Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children.

Abstract

Aspirin (ASA), acetaminophen (APAP) or choline salicylate (chol SA) were administered as a single oral dose to 38 febrile children ages 2–7 years. Two doses (9 and 12 mg/kg) of APAP were evaluated. The 8–10 children in each treatment group were similar with regard to predose averages for fever, pulse, respiration, and demographic factors. About 50% of the children showed a low predose plasma level of salicylic acid (SA) or APAP. The predose level was treated as a known variable for the pharmacokinetic calculations and for assessment of efficacy. Antipyresis was demonstrated for all three drugs. A statistically significant lower maximum antipyretic effect was found for chol SA relative to ASA and APAP. This finding indicates a role for ASA per se on antipyretic response in addition to an action of SA. Average maximum antipyresis for ASA and APAP was about 70% of the possible excursion of rectal temperature to normal. For this 70% EffmaxN, the average plasma level was 58 μ/ml for SA and 4–6 μg/ml for APAP. Pharmacokinetic assessments in these febrile children revealed a similar Cmax of SA for ASA and chol SA (∼70μg/ml), but the tmax of SA from ASA was about 3-fold longer than that of chol SA. A 1.6-fold higher Cmax (9.3 vs. 14.6μg/ml) of APAP was noted for the higher dose, but the tmax (∼0.7 h) was similar for both doses. Drug concentration at the time of maximum antipyresis was less than the Cmax for all three drugs. Chol SA was more rapidly absorbed than ASA (absorption t1/2 = 0.1 vs 0.36 h). APAP absorption was rapid and showed an apparent dose dependency (absorption t1/2 = 0.21 and 0.13 h for the high and low doses, respectively). SA from chol SA and APAP from the low APAP dose showed an average plasma kalpha of about 1.3 h-1 for distribution from the central compartment. Bioavailability was similar for SA from ASA and chol SA, but the higher APAP dose showed a higher than expected AUC. Average apparent volume of distribution of SA was 122 ml/kg and that for APAP (adjusted for estimated presystemic clearance) was about 960 ml/kg. The average t1/2 for plasma SA elimination was 3.43 h, and SA clearance (assuming first-order conditions) was 24.5 ml/kg/h. The t1/2 for APAP was 1.74 h and did not show dose dependence; a two-compartment model t1/2 = 2.9 h was estimated for the terminal elimination phase of APAP in plasma. Average plasma clearance of APAP was 322 \pm 18 ml/kg/h. Computer modeling for APAP gave an estimated k1/2 = 0.4 h-1, Vd = 0.75 I/kg, kabs 5.35 h-1, and bioavailability 90%. Modeling approaches to plasma SA data yielded approximate values for Michaelis-Menten kinetic parameters to adequately characterize disposition by saturation kinet