Dosing of Continuous Fentanyl Infusions in Obese Children: A Population Pharmacokinetic Analysis

Abstract

Differences in fentanyl pharmacokinetics (PK) between obese and nonobese adults have previously been reported; however, the impact of childhood obesity on fentanyl PK is relatively unknown. We developed a population pharmacokinetic (PopPK) model using opportunistically collected samples from a cohort of predominately obese children receiving fentanyl per the standard of care. Using a probability‐based approach, we evaluated the ability of different continuous infusion strategies to provide steady‐state concentrations (Css) within an analgesic concentration range (1‐3 ng/mL). Fifty‐three samples from 32 children were used for PopPK model development. Median (range) age and body weight of study participants were 13 years (2‐19 years) and 52 kg (16‐164 kg), respectively. The majority of children (94%) were obese. A 2‐compartment model allometrically scaled by total body weight provided an appropriate fit to the data. Estimated typical clearance was 32.5 L/h (scaled to 70 kg). A fixed dose rate infusion of 1 µg/kg/h was associated with probabilities between 49% and 58% for achieving Css within target; however, the risk of achieving Css > 3 ng/mL increased with increasing body weight (15% at 16 kg vs 43% at 164 kg). A proposed model‐based infusion strategy maintained consistent probabilities across the examined weight range for achieving Css within (58%) and above (20%) target. Use of an allometric relationship between weight and clearance was appropriate for describing the PK of intravenous fentanyl in our cohort of predominately obese children. Our proposed model‐derived continuous infusion strategy maximized the probability of achieving target Css in children of varying weights.

Use of physiologically‐based pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity

“…In fact, a fentanyl population PK model that evaluated 30 children with obesity found an inverse association between post hoc weightnormalized clearance values and obesity classification. 20 The weight-normalized volume of distribution decreased with obesity in alignment with these findings, which could be attributed to the higher body fat mass in children with versus without obesity. 20 Together, the differences in weight-normalized clearance and volume of distribution in children with and without obesity suggest that similar weight-based infusion regimens can result in higher fentanyl C ss in children with obesity.…”

Effect of CYP3A5 and CYP3A4 Genetic Variants on Fentanyl Pharmacokinetics in a Pediatric Population

“…2 This sampling scheme has already been used in published analyses of fentanyl PKs in children. [3][4][5] These irregular, sparse, opportunistic sampling strategies were the original motivation for application of nonlinear mixed effects models toward population PK (PopPK) analyses 6 and we have used such samples to perform a fentanyl PopPK analysis in children. 7 This prior study was the largest reported pediatric cohort (N = 130) for a PopPK analysis of fentanyl to date but significant residual variability remained, unexplained by the model.…”

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies

“…This research is particularly important in the light of the over-prescription of opioids in recent years, and thus, the spreading wave of opioid addiction worldwide. [4,[38][39][40][41][42][43]. The addition of Mg 2+ may help to adequately control opioid treatment by reducing consumption, and thus, reducing adverse events [11][12][13].…”