John M. Trang

Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis.

The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.

Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections

The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1‐hour intravenous infusion of a single dose of either 4 mg/kg (n = 14) or 6 mg/kg (n = 13). Twenty‐seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I‐II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one‐compartment open model with zero‐order input and first‐order elimination. The mean elimination half‐life (t½) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 ± 70 ml/kg for the 4 mg/kg group and 749 ± 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 ± 28 ml/hr/kg and 213 ± 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight (r = 0.689; p = 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age (r = 0.413; p = 0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (Cmax/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.

Cefotaxime and desacetylcefotaxime pharmacokinetics in very low birth weight neonates

The single-dose pharmacokinetics of cefotaxime (CTX) and desacetylcefotaxime (dCTX) after a 50.0 mg/kg intravenous dose were evaluated in 18 very low birth weight neonates (13 male; 1015.6 +/- 349.8 gm; 28.4 +/- 2.4 weeks gestational age) during the first week of life. Microanalytic high-performance liquid chromatography was used to quantitate both CTX and dCTX from serum. A two-compartment open model best characterized the disposition of CTX during a 24-hour post-dose period. The disposition of dCTX was adequately characterized by a one-compartment model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of CTX (mean +/- SEM) were 4.44 hours, 0.461 +/- 0.027 L/kg, and 0.074 +/- 0.003 L/hr/kg, respectively. Peak concentrations (mean +/- SD) of dCTX (17.96 +/- 5.54 mg/L) occurred at 0.6 to 8.3 hours (5.9 +/- 1.9 hours) after CTX administration, and the apparent elimination half-life of dCTX was 9.36 hours. Comparison of CTX and dCTX pharmacokinetic parameters between very low birth weight neonates who weighed less than 1000 gm (n = 9; 703.3 +/- 46.6 gm; 27.0 +/- 0.8 weeks gestational age) and greater than or equal to 1000 gm (n = 9; 1328.8 +/- 48.6 gm; 29.8 +/- 0.5 weeks gestational age) revealed no significant differences, but significant linear correlations were found between gestational age and weight versus CTX half-life and total body clearance. Because of the prolonged clearance of both CTX and dCTX in the very low birth weight neonate, a CTX dose of 50 mg/kg every 24 hours may provide effective serum concentrations for susceptible infections outside the central nervous system.

Introduction to pharmacokinetics: Aminoglycosides in cystic fibrosis as a prototype

Pharmacokinetics is the study of the time course of drug absorption, distribution, metabolism, and excretion, allowing examination of the potential relationships between drug disposition and pharmacologic or toxicologic effects. The pharmacokinetics of the aminoglycosides and certain other drugs are different in patients with cystic fibrosis (CF), but this topic is controversial. Differences in disease severity between study subjects and in the methods used might explain the disparities. Understanding the fundamental principles of pharmacokinetics is necessary for the clinician to evaluate drug disposition data in patients with CF. To determine whether observed pharmacokinetic differences are attributable to CF, the investigator must consider a number of factors in the design and conduct of pharmacokinetic studies: analytical methods, study population selection, techniques for drug administration, method used to collect biologic specimens, evaluation of parallel rates and routes of drug excretion, and selection of pharmacokinetic and statistical techniques. Pharmacokinetic investigation in patients with CF should permit evaluation of the complete disposition profile for a drug, allow comparison between the experimental data and factors that characterize the disease state, and be rigorous enough to provide explanations for any observed variability in pharmacokinetics.

Ticarcillin/clavulanic acid pharmacokinetics in children and young adults with cystic fibrosis

The single-dose pharmacokinetics of ticarcillin and clavulanic acid (Timentin) were evaluated in children and young adults with cystic fibrosis after a 0.5-hour intravenous infusion of both a 3.1 and a 3.2 gm formulation (representing 3.0 gm ticarcillin combined with 100 mg and 200 mg clavulanic acid, respectively) in a crossover design. A 75 mg/kg dose of the ticarcillin component was used. Model-dependent and noncompartmental pharmacokinetic parameters were congruous. The disposition of ticarcillin and clavulanic acid was characterized adequately by a one-compartment open model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of ticarcillin from serum were 1.19 hours, 0.231 L/kg, and 0.150 L/hr/kg, respectively, for the 3.1 gm formulation and 1.21 hours, 0.211 L/kg, and 0.123 L/hr/kg, respectively, for the 3.2 gm formulation. For ticarcillin, 86% and 93% of the dose of the 3.1 and 3.2 gm formulations, respectively, were excreted unchanged in urine during the first 6 hours after infusion. Concomitant renal clearance values were 0.120 and 0.112 L/hr/kg for the 3.1 and 3.2 gm formulations, respectively. Approximately 50% of a clavulanic acid dose was excreted unchanged in urine during the 6-hour postinfusion period for both formulations. For ticarcillin, no significant differences were observed between the 3.1 and 3.2 gm formulations. For clavulanic acid, a significant difference between the two formulations was observed in comparison of the area under the serum concentration vs time curve and dose size (P less than 0.01). Linear inverse relationships were identified between demographic factors (e.g., age, weight, height, body surface area) and both the apparent volume of distribution and total body clearance of ticarcillin and clavulanic acid for both formulations. The ticarcillin/clavulanic acid combination in either the 3.1 or 3.2 gm formulation is suitable for microbiologic and clinical evaluation in patients with cystic fibrosis.

