Toshinobu Aoyama

Digoxin Population Pharmacokinetics from Routine Clinical Data: Role of Patient Characteristics for Estimating Dosing Regimens

Abstract— Routine clinical pharmacokinetic data collected from patients receiving digoxin have been analysed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one‐compartment steady‐state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the demographic variables of age, total body weight, serum creatinine and sex. The interindividual variability in digoxin clearance was modelled with additive error with an estimated standard deviation of 46·15 L day−1 and the intraindividual variability, or residual error was 0·209 ng mL−1. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady‐state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.

Population-Based Investigation of Valproic Acid Relative Clearance Using Nonlinear Mixed Effects Modeling: Influence of Drug-Drug Interaction and Patient Characteristics

Nonlinear mixed effects modeling (NONMEM) was used to estimate the effects of drug‐drug interaction on valproic acid relative clearance values using 792 serum levels gathered from 400 pediatric and adult patients with epilepsy (age range, 0.3–54.8 years) during their clinical routine care. Patients received valproic acid as monopharmacy or in combination with either the antiepileptic drugs, phenobarbital, or carbamazepine. The final model describing valproic acid relative clearance was CL (mL/hr/kg) = 15.6 · TBW (kg)−0.252 · DOSE (mg/kg/day)0.183 · 0.898GEN · COPB · COCBZ, where COPB equals 1.10 if the patient is treated with phenobarbital, a value of unity otherwise, and COCBZ equals 0.769 · DOSE (mg/kg/day)0.179 if the patient is treated with carbamazepine, a value of unity otherwise. Valproic acid relative clearance was highest in the very young and decreased in a weight‐related fashion in children, with minimal changes observed in adults. This pattern was consistent whether valproic acid was administered alone or coadministered with phenobarbital or carbamazepine. When valproic acid was coadministered with phenobarbital or carbamazepine, valproic acid relative clearance increased as compared with that in monopharmacy. Its magnitude in the presence of carbamazepine increased in a valproic acid daily dose‐related fashion. Concomitant administration of phenobarbital and valproic acid resulted in a 10% increase on valproic acid relative clearance. The clearance in female patients was approximately 10% less than that in male patients.

Eudragit RS and RL (acrylic resins) microcapsules as pH insensitive and sustained release preparations of ketoprofen

Microencapsulation of ketoprofen using Eudragit RS and RL (acrylic resins) was investigated based on the dispersion system of ketoprofen-containing acetone in liquid paraffin. Aluminium tristearate was used as an additive for the preparation of microcapsules. Good reproducibility was observed in the microencapsulation and the resulting microcapsules were uniform, free-flowing particles. The phase diagram of ketoprofen-Eudragit RS or RL-aluminium tristearate indicated that it is only in a very limited region that spherical microcapsules ranging from 250 to 1000 microns in diameter could be prepared. Instrumental analysis using an energy dispersive-type X-ray microanalyser and a scanning electron microscope showed that aluminium tristearate was localized near the surface of the microcapsules. From these results, it was presumed that aluminium tristearate reduces the phase tension between Eudragit microcapsules and liquid paraffin. The dissolution patterns of ketoprofen from Eudragit RS and RL microcapsules were independent of the pH of the dissolution medium, and the dissolution rates were considerably lower than those from ketoprofen powders.

Population‐Based Investigation of Relative Clearance of Digoxin in Japanese Patients by Multiple Trough Screen Analysis: An Update

The steady‐state concentrations of digoxin at trough levels were studied to reestablish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug‐monitoring data. The data (n = 548) showing steady‐state serum concentrations of digoxin after repetitive oral administration in 385 hospitalized patients were analyzed using NONMEM, a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished with a simple steady‐state pharmacokinetic model. The effect of a variety of developmental and demographic factors on the clearance of digoxin was investigated. Estimates generated by NONMEM indicated that clearance of digoxin was influenced by the demographic variables of age, total body weight, serum creatinine, estimated creatinine clearance, gender, the coadministration of spironolactone, the presence or absence of congestive heart failure, and the administration of a half‐tablet. The interindividual variability in the clearance of digoxin was modeled with proportional error with an estimated coefficient of variation of ∼22%; the residual variability was ∼25.0%. An a priori method, based on the value for clearance of digoxin obtained by NONMEM analysis, was proposed as a useful adjunct for the prediction of the steady‐state concentration of digoxin at trough level as a function of the maintenance dose of digoxin.

