title: A pharmacokinetic and tolerance study of romazarit in patients with rheumatoid arthritis.
abstract: Romazarit is a new drug for which animal pharmacology suggests a disease-modifying action in rheumatoid arthritis (RA). These animal studies predict that plasma romazarit concentrations within the range 50-100 mg l-1 may be required for efficacy in the clinic. Therefore, a pharmacokinetic study was designed to estimate the dosage required to achieve these concentrations in man. Twenty-four patients with RA entered a double-blind controlled assessment receiving either placebo, 100 mg t.i.d., 350 mg b.i.d., or 350 mg t.i.d., for 6 days. Pharmacokinetic profiles were measured after single doses and after the last of the multiple doses. Adverse events were mainly trival and were distributed almost equally between all three treatment and the placebo groups. Plasma romazarit concentrations were not dose-proportional after the single doses. Mean peak plasma drug concentrations were 11.8, 66.7, and 159 mg l-1 at steady state after 100 mg t.i.d., 350 mg b.i.d., and 350 mg t.i.d. The mean urinary recovery of drug-related material (mostly ester glucuronides) was 71 per cent of the dose during the dosage interval. The renal clearance of romazarit glucuronides correlated with creatinine clearance (p less than 0.01). Saturable tubular secretion of glucuronides coupled with reversible glucuronidation would explain these findings. It is predicted that oral doses of 450 mg romazarit given 12-hourly will result in plasma concentrations within the target range of 50-100 mg l-1.
authors.affiliation: Roche Products Limited, Welwyn Garden City, Hertfordshire, UK.
authors.forename: P E
authors.initials: PE
authors.lastname: Williams
authors.forename: H A
authors.initials: HA
authors.lastname: Bird
authors.forename: S
authors.initials: S
authors.lastname: Minty
authors.forename: P S
authors.initials: PS
authors.lastname: Helliwell
authors.forename: G J
authors.initials: GJ
authors.lastname: Muirhead
authors.forename: J
authors.initials: J
authors.lastname: Bentley
authors.forename: A
authors.initials: A
authors.lastname: York
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010080:Oxazoles; D003404:Creatinine; C063528:romazarit