Darwin E. Zaske

Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: gentamicin in burn patients.

A general approach to the establishment of dosing regimens for drug administration by multiple intravenous infusions is presented. The method is applicable where the elimination kinetics are first order and can be represented by a one-compartment open model. The approach utilizes serum concentration-time data obtained during any dosing interval for the calculation of the apparent distribution volume and the half-life in individual patients. These values are then used to individualize the dosing regimen where it is required to maintain serum concentrations of the drug within a desired range. Estimation of kinetic parameters for gentamicin in burn patients with normal or only slightly reduced renal function demonstrates a relatively constant distribution volume of 0.25 ± 0.086 liter/kg (mean ±sd)but a relatively variable half-life of 2.1 ± 1.3 hr. This finding supports the view that gentamicin regimens should be individualized even in patients with essentially normal renal function.

Kinetic model for gentamicin dosing with the use of individual patient parameters

Multiple‐infusion dosing regimens for gentamicin were established for 84 patients with the use of individually calculated values of elimination kinetic parameters. Serum level‐time data obtained after a single infusion were used to determine the patients gentamicin half‐life (t½) and distribution volume. Patients with serum creatinine (Cr) <1.2 mg per 100 ml had t½s (mean, 2.25 hr) and total body clearances (mean, 0.082 L/hr/kg) significantly different from those with Cr ≥1.2 mg/100 ml (means, 5.3 and 0.039, respectively). Distribution volumes were not significantly different (means, 0.22 and 0.21 L/kg, respectively). Calculations of dosing intervals and infusion rates, based on each patients kinetic parameters and desired steady‐state peaks and nadirs, assumed a one‐compartment model with first‐order elimination and 1‐hr constant‐rate input at fixed intervals. Follow‐up steady‐state peak and nadir levels were measured in 63 of the regimens. Differences between predicted and measured peak levels averaged ‐0.05 µg/ml with 60% of the measured values falling within 1 µg/ml of that predicted. Predicted‐measured nadir differences averaged −0.62 µg/ml (significantly different from zero) indicating slight bias in the model. Fifty‐six percent of these nadirs were within 1 µg/ml of that predicted.

Pharmacokinetics of vancomycin: observations in 28 patients and dosage recommendations.

Studies of the pharmacokinetics of vancomycin were conducted in a group of 28 patients with serious staphylococcal infection. Serum specimens were collected before and on 11 occasions after vancomycin administration. Serum concentration time data were fitted to a biexponential equation, using nonlinear regression analysis. A prolonged distribution phase with a half-life of 0.5 +/- 0.3 h (standard deviation) and a central component volume of 9.0 +/- 4.0 liters were demonstrated. Wide interpatient variation was observed in the terminal half-life which ranged from 3 to 13 h (mean, 6 h) and in the distribution volume which ranged from 14 to 111 liters (mean, 39 liters). A correlation of 0.45 (Pearson product moment correlation coefficient) was found between vancomycin clearance and creatinine clearance. Multiple regression analyses demonstrated that 50% of the variance (R2) in the terminal half-life and vancomycin clearance could be explained on the basis of renal function, volume of distribution, age, weight, and sex. These observations suggest that adults with normal renal function should receive an initial dosage of 6.5 to 8 mg of vancomycin per kg intravenously over 1 h every 6 to 12 h. After 24 h, and through the period of therapy, trough and peak serum vancomycin concentrations should be monitored, and the dose and dosage interval should be changed to produce the desired peak (30 to 40 micrograms/ml) and trough (5 to 10 micrograms/ml) levels.

Gentamicin pharmacokinetics in 1,640 patients: method for control of serum concentrations.

The pharmacokinetics and dosage requirements of gentamicin were studied in 1,640 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine or normal creatinine clearance. The half-life ranged from 0.4 to 32.7 h in 331 patients who had normal creatinine clearance. The factors related to the elimination rate constant were creatinine clearance, age, distribution volume, weight, gender, and hematocrit. The daily dose necessary to obtain therapeutic serum concentrations ranged from 0.5 to 25.8 mg/kg in patients with normal serum creatinine and from 0.7 to 25.8 mg/kg in patients with normal creatinine clearance. In 13 patients (0.9%), a significant change in base-line serum creatinine (greater than or equal to 0.5 mg/dl) occurred during or after treatment, which may have been gentamicin-associated toxicity. Overt cochlear or vestibular toxicity did not occur in these patients. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.

Increased dosage requirements of gentamicin in burn patients.

