Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates

Abstract

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL(arbekacin) = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL(arbekacin) = 0.0367 x BW/serum creatinine level for PCAs of > or = 33 weeks, V(arbekacin) = 0.54 liters/kg, CL(vancomycin) = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL(vancomycin) = 0.0323 x BW/serum creatinine level for PCAs of > or = 34 weeks, V(vancomycin) = 0.66 liters/kg, CL(panipenem) = 0.0832 for PCAs of <33 weeks and CL(panipenem) = 0.179 x BW for PCAs of > or = 33 weeks, and V(panipenem) = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of > or = 33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

FIG. 1.

Relationship between CL_arbekacin normalized by weight and PCA. CL_arbekacin was estimated by the Bayesian method. The horizontal lines show the average CL_arbekacin for neonates with PCAs of <33 and ≥33 weeks. CL_arbekacin was normalized by weight but depends on PCA and Cr (Scr).

FIG. 2.

Relationship between CL_vancomycin normalized by weight and PCA. CL_vancomycin was estimated by the Bayesian method. The horizontal lines shows the average CL_vancomycin for neonates with PCAs of <34 and ≥34 weeks. CL_vancomycin normalized by weight still depends on PCA and Cr (Scr).

FIG. 3.

Relationship between CL_panipenem and PCA. CL_panipenem for neonates with PCAs of <33 weeks was not dependent on maturation but was constant for extrarenal CL; CL_panipenem for neonates with PCAs of ≥34 weeks increased by PCA.

FIG. 4.

Scatterplot of V_arbekacin, V_vancomycin, and V_panipenem versus PCA. Each value of V was estimated by the Bayesian method. There was no significant relationship between V and time.

FIG. 5.

Scatterplot of observed concentrations versus estimated concentrations of three kinds of antibiotics. Estimated concentrations were calculated by using our population model, according to the covariate results for each individual from NONMEM analysis.

FIG. 6.

Correlation between total and renal CL of antibiotics with protein binding ratios reported in the literature. Fourteen antibiotics were reviewed in 16 studies. The values of antibiotic CL from the literature were divided into two groups: circles indicate PCA of ≥33 weeks or BW of ≥2,000 g for amikacin (36), amoxicillin (11, 23), aztreonam (13), cefoperazone (38), cefotaxime (21), ceftazidime (40, 44), ceftizoxime (26), ceftriaxone (32), meropenem (46), and piperacillin (25); squares indicate PCA of <33 weeks or BW of <2,000 for cefoperazone (8), flucloxacillin (10), piperacillin (25), ticarcillin (11), and vancomycin (12). The figure shows that CL is associated with protein binding ratios and that the relationship between renal CL and protein binding is stronger than that between total CL and protein binding.

FIG. 7.

Correlation between PCA and CL of arbekacin, vancomycin, and panipenem. Antibiotic CL was estimated by the Bayesian method.

FIG. 8.

(A) Correlation between apparent V for antibiotics in adults and neonates reported in the literature. Apparent V for amikacin (36), amoxicillin (11, 23), cefazolin (14), cefoperazone (8, 38), cefotaxime (21), ceftazidime (40, 44), ceftizoxime (26), ceftriaxone (30, 32), flucloxacillin (22), meropenem (46), piperacillin (25), and ticarcillin (10) are low (less than 0.4 liters/kg) in adults due to aqueous solubility. (B) Correlation between protein binding ratio and V. The apparent V was strongly associated with the protein binding ratio. As the protein binding ratio increases in serum (f_u decreases), the apparent V is decreased.