Population Pharmacokinetic Modelling of Acetaminophen and Ibuprofen: the Influence of Body Composition, Formulation and Feeding in Healthy Adult Volunteers.

BACKGROUND AND

objectiveCombined acetaminophen and ibuprofen are common antipyretic and analgesic drugs. Formulation and feeding affect drug absorption. Drug clearance has a nonlinear relationship with total body weight. The covariate effect of fat mass on acetaminophen and ibuprofen pharmacokinetics remains unexplored. This study sought to quantify acetaminophen and ibuprofen pharmacokinetics with intravenous, tablet, sachet and oral suspension formulations in fed and fasted states.

methodsPooled time-concentration data for acetaminophen and ibuprofen were available from fasting and fed healthy adults. Data from intravenous, tablet, sachet and suspension formulations were analysed using nonlinear mixed-effects models. Body composition was considered as a covariate on clearances and volumes of distribution (V

resultsPooled data included 116 individuals (18-49 years, 49-116 kg) with 6095 acetaminophen and 6046 ibuprofen concentrations available for analysis. A two-compartment pharmacokinetic model with first-order elimination described disposition for both drugs. Normal fat mass was the best covariate to describe acetaminophen clearance (CL), with a factor for fat contribution (FFATCL) of 0.816. Acetaminophen volume of distribution was described using total body weight. Normal fat mass was the best covariate to describe ibuprofen clearance (FFATCL = 0.863) and volume of distribution: (FFATV = 0.718). Clearance and central volume of distribution were 24.0 L/h/70 kg and 43.5 L/h/70 kg for acetaminophen. Ibuprofen clearance and central volume of distribution were 3.79 L/h/70 kg and 10.5 L/h/70 kg. Bioavailability and absorption half-life were 86% and 12 min for acetaminophen and 94% and 27 min for ibuprofen. Absorption lag times were 5.3 min and 6.7 min for acetaminophen and ibuprofen, respectively. Feeding increased both absorption half-life and absorption lag time when compared to the tablet formulation under fasting conditions. Feeding had the most pronounced effect on the lag time associated with tablet formulation for both drugs. Time to a pain score reduction of 2 points (visual analogue score, 0-10) differed by only 5-10 min across all formulations for acetaminophen and ibuprofen.

conclusionFat mass was an important covariate to describe acetaminophen and ibuprofen pharmacokinetics. The absorption half-lives of acetaminophen and ibuprofen were increased in fed states. The delay in absorption, quantified by a lag time, was protracted for both drugs.