Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients with haematological malignancy

C J Byrne; J A Roberts; B McWhinney; S A Ryder; J P Fennell; P O'Byrne; E Deasy; S Egan; R Desmond; H Enright; D M D'Arcy; J McHugh

doi:10.1016/j.cmi.2017.02.032

Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients with haematological malignancy

Clin Microbiol Infect. 2017 Sep;23(9):674.e7-674.e13. doi: 10.1016/j.cmi.2017.02.032. Epub 2017 Mar 6.

Authors

C J Byrne¹, J A Roberts², B McWhinney³, S A Ryder¹, J P Fennell⁴, P O'Byrne⁴, E Deasy⁴, S Egan⁴, R Desmond⁴, H Enright⁴, D M D'Arcy⁵, J McHugh⁴

Affiliations

¹ School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland.
² Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia; Centre for Translational Anti-Infective Pharmacodynamics, The University of Queensland, Brisbane, Australia.
³ Pathology Queensland, Brisbane, Australia.
⁴ Tallaght Hospital, Dublin, Ireland.
⁵ School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland. Electronic address: ddarcy@tcd.ie.

PMID: 28267636
DOI: 10.1016/j.cmi.2017.02.032

Abstract

Objectives: To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations.

Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics.

Results: Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC_48-72h) was 679 (319) mg.h/L. There was a strong correlation between the AUC_48-72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p <0.001). Dosing simulations showed that administration of five loading doses at 12-hourly intervals, stratified by total body weight and creatinine clearance, increased the probability of achieving target concentrations within 72 hours.

Conclusions: To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.

Keywords: Glycopeptides; Haematological malignancy; Monte Carlo simulations; Population pharmacokinetics; Teicoplanin; Therapeutic drug monitoring.

MeSH terms

Aged
Anti-Bacterial Agents / blood
Anti-Bacterial Agents / pharmacokinetics*
Anti-Bacterial Agents / pharmacology*
Anti-Bacterial Agents / therapeutic use
Drug Monitoring
Female
Gram-Positive Bacterial Infections / drug therapy
Gram-Positive Bacterial Infections / prevention & control
Hematologic Neoplasms / epidemiology*
Humans
Male
Middle Aged
Prospective Studies
Teicoplanin / blood
Teicoplanin / pharmacokinetics*
Teicoplanin / pharmacology*
Teicoplanin / therapeutic use

Substances

Anti-Bacterial Agents
Teicoplanin