Population Pharmacokinetic Modeling of Acetaminophen Protein Adducts in Adults and Children

Abstract

Acetaminophen protein adducts (adducts) are a well‐established biomarker to diagnose acetaminophen toxicity. To date, the quantitative relationship between acetaminophen exposure, which drives adduct formation, and adduct exposure remains to be established. Our study characterized the adduct formation and disposition in adults using the approach of population parent‐metabolite modeling. It demonstrated formation‐limited pharmacokinetics (PK) for adducts in healthy subjects. This finding expands the existing knowledge on adduct PK that showed an apparent long elimination half‐life. We then allometrically scaled the adduct PK model to children, simulated the adduct profiles, and compared these simulated profiles with those observed in an independent cohort of children. The scaled model significantly overpredicted the adduct concentrations in children early on in treatment and underpredicted concentrations following repeated acetaminophen doses. These results suggest that children demonstrate different adduct PK behavior from that of adults, most likely because of increased reactive metabolite detoxification in children. In summary, we described the first PK model linking acetaminophen and acetaminophen protein adduct concentrations, which provides a semimechanistic understanding of varying profiles of adduct exposure in adults and children.

Population pharmacokinetic of paracetamol and atorvastatin with co‐administration of semaglutide

“…The ka of 4.33 h −1 for immediate release tablets found by Jiang et al, 28 was close to the current finding where paracetamol was blended in yoghurt. Following dosing with 80 mg/kg paracetamol, the oral clearance of 11.1 L/h for a young adult weighing 70 kg was reported by Jiang et al 28 This was close to the present CL/F of 25.9 L/h considering the, on average, lower dose of 15 mg/kg used in the current analysis. Further, intravenous CL of 17 L/h from population PK analysis in elderly people have also been reported 29 .…”

“…The two‐compartment model identified for paracetamol in this analysis is in line with models obtained from previous analysis when adjusted for body weight differences 28,29 . In young adults with a body weight range of 62–84 kg, a two‐compartment model with first order absorption was described for immediate release tablets where V1/F = 30.7 L and V 2 /F = 19.9 L 28 .…”

“… 28 , 29 In young adults with a body weight range of 62–84 kg, a two‐compartment model with first order absorption was described for immediate release tablets where V1/F = 30.7 L and V 2 /F = 19.9 L. 28 Correlation between body weight and the apparent volume of distribution V 1 /F of paracetamol have previously been reported. 28 The ka of 4.33 h −1 for immediate release tablets found by Jiang et al, 28 was close to the current finding where paracetamol was blended in yoghurt. Following dosing with 80 mg/kg paracetamol, the oral clearance of 11.1 L/h for a young adult weighing 70 kg was reported by Jiang et al 28 This was close to the present CL/F of 25.9 L/h considering the, on average, lower dose of 15 mg/kg used in the current analysis.…”

“… 29 However, our estimate of intercompartmental clearance Cl 2 /F was 199 L/h compared to 22.2 L/kg previously described. 28 …”

“…In young adults with a body weight range of 62–84 kg, a two‐compartment model with first order absorption was described for immediate release tablets where V1/F = 30.7 L and V 2 /F = 19.9 L 28 . Correlation between body weight and the apparent volume of distribution V 1 /F of paracetamol have previously been reported 28 . The ka of 4.33 h −1 for immediate release tablets found by Jiang et al, 28 was close to the current finding where paracetamol was blended in yoghurt.…”