Muhammad Usman, Muhammad Muaaz Munir, Huma Rasheed
Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Outfall Road Lahore, Pakistan
Background: Vancomycin is a narrow therapeutic agent and there is a need to optimize the dose of vancomycin for achieving safe therapeutic outcomes. The plasma level of vancomycin below the target trough concentration may cause insufficient eradication of the bacteria while over-dosing may lead to toxicity [1]. To achieve the antibacterial effect and reduction in microbial resistance, therapeutic trough concentration of vancomycin is a crucial pharmacokinetic parameter. Therefore, therapeutic drug monitoring (TDM) is recommended for safe and effective outcomes of vancomycin [2]. The recently published guidelines by American Society of Health-System Pharmacists (ASHP) and Infectious Diseases Society of America (IDSA) has suggested vancomycin trough concentration of 15 to 20 µg/mL in most infections[3]. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize dose among surgical patients in Pakistan.
Methods: The plasma concentration data of 176 samples collected from 38 surgical patients treated with vancomycin was used for this study. Population pharmacokinetic model was developed on NONMEM® by using the plasma concentration time data. The effect of all the available covariates was evaluated on pharmacokinetic parameters of vancomycin by stepwise covariate modelling. The final model was evaluated by bootstrap, goodness-of-fit plots and visual predictive checks. Monte Carlo simulations of vancomycin doses were performed to determine the most appropriate dose for individual patients based on the renal status of the patients.
Results: The pharmacokinetics of vancomycin followed one compartment model with first order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.46 L/h and 23.7 L respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and age of the patients however, no covariate was significant for its effect on volume of distribution. The population parameter estimates were in close agreement with 1000 bootstrap estimates. Moreover, the VPC revealed that the observed concentrations of vancomycin along with median, 5th and 95th percentiles were within the 90% prediction interval of the simulated concentrations. Dose tailoring was performed by the simulation of dosage regimens at steady state based on CRCL of the patients. The tailored dose was 400 mg, 600 mg, 800 mg and 1000 mg respectively for the patients with CRCL of 20 mL/min, 60 mL/min, 100 mL/min and 140 mL/min.
Conclusion: The pharmacokinetic parameters of vancomycin in adult Pakistani patients are comparable with other populations. Vancomycin CL is influenced by the CRCL and age of the patient. This model can be helpful for dose tailoring of vancomycin in Pakistani patients by performing simulations based on CRCL and age of the patients. The recommended dose of vancomycin based on renal status of the pateints should be 400 mg, 600 mg, 800 mg and 1000 mg respectively for the patients with CRCL of 20 mL/min, 60 mL/min, 100 mL/min and 140 mL/min.
References:
[1] Ingram, P.R., et al., Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy. J Antimicrob Chemother, 2008. 62(1): p. 168-71.
[2] Martin, J.H., et al., Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society Of Infectious Diseases Pharmacists. Clin Biochem Rev, 2010. 31(1): p. 21-4.
[3] Helgason, K.O., A.H. Thomson, and C. Ferguson, A review of vancomycin therapeutic drug monitoring recommendations in Scotland. J Antimicrob Chemother, 2008. 61(6): p. 1398-9.
Reference: PAGE 29 (2021) Abstr 9640 [www.page-meeting.org/?abstract=9640]
Poster: Clinical Applications