Lacey LF(1), Kler L.(2)
(1)Department of Clinical Pharmacokinetics; (2)Department of Gastrointestinal Clinical Research.
A large clinical trial was carried out which compared the healing and relapse rates after oral dosing with GR122311X (a salt of ranitidine with a bismuth citrate complex) 200mg, 400mg or 800mg bd or ranitidine hydrochloride 150mg bd in patients with endoscopically confirmed duodenal ulcer . A total of 1625 patients were randomised to receive one of the study drugs for 4 weeks. Of these approximately 1300 patients provided a pre-treatment plasma bismuth concentration or a steady-state trough plasma bismuth concentration after the last dose; these samples were taken to monitor plasma bismuth concentrations and to identify those covariates which may have a clinically relevant effect on the pharmacokinetics of bismuth from GR12231IX. Plasma bismuth concentrations were determined using a validated inductively coupled plasma mass-spectroscopy method with a lower limit of quantification (BQL) of (0.2 – l.0ng/ml).
The median (and 95 percentile) trough plasma bismuth concentrations (ng/ml) were as follows for each treatment:
| GR122311X(200mgbid) | 1.3 | (4.6) |
| GR122311X(400mgbid) | 2.3 | (7.6) |
| GR122311X(800mgbid) | 3.3 | (15.1) |
| Zantac (150mg bid) | BQL | (BQL) |
A highly statistically significant linear relationship was found between age and day 28 trough plasma bismuth concentrations. This effect was only observed at the 800mg GR12231IX dose level; the mean model predicted trough plasma bismuth concentration increased from approximately 2ng/ml in a 20 year old patient to approximately 8ng/ml in an 80 year old patient. Such plasma bismuth concentrations are an order of magnitude below those which may be of clinical concern. This effect was due at least in part to an age-related decrease in renal function, as measured by creatinine clearance. Neither the patient’s gender, racial origin, nor weight were found to have any clinically significant effect on bismuth exposure from GR122311X. All treatments were found to be safe and well tolerated.
Reference: PAGE 3 (1994) Abstr 859 [www.page-meeting.org/?abstract=859]
Poster: poster