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Kidney and Liver Disease Do Not Appear to Significantly Affect Pharmacokinetic Exposure of Tramadol Extended-Release: Presented at ACCP

By Maria Bishop

BOSTON, MA -- September 22, 2006 -- There were no differences in the stereoselective pharmacokinetics of tramadol (Ultram) extended-release (ER) and its metabolite between hepatic-impaired patients and normal subjects, in a trial presented here at the American College of Clinical Pharmacology 35^th Annual Meeting (ACCP).

In a separate trial, systemic exposure of tramadol did not differ significantly between renal-impaired groups and healthy controls, said researchers from Biovail Technologies and Ortho-MacNeil Janssen.

The synthetic opioid analgesic tramadol is an analgesic agent, its two primary metabolites are O-desmethyltramadol (M1) and di-NO-desmethyl tramadol (M5).

Previous research showed that since tramadol and the pharmacologically active metabolite M1 are eliminated both metabolically and renally, the terminal half life may be prolonged in hepatic or renal impairment.

The hepatic-impairment trial of tramadol was led by Okponanabofa Eradiri, PhD, department of pharmacokinetics & toxicology, Biovail Technologies Ltd., Chantilly, Virginia. This single-center, open-label trial, enrolled 6 healthy controls, 6 patients with mild hepatic impairment, and 6 patients with moderate hepatic impairment according to Child-Pugh classification.

Following a 10-hour fast all 3 groups were given a single oral dose of a 100-mg Ultram ER tablet at 7 a.m. with water, from day 1 through day 6.

Plasma samples indicated similar concentrations of tramadol's positive and negative enantiomers in all patients, and lower formulation of the metabolite in the patient population as compared to healthy controls.

Differences in all pharmacokinetic parameters between the 3 groups did not achieve statistical significance, but that may have been due to the small sample size of each group, the researchers noted.

The drug was well tolerated over the course of the study, Dr. Eradiri said.

The renal-impairment trial was led by John Chi-Keung Lai, PhD, department of pharmacokinetics & toxicology, Biovail Technologies Ltd. The single-center, open-label, renal-impairment trial was designed in a similar fashion to the hepatic-impairment trial, with 6 healthy controls, 6 patients with mild renal impairment, and 6 patients with moderate renal failure determined by creatinine clearance.

All 3 groups were given a single oral dose of Ultram ER 100 mg at 8 a.m. with water following a 10-hour fast from day 1 through day 6.

Urine samples indicated that excretion of tramadol M1 and M5 were decreased in renal-failure patients, but that the decrease in amount was consistent with the severity of renal impairment. There was no perceptible trend between the renal clearance of tramadol and creatinine clearance.

In blood samples, the systemic exposure of tramadol did not differ significantly between renal-impaired groups and healthy controls. A weak but positive relationship was observed between the clearance of M1 and M5 and creatinine clearance.


[Presentation title: Stereospecific Pharmacokinetics of Tramadol HCl Extended-Release Tablets in Patients with Mild and Moderate Hepatic Impairment. Abstract 127. Presentation title: Steady-State Pharmacokinetics of Tramadol HCl Extended-Release Tablets in Patients with Mild and Moderate Renal Failure. Abstract 129]

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