Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review

Abstract

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.

Conflict of interest statement

Conflict of Interest Statements

Victoria C. Ziesenitz, Janelle D. Vaughns, Gilbert Koch, Gerd Mikus and Johannes N. van den Anker declare no conflicts of interest that are directly relevant to the content of this review.

Figures

Fig. 1

Linear regression of fentanyl clearance and bodyweight in preterm and term neonates (R2=0.22, solid grey line).

Fig. 2

Nonlinear regression (Hill function) of sufentanil clearance and bodyweight in children including term neonates (R2=0.71, solid grey line). Allometric function of sufentanil clearance and bodyweight in children including term neonates (R2=0.67, dotted black line). Abbreviations:Bmax maximum clearance,K50 bodyweight at which half-maximum clearance is reached, h Hill coefficient.

Fig. 3

Nonlinear regression (Hill function) of alfentanil clearance and bodyweight in children including preterm and term neonates (R2=0.70, solid grey line). Allometric function of alfentanil clearance and bodyweight in children including preterm and term neonates (R2=0.65, dotted black line). Abbreviations: Bmax maximum clearance,K50 bodyweight at which half-maximum clearance is reached, h Hill coefficient.

Fig. 4

Linear regression of remifentanyl clearance and bodyweight in children including neonates (R2=0.69, solid grey line). Allometric function of remifentanil clearance and bodyweight in children neonates (R2=0.72, dotted black line).