Revising paediatric vancomycin dosing accounting for nephrotoxicity in a pharmacokinetic-pharmacodynamic model.

This study aimed to suggest an initial paediatric vancomycin dose regimen through population pharmacokinetic-pharmacodynamic modelling. A population pharmacokinetic approach was used to analyse vancomycin concentration-time data from a large paediatric cohort. Pharmacokinetic target attainment for patients with blood stream isolates was compared with clinical outcome using logistic regression and classification and regression trees. Change in serum creatinine during treatment was used as an indicator of acute nephrotoxicity. Probability of acute kidney injury (50% increase from baseline) or kidney failure (75% increase from baseline) was evaluated using logistic regression. An initial dosing regimen was derived, personalised by age, weight and serum creatinine using stochastic simulations. Data from 785 hospitalised paediatric patients (1 day to 21 years) with suspected Gram-positive infections were collected. Estimated (RSE) typical CL, V1, Q and V2 were (standardised to 70 kg) 4.84 (2.38) L/h, 39.9 (8.15) L, 3.85 (17.3) L/h, and 37.8 (10.2) L, respectively. Whilst cumulative vancomycin exposure correlated positively with the development of nephrotoxicity (713 patients) no clear relationship between vancomycin AUC and efficacy was found (102 patients). Predicted probability of acute kidney injury and kidney failure with the optimised dosing regimen at day 5 was 10-15% and 5-10 %, increasing by approximately 50% on day 7 and roughly 100% on day 10 across all age groups. This study presents the first data driven paediatric dose selection to-date accounting for nephrotoxicity and indicated that cumulative vancomycin exposure best described risk of acute kidney injury and acute kidney failure