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.

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 approximately 22%; the residual variability was approximately 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.

Routine clinical pharmacokinetic data collected from patients receiving phenobarbitone 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 phenobarbitone 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 a nonlinear function of total body weight as the optimum adjustment of phenobarbitone clearance. Concomitant administration of phenobarbitone and other antiepileptic drugs showed a decrease of phenobarbitone clearance in young children. 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.

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 increased 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.

Seven hours after suicidal ingestion of about 21 g of boric acid, a 26-year-old female admitted to our hospital in a state of slightly impaired consciousness, with frequent vomiting, shivering, fever and skin flush. Immediately, gastric lavage, followed by administration of activated charcoal and laxative (MgSO4), was performed. In order to ensure her urination, fluid infusion therapy was conducted with the aid of diuretics (furosemide). Since the serum concentrations of boric acid was very high, hemodialysis was carried out twice during the first 39 h. She responded well to the above mentioned treatment and was discharged 12 d post-admission without any sequelae. The concentrations of boric acid in serum and urine were measured in appropriate intervals with our modified Miyamoto's method, and the pharmacokinetics of boric acid were analyzed. The concentration of boric acid in serum and urine at the beginning of treatment was 465 micrograms/ml and 3.40 mg/ml, respectively. The half-life of boric acid in serum was 13.46 h, whereas it was shortened to 3.76 h during hemodialysis. The total body clearance was 0.99 l/h, while it increased to 3.53 l/h by hemodialysis. The additional removal of boric acid by hemodialysis was estimated to be about 5 g. It was concluded that the hemodialysis was very useful in the treatment of boric acid poisoning, because it accelerated the elimination of boric acid about four times faster than with conventional treatment.