Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

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Abstract

Objectives

There is uncertainty about the optimal teicoplanin regimens for neonates. The study aim was to determine the population pharmacokinetics (PK) of teicoplanin in neonates, evaluate currently recommended regimens and explore the exposure–effect relationships.

Methods

An open-label PK study was conducted. Neonates from 26 to 44 weeks post-menstrual age were recruited (n = 18). The teicoplanin regimen was a 16 mg/kg loading dose, followed by 8 mg/kg once daily. Therapeutic drug monitoring and dose adjustment were not conducted. A standard two-compartment PK model was developed, followed by models that incorporated weight. A PK/pharmacodynamic (PD) model with C-reactive protein serial measurements as the PD input was fitted to the data. Monte Carlo simulations (n = 5000) were performed using Pmetrics. The AUCs at steady state and the proportion of patients achieving the recommended drug exposures (i.e. Cmin >15 mg/L) were determined. The study was registered in the European Clinical Trials Database Registry (EudraCT: 2012-005738-12).

Results

The PK allometric model best accounted for the observed data. The PK parameters medians were: clearance = 0.435 × (weight/70)0.75 (L/h); volume = 0.765 (L); Kcp = 1.3 (h−1); and Kpc = 0.629 (h−1). The individual time-course of C-reactive protein was well described using the Bayesian posterior estimates for each patient. The simulated median AUC96-120 was 302.3 mg·h/L and the median Cmin at 120 h was 12.9 mg/L; 38.8% of patients attained a Cmin >15 mg/L by 120 h.

Conclusions

Teicoplanin population PK is highly variable in neonates, weight being the best descriptor of PK variability. A low percentage of neonates were able to achieve Cmin >15 mg/L. The routine use of therapeutic drug monitoring and improved knowledge on the PD of teicoplanin is required.

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