In 14 burn patients treated for serious Gram-negative infections, the use of the previously recommended gentamicin dose of 5 mg/kg/day was found to result in subtherapeutic serum concentrations (peak concentration less than 4 mg/L). The gentamicin half-life was found to be unusually short especially in the younger burn patients. Because of this shorter half-life the dosage interval was decreased to 4 hours to prevent extended periods of subtherapeutic serum concentrations. In addition, the daily dose of gentamicin was increased to achieve therapeutic peak concentration. Individualizing each patients gentamicin regimen was thought to be instrumental in the favorable response of two patients with Pseudomonas ecthyma gangrenosum. The results of this study would strongly support the measurement of serum gentamicin levels in all burn patients with life-threatening infection. The gentamicin dosage regimen should then be individualized for each patient to provide optimal peak concentrations. In addition, patients demonstrating a short drug half-life may require a decreased dosage interval to prevent prolonged periods of sub-therapeutic concentrations.

Heparin kinetics: Variables related to disposition and dosage

A method to determine heparin kinetics and dosage requirements was examined in 20 patients with active thromboembolic disease. Pretreatment heparin sensitivities were determined to establish the relationship between heparin concentration and activated partial thromboplastin times (APTTs). After an initial bolus dose, serial APTTs were measured, heparin concentrations were estimated, and kinetic determinations followed. Heparin elimination rate, distribution volume, and clearance were used to calculate dosage requirements. There was a 500% range in pretreatment heparin sensitivities. Smokers had more rapid heparin elimination rates and t½s than nonsmokers did. Men had more rapid drug clearances than women did. Body weight was related to heparin dosage requirements. Patients treated early after onset of symptoms required higher doses than patients in whom treatment was delayed. A multiple regression model was developed for heparin dosage requirements from body weight, sex, delay between onset of symptoms and treatment, and smoking. This statistical model explained 78% of the variance in heparin requirements.

Phenobarbital dosage for control of neonatal seizures

The relationship of the initial phenobarbital dose to weight, gestational age, blood level, and seizure control was studied in 39 neonates. The blood level was proportional to the dosage per kilogram, and was not related to weight or gestational age. Seizures remitted only at blood phenobarbital concentrations above 16.9 pg per milliliter. Therapeutic levels can be achieved by the intravenous or intramuscular administration of 16 to 23 mg per kilogram of phenobarbital.

Effect of Obesity on Gentamicin Pharmacokinetics

Abstract: The effect of obesity on gentamicin disposition was studied in 60 obstetric and gynecologic patients receiving treatment for Gram‐negative infections. Thirty patients whose body weights were within 20 per cent of their ideal body weight were the control group. Thirty additional patients had body weights at least 30 per cent greater than ideal body weight and were the obese group. The two groups had similar ages, heights, ideal body weights (IBW), lean body weights (LBW), and elimination rates of gentamicin. The distribution volumes, expressed as liters or standardized to ideal body weight, lean body weight, or total body weight, were significantly different in the controls from those in obese patients. The distribution volume averaged (± S.D.) 0.19 ± 0.06 l./kg in controls. The contribution of excess weight to additional drug volume averaged (± S.D.) 0.05 ± 0.16 l./kg. Excess weight thus contributes less volume per kilogram than ideal body weight or lean body weight. A substantial interpatient variability existed in the measured distribution volume for all groups. Measuring serum concentrations and adjusting a patients dosage regimen are imperative to ensure therapeutic serum concentrations.

Phenobarbital maintenance dose requirements in treating neonatal seizures

we studied the pharmacokinetics of phenobarbital in 15 neonates after a single intramuscular dose. The mean apparent distribution volume, half-life, and apparent total body clearance were 0.81 liter per kilogram, 103.4 hours, and 6.4 ml per hour per kilogram, respectively. Substantial interpatient variation was observed in the half-life and apparent total body clearance. Maintenance doses of 3.1 and 3.8 mg per kilogram per day were projected from the mean apparent total body clearance to produce plasma concentrations of 20 and 25 pg per milliliter, respectively. These recommendations provide initial maintenance dosage guidelines, which should be adjusted according to plasma concentrations and clinical effects.

Effect of cardiopulmonary bypass on cefazolin disposition

Cefazolin kinetics was studied in 8 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass (CPB) surgery. PREOP (48.6 ml/min) and POSTOP (46.6 ml/min) total body clearances were of the same order and both were greater than the SURG (27.4 ml/min) total body clearance. Since cefazolin is almost entirely eliminated by the kidney, the lower SURG clearance is a result of reduced renal elimination, as confirmed by measuring cefazolin SURG (28.7 ml/min) and POSTOP (52.9 ml/min) renal clearance. The reduction in cefazolin renal elimination was the same throughout the surgical procedure, including the period of extracorporeal circulation. Cefazolin distribution was altered by the operative procedure as evidenced by a higher SURG steady‐state volume of distribution. This increase in apparent cefazolin distribution volume brought about by surgery was not seen with cephalothin, which was investigated by us in a similar group of patients. The different effect of CPB surgery on cefazolin and cephalothin distribution may be due to differences in plasma protein binding.