability and distribution volume, observed in critical patients.

Micafungin does not influence the concentration of tacrolimus in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs. OBJECTIVE To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation. RESULTS The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 ± 306, 653 ± 328, 699 ± 340 and 671 ± 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 ± 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%. CONCLUSION We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients.

Differences in antithrombin III activities by administration method in critical patients with disseminated intravascular coagulation: a pharmacokinetic study.

Pharmacokinetic (PK) data for antithrombin III (AT) are limited in the critical patients. We therefore performed PK analysis using a two-compartment model and also examined whether plasma AT activity would change depending on two administration methods, AT agent at 500 U/8 h (divided group) or 1,500 U/24 h (combined group) for 3 days, a regulated dosage for disseminated intravascular coagulation (DIC) treatment in Japan, in critical patients with DIC. Clinical prospective randomized study. A high care unit in a university hospital. Twenty-four consecutive critical patients with DIC. Ages ranged from 34 to 91 years. Acute physiology age and chronic health evaluation II scores were 25 to 35. Antithrombin III activities in the combined group caused remarkable transient increases but returned to near the preadministration level 24 h after the infusion. Antithrombin III level in the divided group showed small elevations on each session; therefore, steady increases were found after serial administrations of the agent. On the third day, AT trough activities in the divided group were significantly higher than those in the combined group (P = 0.005). However, peak AT activities in the combined group after AT administration were higher than those in the divided group throughout the study (P = 0.024). Aggravation of bleeding tendency occurred more frequently in the combined group (P = 0.03). Half-life times on the distribution phase in both groups were remarkably shorter than those of previously reported control in congenital AT deficiency. This suggests an increased vascular permeability in the critical patients in this study. Distribution volume in the patients here increased significantly as compared with the previous controls. This is the first PK report using a two-compartment model to demonstrate that remarkable increases in vascular permeability and distribution volume occur in critical patients with DIC, and if the same dose is administered intermittently in such PK situation, AT administration in divided manner can maintain plasma AT trough activity higher than that in the combined method.

Problems associated with prophylactic use of erythromycin in 1566 staff to prevent hospital infection during the outbreak of pertussis.

Background and objective:  Pertussis developed in Kagawa University Medical School and University Hospital in May 2007. To control the outbreak and prevent the infection of hospital inpatients, the Infection Control Team (ICT) carried out the prophylactic administration of erythromycin (EM) to hospital staff (1566 staff) who might be exposed to Bordetella pertussis.

Dose adjustment of phenytoin for comedication in Japanese patients with epilepsy.

This study sought a suitable physiological parameter related to daily phenytoin (PHT) dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of coadministered antiepileptic drugs on Ct quantitatively to adjust PHT dose. Data were derived from a total of 368 patients with epilepsy treated with multiple oral administrations of PHT. Phenobarbital, carbamazepine, valproic acid, zonisamide, clonazepam, and ethosuximide were coadministered. For the administration of PHT alone, 4 types of parameter, that is, total body weight, total body water volume, body surface area, and extracellular water volume (VECW) were examined. Then, a Michaelis-Menten kinetic model was postulated including VECW, which was assumed to detect the effect of the coadministered drug quantitatively. Adopting VECW as a transforming factor, the concentration to dose (L:D) ratio [Ct/(D/VECW)] was independent of the patients age and gender in relation to Ct and expressed as Ct/(D/VECW) = 0.0245 × Ct + 0.076. Analysis clarified that ratios were estimated as 0.90, 0.91, 0.89, and 0.84 for phenobarbital, carbamazepine, valproic acid, and zonisamide, respectively, to maintain the same Ct concentration of PHT. Influences were not detected as the number (≧2) of coadministered drugs increased, regardless of factor type. PHT clearance changed in an age-dependent manner and was usually poorly correlated with weight-based doses. VECW was more closely correlated with age-dependent changes in physiological parameters such as clearance. VECW was considered to remove the influence of age on clearance, and estimated ratios could be used for all age groups. In the case of the addition or removal of concomitant treatment with antiepileptic drugs in the same patient, the daily PHT dose was calculated using the value of each ratio or its reciprocal. Our results could be helpful in determining PHT dosing.

