Sean N Avedissian1,2,3,4, Nathaniel J Rhodes1,2, Yuna Kim5, John Bradley6, Joshua L Valdez7, Jennifer Le5,8. 1. Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA. 2. Midwestern University Chicago College of Pharmacy Center of Pharmacometric Excellence, Midwestern University, Downers Grove, IL, USA. 3. Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, UNMC, Omaha, NE, USA. 4. University of Nebraska Medical Center, College of Pharmacy, Omaha, NE, USA. 5. University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, CA, USA. 6. Division of Infectious Diseases, University of California San Diego School of Medicine and Rady Children's Hospital San Diego, CA, USA. 7. Kaiser Permanente San Diego Medical Center, San Diego, CA, USA. 8. Miller Children's and Women's Hospital of Long Beach, Long Beach, CA, USA.
Abstract
OBJECTIVE: To evaluate augmented renal clearance (ARC) using aminoglycoside clearance (CLAMINO24h) derived from pharmacokinetic (PK) modelling. METHODS: A retrospective study at two paediatric hospitals of patients who received tobramycin or gentamicin from 1999 to 2016 was conducted. Compartmental PK models were constructed using the Pmetrics package, and Bayesian posteriors were used to estimate CLAMINO24h. ARC was defined as a CLAMINO24h of ≥130 mL/min/1.73 m2. Risk factors for ARC were identified using multivariate logistic regression. RESULTS: The final population model was fitted to 275 aminoglycoside serum concentrations. Overall clearance (L/h) was=CL0×(TBW/70)0.75×AGEH/(TMH + AGEH) + CL1 (0.5/SCr), where TBW is total body weight, H is the Hill coefficient, TM is a maturation term and SCr is serum creatinine. Median CLAMINO24h in those with versus without ARC was 157.36 and 93.42 mL/min/1.73 m2, respectively (P<0.001). ARC was identified in 19.5% of 118 patients. For patients with ARC, median baseline SCr was lower than for those without ARC (0.38 versus 0.41 mg/dL, P=0.073). Risk factors for ARC included sepsis [adjusted OR (aOR) 3.77, 95% CI 1.01-14.07, P=0.048], increasing age (aOR 1.11, 95% CI 1-1.23, P=0.04) and low log-transformed SCr (aOR 0.16, 95% CI 0.05-0.52, P=0.002). Median 24 h AUC (AUC24h) was significantly lower in patients with ARC at 45.27 versus 56.95 mg·h/L, P<0.01. CONCLUSIONS: ARC was observed in one of every five patients. Sepsis, increasing age and low SCr were associated with ARC. Increased clearance was associated with an attenuation of AUC24h in this population. Future studies are needed to define optimal dosing in paediatric patients with ARC.
OBJECTIVE: To evaluate augmented renal clearance (ARC) using aminoglycoside clearance (CLAMINO24h) derived from pharmacokinetic (PK) modelling. METHODS: A retrospective study at two paediatric hospitals of patients who received tobramycin or gentamicin from 1999 to 2016 was conducted. Compartmental PK models were constructed using the Pmetrics package, and Bayesian posteriors were used to estimate CLAMINO24h. ARC was defined as a CLAMINO24h of ≥130 mL/min/1.73 m2. Risk factors for ARC were identified using multivariate logistic regression. RESULTS: The final population model was fitted to 275 aminoglycoside serum concentrations. Overall clearance (L/h) was=CL0×(TBW/70)0.75×AGEH/(TMH + AGEH) + CL1 (0.5/SCr), where TBW is total body weight, H is the Hill coefficient, TM is a maturation term and SCr is serum creatinine. Median CLAMINO24h in those with versus without ARC was 157.36 and 93.42 mL/min/1.73 m2, respectively (P<0.001). ARC was identified in 19.5% of 118 patients. For patients with ARC, median baseline SCr was lower than for those without ARC (0.38 versus 0.41 mg/dL, P=0.073). Risk factors for ARC included sepsis [adjusted OR (aOR) 3.77, 95% CI 1.01-14.07, P=0.048], increasing age (aOR 1.11, 95% CI 1-1.23, P=0.04) and low log-transformed SCr (aOR 0.16, 95% CI 0.05-0.52, P=0.002). Median 24 h AUC (AUC24h) was significantly lower in patients with ARC at 45.27 versus 56.95 mg·h/L, P<0.01. CONCLUSIONS: ARC was observed in one of every five patients. Sepsis, increasing age and low SCr were associated with ARC. Increased clearance was associated with an attenuation of AUC24h in this population. Future studies are needed to define optimal dosing in paediatric patients with ARC.