No 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.

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed‐effects modeling in NONMEM to perform dose‐exposure simulations in children with variable renal function. We included children aged <21 years who received intravenous milrinone per clinical care. Plasma milrinone concentrations were measured using a validated liquid chromatography–tandem mass spectrometry assay (range 1‐5000 ng/mL). We performed dose‐exposure simulations targeting steady‐state therapeutic concentrations of 100‐300 ng/mL previously established in adults and children with cardiac dysfunction. We simulated concentrations over 48 hours in typical subjects with decreasing creatinine clearance (CrCl), estimated using the updated bedside Schwartz equation. Seventy‐four patients contributed 111 plasma samples (concentration range, 4‐634 ng/mL). The median (range) postmenstrual age (PMA) was 3.7 years (0‐18), and median weight (WT) was 13.1 kg (2.6‐157.7). The median serum creatinine and CrCl were 0.5 mg/dL (0.1‐3.1) and 117.2 mL/min/1.73 m2 (13.1‐261.3), respectively. A 1‐compartment model characterized the pharmacokinetic data well. The final model parameterization was: Clearance (L/h) = 15.9*(WT [kg] / 70)0.75* (PMA1.12 / (67.71.12+PMA1.12)*(CrCl / 117)0.522; and Volume of Distribution (L) = 32.2*(WT [kg] / 70). A loading dose of 50 µg/kg followed by a continuous infusion of 0.5 µg/kg/min resulted in therapeutic concentrations, except when CrCl was severely impaired at ≤30 mL/min/1.73 m2. In this setting, a 25 µg/kg loading dose and 0.25 µg/kg/min continuous infusion resulted in therapeutic exposures.

Pediatric patients with sickle cell pain crises experienced significant delays to initial analgesic medication. A standardized approach to pain management may improve ED management of SCD crises.