Flip-Flop Phenomenon in Epidural Sufentanil Pharmacokinetics: A Population Study in Children and Infants
The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis—20 infants aged 3–36 months receiving sufentanil as an epidural infusion and 41 children 0–17 years old receiving sufentanil as a long-term intravenous infusion. A population nonlinear mixed-effects model was built in NONMEM. Sufentanil pharmacokinetics were described by a 2-compartment model with first-order absorption. The effect of body size on all volume and clearance parameters was included in the model according to allometric scaling with theoretical exponents. The maturation process of metabolic clearance was described by the Hill model. During the model-building process the population was divided into 2 fractions with different typical values of metabolic clearance (CL1 and CL2). The typical values of systemic clearance scaled to a 70-kg patient for the 2 subpopulations were CL1 = 52.6 L/h and CL2 = 158 L/h. The parameters of the Hill function were 54.9 weeks for the postmenstrual age of 50% clearance maturation and 0.802 for the Hill coefficient. The typical values of distribution clearance and volumes of the central and peripheral compartments for a patient with a weight of 70 kg were Q = 40.5 L/h, VC = 7.63 L, and VT = 473 L, respectively. The value of the absorption rate constant from the epidural space was 0.0459/h, which suggests flip-flop pharmacokinetics of sufentanil after epidural administration.