Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations

Abstract

Objectives

The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures.

Methods

We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4.

Results

The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower C_max, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR.

Conclusions

Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower C_max and later T_max than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

Keywords:

• Acetaminophen
• overdose
• population PK
• extended release and modified release

Acknowledgements

The authors wish to thank Drs. Paul Chapman, Ronald Kirschner, Helene Salmonson, Christine Stork, and Jedd Wolchok, and for their generous sharing of data for this analysis.

Disclosure statement

Dr. Dart and Ms. Reynolds are employees of Denver Health and Hospital Authority, which receives grants and other funding from Johnson & Johnson Consumer Healthcare. Drs. Spyker, Yarema, and Yip declare no conflicts of interest.

Additional information

Funding

This work was funded by an investigator-initiated study award from Johnson & Johnson Consumer Healthcare to Denver Health’s Rocky Mountain Poison & Drug Safety. Johnson & Johnson Consumer Healthcare did not have any involvement in the conduct of the study or the decision making. The authors had full access to the data, performed the analysis, and prepared this manuscript, over which they had full editorial control.