Single-dose pharmacokinetics of imipenem in children.

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin) was evaluated in 13 pediatric patients (mean age 5.2 +/- 3.5 years). Imipenem was administered in combination with cilastatin as either a 10 mg/kg or 25 mg/kg dose (not to exceed 500 mg) over 15 minutes. Plasma disposition in children was best described by a two-compartment open model. The distribution phase was rapid (t1/2 lambda 1 = 0.18 hours) and was followed by a monoexponential elimination phase (t1/2 lambda 2 = 1.2 hours). The calculated value for the apparent volume of distribution (0.66 L/kg) was similar to that of total body water. The total plasma clearance was rapid (0.36 L/hr/kg). Direct proportionality was exhibited between administered dose and either resultant plasma concentration or area under the plasma concentration versus time curve. Comparison of imipenem plasma pharmacokinetic data derived from these children with data reported from adult subjects revealed disparities for both the apparent volume of distribution and plasma clearance. Based on preliminary pharmacokinetic simulations using parameters generated from our study, a 25.0 mg/kg dose of imipenem administered every 6 hours appears adequate for initiation of therapy in children.

Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections

Clinical Pharmacology & Therapeutics (1996) 59, 184–184; doi: 10.1038/sj.clpt.1996.236

Rapid estimation of serum theophylline clearance in children with acute asthma.

Serum theophylline clearance was estimated prior to reaching steady state in 29 asthmatic children, aged 1–14 years, using methods described by Chiou et al. and Vozeh et al. Comparison of the estimated clearance by the Vozeh method (0.094 ± 0.005 L/kg/h) did not differ significantly from that estimated by the Chiou method (0.094 ± 0.005 L/kg/h). Neither estimate of serum theophylline clearance differed significantly from the calculated clearance at steady state (0.092 ± 0.006 L/kg/h). Linear correlations between predicted and observed serum theophylline clearances were found for both the Chiou (p = 0.002, r = 0.54) and Vozeh (p = 0.02, r = 0.49) methods. Estimates of the steady-state serum theophylline concentrations by the Vozeh method (10.32 ± 0.56 mg/L) and the Chiou method (10.28 ± 0.52 mg/L) did not differ significantly from each other or from the observed steady-state serum theophylline concentration (10.54 ± 0.48 mg/L). A linear correlation between predicted and observed serum theophylline concentrations was found for both the Chiou (p = 0.02, r = 0.43) and Vozeh (p = 0.001, r = 0.57) methods. These results suggest that either method of estimating serum theophylline clearance can be used to rapidly individualize therapy in children with acute asthma.

Effect of age and renal function on cefonicid pharmacokinetics.

Cefonicid (15 mg/kg) was administered intravenously at a constant rate of infusion over 15 min to 10 geriatric patients (mean age, 77 years) and to 4 young subjects (mean age, 35 years). Model-dependent and noncompartmental pharmacokinetic parameters were calculated and found to be congruous; noncompartmental data are reported. Significant differences in the values for area under the curve, mean residence time, total body clearance, and renal clearance were observed between the geriatric and young groups. Mean elimination half-life values were 9.59 and 4.88 h for the geriatric and young groups, respectively. Total body and renal clearances were inversely correlated to age and directly correlated to creatinine clearance. Free fraction was not correlated to albumin concentration but was correlated exponentially to total cefonicid concentration. Despite the prolonged half-life values observed in our geriatric patients, the difference in mean trough concentrations was slight. Daily administration of a 15-mg/kg dose should provide adequate concentrations in serum and should not produce appreciable accumulation in geriatric patients.