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.

Keywords: acetaminophen protein adducts; biomarkers; hepatotoxicity; parent-metabolite model; pediatrics.

Figure 1:

Structure of the parent-metabolite model in adults following oral APAP administration. †: Two parallel pathways (first-order and zero-order) were used to describe the mixed absorption of extended release formulation. §: lumped model to describe the adduct formation (see discussion for details).

Figure 2.

Individual fitting of the parent-metabolite model for APAP protein adducts in adults. The results were stratified by molecules (A,B and C,D) and formulations (A,C and B,D). Blue dots: observed APAP or adduct concentrations. Red line: individual prediction. Black line: population prediction.

Figure 3.

Qualification of the literature parent model (Wang et al.) in a pediatric group receiving a single dose of APAP. The simulations were stratified by infants (29 days to 2 years) and children & adolescents (2 years to < 14 years) with the age ranges defined by Zuppa et al. Blue dots: observed APAP concentrations. Middle solid, upper and lower dotted red line: medians, 95^th and 5^th percentiles of predicted APAP concentrations, respectively.

Figure 4.

Simulation of the adduct concentrations in the pediatric group by the scaled parent-metabolite model. (A) ratios stratified by infants (1 year to <2 years), children (2 to <12 years), and adolescents (12 to <18 years); (B) ratios stratified suspected infection and non-infection. The median time of sampling is approximately 3.0 days after the first dose. The rising ratio over time reflects the increasing adduct concentrations following repeated dosing. The solid line represents the line of identity (ratio = 1.0); the upper and lower dotted line represent the ratios of 2.0 and 0.5, respectively.