Abstract
Purpose: Serum creatinine (SCr) is used as a marker of kidney function to guide dosing of renally eliminated drugs. Serum Cystatin C (S-CysC) has been suggested as a more reliable kidney marker than SCr in adults and children. Purpose of this study was to investigate S-CysC as alternative renal marker to SCr for estimating vancomycin clearance in neonates undergoing intensive care. Methods: Vancomycin pharmacokinetics (PK), SCr and S-CysC data were collected in patients undergoing vancomycin treatment in the neonatal intensive care unit of Robert Debré Hospital - Paris. A population PK analysis was performed utilizing routine therapeutic drug monitoring samples. S-CysC and SCr were compared as covariates on vancomycin clearance using stepwise covariate modeling (forward inclusion [p < 0.05] and backward elimination [p < 0.01]). Model performance was evaluated by graphical and statistical criteria. Results: A total of 108 vancomycin concentrations from 66 patients (postmenstrual age [PMA] of 26–46 weeks) were modeled with an allometric one-compartment model. The median (range) values for SCr and S-CysC were 41 (12–153) µmol/l and 1.43 (0.95–2.83) mg/l, respectively. Following stepwise covariate model building, SCr was retained as single marker of kidney function (after accounting for weight and PMA) in the final model. Compared to the final model based on SCr, the alternative model based on S-CysC showed very similar performance (e.g. BIC of 578.3 vs. 576.4) but included one additional covariate: impact of mechanical ventilation on vancomycin clearance, in addition to the effects of size and maturation. Conclusion: ill neonates. However, if using S-CysC for this purpose mechanical ventilation needs to be taken into account.
Highlights
Kidney function is a major determinant of clearance (CL) of renally eliminated drugs
To summarize, compared to the final model based on Serum Creatinine (SCr), the alternative model based on S-CysC provided a very similar fit of the data but included the effect of mechanical ventilation on vancomycin CL as additional covariate
Compared to the final model based on SCr, the alternative model based on S-CysC showed very similar performance (e.g. Bayesian information criterion (BIC) of 578.3 vs. 576.4) but included, besides the effects of size and maturation, the impact of mechanical ventilation as additional covariate on vancomycin CL
Summary
Kidney function is a major determinant of clearance (CL) of renally eliminated drugs. Markers reflecting kidney function are essential for dosing individualization. Utilizing optimal renal markers for optimizing drug dosing is a current pharmacological challenge in neonatal medicine. Serum Creatinine (SCr) is used as a marker of glomerular filtration rate (GFR) to guide dosing of drugs eliminated by the kidney across all age groups. The use of SCr for this purpose raises two specific issues in neonates. SCr concentrations in the first days after birth are influenced by maternal creatinine, because of placenta transfer (Kastl, 2017). SCr may be falsely elevated in the first days to weeks of life in premature neonates, because of tubular reabsorption by the immature kidney (Kastl, 2017)
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