25% Albumin Infusion Maintains Antithrombin III (AT) Activity after AT AgentAdministration in Critically Ill Patients with Disseminated IntravascularCoagulation (DIC)

Objective: To report for the first time critically ill patients with disseminated intravascular coagulation (DIC) in whom the infusion of 25% albumin solution produces remarkable elevations in plasma antithrombin III (AT) activities after administration of AT agents. Design: A prospective observational study. Interventions: 1) Plasma AT activities were serially measured in DIC patients after AT administration, enable us to analyze their pharmacokinetics; 2) Comparisons of AT activities between two groups of receiving AT agent with or without the infusion of 25% albumin solution; 3) in vitro examinations were conducted to define whether albumin application itself would influence directly an AT measurement system using samples already determined the levels of AT activities. Methods and main results: Twenty consecutive critical patients with DIC were divided into two groups: groups receiving AT agents of 1500 units with (N=11) and without (N=9) the application of 25% albumin solutions. Patients treated with albumin solutions after AT agents showed remarkable elevations in AT peak and trough activities, whereas patients receiving the same dose of the AT agents without albumin co-administration did not maintain its trough activity. Pharmacokinetic analyses revealed that patients had shortened the distribution half-life time of AT, suggesting enhanced vascular permeability. The levels of AT activities in patients treated with both albumin and AT agents (N=11) were significantly higher than those without albumin administration (N=9, p=0.01). Furthermore, in vitro albumin applications to the AT measurement system did not effect on its values in the samples. Conclusion: This is the first report indicating that 25% albumin administration could elevate and sustain AT activities, even when a limited AT dose was administered to DIC patients with increased vascular permeability. This may be due to a certain binding effect of albumin, which needs to be defined in the future.

Voriconazole concentration is inversely correlated with corticosteroid usage in immunocompromised patients

Voriconazole (VRCZ) is a broad‐spectrum antifungal agent that can be administered both orally and intravenously. A high level of intra‐ and interindividual variability in serum drug therapeutic concentrations has been reported. We analyzed the influence of corticosteroid use on serum VRCZ concentration by assessing the correlation between corticosteroid dose and VRCZ trough level.

Prediction Model of Serum Lithium Concentrations

INTRODUCTION Therapeutic drug monitoring is necessary for lithium, but clinical application of several prediction strategies is still limited because of insufficient predictive accuracy. We herein proposed a suitable model, using creatinine clearance (CLcr)-based lithium clearance (Li-CL). METHODS Patients receiving lithium provided the following information: serum lithium and creatinine concentrations, time of blood draw, dosing regimen, concomitant medications, and demographics. Li-CL was calculated as a daily dose per trough concentration for each subject, and the mean of Li-CL/CLcr was used to estimate Li-CL for another 30 subjects. Serum lithium concentrations at the time of sampling were estimated by 1-compartment model with Li-CL, fixed distribution volume (0.79 L/kg), and absorption rate (1.5/hour) in the 30 subjects. RESULTS One hundred thirty-one samples from 82 subjects (44 men; mean±standard deviation age: 51.4±16.0 years; body weight: 64.6±13.8 kg; serum creatinine: 0.78±0.20 mg/dL; dose of lithium: 680.2±289.1 mg/day) were used to develop the pharmacokinetic model. The mean±standard deviation (95% confidence interval) of absolute error was 0.13±0.09 (0.10-0.16) mEq/L. DISCUSSION Serum concentrations of lithium can be predicted from oral dosage with high precision, using our prediction model.

Calculation of Lithium Clearance for Clinical use Based on Renal Excretion in Japanese Patients

Background: It is recommended to adjust the dosage of lithium carbonate, primarily used in the treatment of mania, based on the serum lithium concentration at steady-state (Css). It has been suggested that factors associated with renal function should be included in the estimation of lithium clearance (Li-CL) due to its elimination via renal excretion. In the present study, parameters affecting Li-CL were investigated in Japanese patients. Methods: Retrospective analysis was performed in patients who had chronically received lithium carbonate, by stepwise regression analysis, with Li-CL as the dependent variable and gender, age, weight and creatinine clearance (Ccr) as independent variables. Ccr was calculated using the Cockcroft-Gault equation, and Li-CL was calculated as the reciprocal value of Css per daily dose. Results: Seventy-two patients were enrolled in this study. Regression analysis revealed that only Ccr was an independent variable (P<0.001), and the following equation was obtained: Li-CL (mL/min) = 0.161 × Ccr (mL/min) + 6.47. This equation was then validated by comparison with previously reported methods using a separate population of patients. The bias and precision of the equation’s predictions were evaluated by calculating the mean prediction error, mean absolute error and root mean squared prediction error. Although the Jermain method had the least bias, no significant differences were observed between the present and Jermain methods. Conclusion: Because the equation of the present study includes Ccr as a parameter of renal function, this may better provide appropriate dosing and safety of lithium therapy in Japanese patients.