Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

Vu, Dinh H.;Nguyen, Duy A.;Delattre, Isabelle K.;Ho, Trong T.;Nguyen, Hoang A.;et.al.
(2019) International Journal of Antimicrobial Agents — Vol. 54, n° 6, p. 702-708 (2019)

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Authors
  • Vu, Dinh H.orcid-logo
    Author
  • Nguyen, Duy A.orcid-logo
    Author
  • Delattre, Isabelle K.UCLouvain
    Author
  • Ho, Trong T.
    Author
  • Van Bambeke, Françoiseorcid-logoUCLouvain
    Author
  • Tulkens, Paul M.orcid-logoUCLouvain
    Author
  • Nguyen, Hoang A.
    Author
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Abstract
OBJECTIVES: Despite extensive clinical use, limited data are available on optimal loading and maintenance doses of vancomycin in critically ill patients. This study aimed to develop a rational approach for optimised dosage of vancomycin given in a continuous infusion in critically ill patients. METHODS: Vancomycin pharmacokinetic (PK) data (total serum concentrations) were obtained from 55 intensive care unit (ICU) patients (Bach Mai Hospital, Hanoi, Vietnam) receiving a 20 mg/kg loading dose followed by continuous infusion stratified by creatinine clearance (CLCr). Population PK modelling and Monte Carlo simulations were performed using a nonlinear mixed-effects modelling (NONMEM) program for a target of 20-30 mg/L to optimise efficacy and minimise nephrotoxicity. RESULTS: A two-compartment model with first-order elimination best fitted the PK data with central and peripheral volumes of distribution of 1.01 and 2.39 L/kg, respectively (allometric scaling to a 70 kg standard subject). The population total clearance of 3.63 L/h was only explained by renal function in the covariate and final model. The simulations showed that a 25-mg/kg loading dose infused over 90 minutes was optimal to reach the target range. The optimal maintenance dose for low renal function (CLCr < 45 mL/min) was 1000-1500 mg/day. For augmented renal clearance (CLCr > 130 mL/min) the dose should be up to 3500 mg/day or even 4500 mg/day to achieve adequate exposure. These simulated maintenance doses were larger than previously proposed for non-ICU patients. CONCLUSION: Large loading and maintenance doses of vancomycin are generally needed in critically ill patients. Because of high interindividual variability in vancomycin PK, drug monitoring may still be necessary.
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Vu, D. H., Nguyen, D. A., Delattre, I. K., Ho, T. T., Do, H. G., Pham, H. N., Dao, X. C., Tran, N. T., Nguyen, G. B., Van Bambeke, F., Tulkens, P. M., & Nguyen, H. A. (2019). Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes. International Journal of Antimicrobial Agents, 54(6), 702-708. https://doi.org/10.1016/j.ijantimicag.2019.09.018 (Original work published 2019)