Aminotransferase activities in healthy subjects receiving three-day dosing of 4, 6, or 8 grams per day of acetaminophen

Abstract

Introduction. This multiple-dose pharmacokinetic study has a randomized, double-blind, placebo-controlled, parallel-group design with three dosing regimens. Healthy subjects received repeated doses of acetaminophen (4 then 6 g/d or 4 then 8 g/d) or placebo. Methods. The disposition of acetaminophen and its metabolites and the tolerability of increased acetaminophen doses over 3 days of continuous consumption were characterized. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities measured throughout the study were consistent across the acetaminophen 4, 6, and 8 g/d dose levels and with placebo. Results. Serum aminotransferase activities did not exceed the upper limit of the reference range (ULRR), except for one subject with an AST of 43 U/L (ULRR, 42 U/L), which was not considered clinically significant. All doses were generally well tolerated. Conclusions. In a multiple-dose pharmacokinetics study of 4, 6, and 8 g/d of acetaminophen for 3 days, multiple aminotransferase determinations demonstrated no clinically important elevations at 1, 1.5, or 2 times the maximum recommended acetaminophen dose.

Keywords :

• Acetaminophen
• Analgesics
• Nonnarcotic
• Osteoarthritis
• Pain
• Paracetamol
• Safety

Notes

*Data from this article were previously presented, in part only, at the following meetings:

1. Society of Toxicology; Salt Lake City, UT, USA; March 2003 (Gelotte CK, Auiler JF, Lynch JM, Temple AR, Bowen DL. Tolerability and repeat-dose pharmacokinetics [PK] of acetaminophen [APAP] at 4, 6, and 8 g/d in healthy adults. Toxicol Sci 2003; 72[S-1: The Toxicologist]:145).

2. North American Congress of Clinical Toxicology; Chicago, IL, USA; September 2003 (Gelotte CK, Auiler JF, Temple AR, Lynch JM, Bowen DL. Clinical features of a repeat-dose multiple-day pharmacokinetics trial of acetaminophen at 4, 6 and 8 g/day. J Toxicol Clin Toxicol 2003; 41:726).

3. International Congress of Therapeutic Drug Monitoring & Clinical Toxicology; Basel, Switzerland; September, 2003 (Gelotte CK, Auiler JF, Lynch JM, Temple AR, Bowen DL. Three-day dosing of paracetamol up to 8 g/d in healthy adults: pharmacokinetic [PK] and clinical laboratory outcomes. Ther Drug Monit 2003; 25:529).

4. American Society for Clinical Pharmacology and Therapeutics; Miami Beach, FL, USA; March 2004 (Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT, Bowen DL. Metabolite patterns measured during repeated dosing of acetaminophen [APAP] at 4, 6, and 8 g/day in healthy adults. Clin Pharmacol Ther 2004; 75: P79).

5. European Association of Poisons Centres and Clinical Toxicologists; Strasbourg, France (poster presentation) June 2004. (Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT, Bowen DL. Time- and dose-dependent changes in the phramacokinetics and metabolite patterns of paracetamol dosed at 4, 6, and 8 g/day in healthy volunteers. J Toxicol Clin Toxical 2004; 42:468).

Clinical trials registration. Please note that Clinical Trials Registry information is not included in the article, as it reports on a clinical pharmacokinetics trial. As such, the reported study concerns safety in healthy volunteers and contains no efficacy data; thus, the study has not been registered.