Population pharmacokinetics of paracetamol across the human age‐range from (pre)term neonates, infants, children to adults

Abstract

In order to characterize the variation in pharmacokinetics of paracetamol across the human age span, we performed a population pharmacokinetic analysis from preterm neonates to adults with specific focus on clearance. Concentration-time data obtained in 220 neonates (post-natal age 1-76 days, gestational age 27-42 weeks), infants (0.11-1.33 yrs), children (2-7 yrs) and adults (19-34 yrs) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight-dependent exponent were tested. Between preterm neonates and adults, linear bodyweight functions were identified for Q2, Q3, V1, V2, and V3, while for CL a power function with a bodyweight-dependent exponent k was identified (CLi = CLp × (BW/70)(k) ). The exponent k was found to decrease in a sigmoidal manner with bodyweight from 1.2 to 0.75, with half the decrease in exponent reached at 12.2 kg. No other covariates such as age were identified. A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the pediatric age-range was developed. Clearance was found to change in a nonlinear manner with bodyweight. Based on the final model, dosing guidelines are proposed from preterm neonates to adolescents resulting in similar exposure across all age ranges.

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

“…In particular, our findings for our BCS class I compounds, theophylline and paracetamol, indicate that both compounds are absorbed to a similar extent at different absorption sites throughout the GI tract ( Figure 2) [33], which is reflected by the very similar absorption half-life and k a values in adults ( Table 1). Given that theophylline is almost completely absorbed (f a~1 ) and that there are no known absorption transporter effects for theophylline [56], it seemed reasonable to assume that the maturation function identified for the changes in oral drug absorption in paracetamol after birth can also be applied to theophylline.…”

“…Paracetamol There are a number of paediatric popPK models for paracetamol published in the literature, which range from simple one compartment models to more complex three compartment models [31][32][33]. The model by Anderson et al [7], which contains the maturation function introduced in Equation [1], is a one compartment model.…”

Randomized Controlled Trial Comparing Different Single Doses of Intravenous Paracetamol for Placement of Peripherally Inserted Central Catheters in Preterm Infants

“…Pharmacokinetics studies on intravenous paracetamol in preterm infants also suggest that a loading dose of 20 mg/kg intravenous paracetamol for neonates with postconceptional ages of 28-32 weeks and body weights above 1.5 kg is sufficient for pain relief [15]. Pharmacokinetics/pharmacodynamics data in older infants suggest a target plasma concentration of >9 mg/L [13]. Our study showed plasma concentrations >9 mg/L in 95% of all subjects.…”

“…While there are data from pharmacokinetics studies [12,13], the pharmacodynamics of paracetamol in neonates are poorly described. Allegaert et al [14] showed a reduction of pain after 20 mg/kg of paracetamol in preterm and term infants suffering from delivery trauma.…”

Population pharmacokinetics of intravenous acetaminophen in Japanese patients undergoing elective surgery

“…The aim of this study was therefore to evaluate the predictive performances of three published PK models [2,3,6] for i.v. acetaminophen and to build a compartmental population PK model for i.v.…”