Population pharmacokinetics of teicoplanin in children

Abstract

Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. (This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.).

FIG 1

Teicoplanin serum concentrations in 39 patients. Patients were dosed according to recommended regimens. Children more than 1 month old: 3 loading doses every 12 h, then once daily.

FIG 2

Evaluation of relationships between the Bayesian PK parameter estimates from the standard model for clearance and weight of patients. (A) Linear relationship between Bayesian clearance estimates and weight. (B) Linear relationship of the log-transformed values of Bayesian clearance estimates versus weight. Dotted lines represent the 95% confidence interval (CI) of the regression line.

FIG 3

Observed versus predicted plots for the population and Bayesian posterior values in the linear model for children (n = 39) (A and B, respectively) and for the population and Bayesian posterior values in the standard model for adults (n = 33) (C and D).

FIG 4

AUC distributions from the Bayesian posterior estimates from the linear model in children.

FIG 5

AUC distributions based on Monte Carlo simulations for children at fixed weights of 10, 25, and 50 kg and for adults (not fixed weight) with measures of medians, 25th and 75th percentiles (P₂₅ and P₇₅).