Detection of Carbamazepine Drug Interaction by Multiple Peak Approach Screening using Routine Clinical Pharmacokinetic Data

Multiple peak approach screening was used to detect the effects of other antiepileptic drugs on the population estimates of relative clearance of carbamazepine. Routine clinical pharmacokinetic data (N = 1,010) collected from 466 patients receiving carbamazepine were analyzed according to a simple steady‐state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. NONMEM estimates indicated that carbamazepine clearance decreased nonlinearly with increasing total body weight (TBW) in the maturation process (over an age range of 5 months to 15 years) and increased nonlinearly with increasing daily dose (mg/kg) of carbamazepine. Concomitant administration of other antiepileptic drugs resulted in an increase in clearance of carbamazepine as follows: valproic acid alone (VPA), 7%; phenobarbital alone (PB), 16%; more than two antiepileptic drugs (POLY), 27%. Final regression model of relative clearance (Cl) for all data was: Cl (mL/hr/kg) = 64.9 · TBW (kg)−0.336. DOSE (mg/kg/day)0.465 1.07VPA 1.16PB 1.27POLY

Influence of Additional Therapy with Zonisamide (Excegran) on Protein Binding and Metabolism of Carbamazepine

Summary: The influence of comedication with zonisamide (ZNS) on protein binding and carbamazepine (CBZ) metabolism was studied in 16 pediatric epileptic patients. Correlations were evaluated between ZNS daily dose and individual change of level per dose ratio (L/D ratio), free fraction, and carbamazepine‐10,11‐epoxide/CBZ level ratio (CBZEKBZ). Statistical significant negative correlation was observed between LID ratio and ZNS daily dose. Despite alteration in the L/D ratio, the free fraction of CBZ was unaltered in combination with ZNS. To assess the effect of addition of ZNS on CBZ metabolism, the CBZE/CBZ level ratio was compared; this ratio showed a tendency to increase with increase in ZNS dose. Consequently, ZNS is considered to have a significant effect on CBZ metabolism but not on protein binding.

Clonal propagation of Cephaelis ipecacuanha.

Shoot cultures of Cephaelis ipecacuanha A. Richard were established by using shoot tips as initial explants. Multiple shoots were obtained from node segments upon culture on B5 medium supplemented with NAA-BA (0.01–3, 5 mg/l). These shoots were rooted on B5 and 1/2 MS media containing IAA or NAA, and the regenerated plants were transferred to soil and grown in a greenhouse. The emetic alkaloids of the regenerated plants, mother plants and leaves of shoot cultures were analyzed by TLC and HPLC. Seven months of growth under greenhouse condition, the contents of the emetic alkaloids in the regenerated plants were comparable to those of the mother plants.

Production of emetic alkaloid by in vitro culture of cephaelis ipecacuanha A. Richard

Callus and adventitious roots were induced on leaf segments from shoot culture of Cephaelis ipecacuanha A. Richard on Murashige-Skoog medium containing 2,4-dichlorophenoxyacetic acid, indole-3-acetic acid, 1-naphthaleneacetic acid and kinetin. The contents of emetic alkaloids in calli, roots and root suspension cultures were quantified by HPLC. Roots cultured in solid and liquid Murashige-Skoog media yielded emetine and cephaeline. The amount of the two alkaloids in the root suspension culture was very similar to that of roots from ipecac mother plant grown in a greenhouse. In contrast, calli subcultured on Murashige-Skoog media containing combinations of 2,4-dichlorophenoxyacetic acid and kinetin produced only trace amounts of emetic alkaloids.

Lithium population pharmacokinetics from routine clinical data: Role of patient characteristics for estimating dosing regimens

Summary: Routine clinical pharmacokinetic data (n = 303) collected from 90 patients receiving lithium have been analyzed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of lithium was described using a one-compartment steady-state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicated that lithium clearance was influenced by the demographic variables of age, total body weight, and serum creatinine. The interindividual variability in lithium clearance was modeled with proportional error with an estimated coefficient of variation of 25.1%. The intraindividual variability, or residual error, was 14.3%. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the minimum steady-state lithium concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.

Eudragit E, L and S (acrylic resins) microcapsules as pH sensitive release preparations of ketoprofen

Microencapsulation of ketoprofen using Eudragit E, L and S (acrylic resins) was investigated. The preparation is based on the dispersion of acetone containing ketoprofen in liquid paraffin. Aluminium tristearate was used as an additive for the preparation of microcapsules. In the preparation of microcapsules, the reproducibility of the Eudragit E microcapsule was better than that of Eudragit L and S microcapsules. The microcapsules obtained were uniform and free-flowing particles. From the phase diagram of ketoprofen-Eudragit E or S-aluminium tristearate, it became clear that the region in which the spherical microcapsules ranging from 250 to 1000 microns in size could be prepared was limited. The dissolution patterns of ketoprofen from Eudragit E, L and S microcapsules were dependent on the pH of the dissolution medium.