Toshimi Kimura

Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates

ABSTRACT Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CLarbekacin = 0.0238 × BW/serum creatinine level for PCAs of <33 weeks and CLarbekacin = 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks, Varbekacin = 0.54 liters/kg, CLvancomycin = 0.0250 × BW/serum creatinine level for PCAs of <34 weeks and CLvancomycin = 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks, Vvancomycin = 0.66 liters/kg, CLpanipenem = 0.0832 for PCAs of <33 weeks and CLpanipenem = 0.179 × BW for PCAs of ≥33 weeks, and Vpanipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of ≥33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

Comparative study of population pharmacokinetics upon switching of cyclosporine formulation from Sandimmune to Neoral in stable renal transplant patients.

CYCLOSPORINE A (CyA) is the most commonly used immunosuppressant in renal transplantation. Because of its narrow therapeutic window, therapeutic drug monitoring by measuring the trough level is widely employed. However, the original formulation of CyA, Sandimmune (SIM), has considerable interand intrapatient variability because of its variable absorption. Neoral (MEPC), a new microemulsion form of CyA, has been reported to have improved interand intrapatient variability, but it may need different TDM than the trough level, such as AUC0–4 or C2 level. In this report we performed a population pharmacokinetic study before and after switching from SIM to MEPC in 69 stable renal transplant patients, thereby determining the population pharmacokinetic parameters for a comparison of the bioequivalence of the two different CyA formulations, using the nonlinear mixed-effects model (NONMEM with first-order method) population pharmacokinetic program.

Modeling and Simulation for Estimating the Influence of Renal Dysfunction on the Hypouricemic Effect of Febuxostat in Hyperuricemic Patients Due to Overproduction or Underexcretion of Uric Acid

Whether renal dysfunction influences the hypouricemic effect of febuxostat, a xanthine oxidase (XO) inhibitor, in patients with hyperuricemia due to overproduction or underexcretion of uric acid (UA) remains unclear. We aimed to address this question with a modeling and simulation approach. The pharmacokinetics (PK) of febuxostat were analyzed using data from the literature. A kinetic model of UA was retrieved from a previous human study. Renal UA clearance was estimated as a function of creatinine clearance (CLcr) but non-renal UA clearance was assumed constant. A reversible inhibition model for bovine XO was adopted. Integrating these kinetic formulas, we developed a PK-pharmacodynamic (PK-PD) model for estimating the time course of the hypouricemic effect of febuxostat as a function of baseline UA level, febuxostat dose, treatment duration, body weight, and CLcr. Using the Monte Carlo simulation method, we examined the performance of the model by comparing predicted UA levels with those reported in the literature. We also modified the models for application to hyperuricemia due to UA overproduction or underexcretion. Thirty-nine data sets comprising 735 volunteers or patients were retrieved from the literature. A good correlation was observed between the hypouricemic effects of febuxostat estimated by our PK-PD model and those reported in the articles (observed) (r=0.89, p<0.001). The hypouricemic effect was estimated to be augmented in patients with renal dysfunction irrespective of the etiology of hyperuricemia. While validation in clinical studies is needed, the modeling and simulation approach may be useful for individualizing febuxostat doses in patients with various clinical characteristics.

Evaluation of a pharmacokinetic–pharmacodynamic model for hypouricaemic effects of febuxostat using datasets obtained from real‐world patients

Febuxostat is an active xanthine oxidase (XO) inhibitor which is widely used in the treatment of hyperuricaemia. We aimed to evaluate the predictive performance of a pharmacokinetic–pharmacodynamic (PK–PD) model of the hypouricaemic effects of febuxostat.

Current State of Drug Information Services in Japan. Based on a Hospital Survey in Kanagawa Prefecture.

The rapid growth of pharmaceutical care in Japan has resulted in the need for a new clinical support system for drug information (DI) services. The DI committee of the Kanagawa Society of Hospital Pharmacists conducted a survey of hospitals in 1997-1998. The purpose of the survey was to determine such things as the number of pharmacists actually working in DI, the number of hospitals publishing a DI newsletter and also the number of hospitals utilizing computer automation in their DI programs. The survey consisted of 16 questions that were mailed to 353 hospital pharmacies, out of which 155 responses were returned. The results of the survey were compared to the findings of a similar study performed in 1996. One hundred-two of the 155 pharmacies (66%) indicated that they had a DI-room within their facility. Eighty-five percent of the facilities had their own hospital formulary. In addition many (56.8%) of the DI-rooms had a computer system, but on the other hand only 11.0% of all institutions used it for computer communication and literature seachs such as for MEDLINE. As changes occur in the medical environment, the DI related job should respond accordingly. An average citizen can now access much DI through the Internet, but the qualify of that information may be suspect. The problem today is how to encourage the hospital pharmacies to also access the Internet and both use and evaluate the huge amount of DI that is to be found there.

Preparation of Compliance Instructions Using a Macintosh Personal Computer.

Employing Macintosh application software, we created a systematic method for recording compliance sheet data. This new method improved the quality of patient care services, such that after entering the date, the patient is provided with a through knowledge of the prescription, even if varied use is indicated. The method also remarkably reduces the amount of paperwork required by the pharmacist and administrative staff since the personal computer is programmed to accomplish these tasks.