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Pharmacokinetics of meropenem in patients with liver disease
P T Thyrum1, C Yeh, B Birmingham
1Zeneca Pharmaceuticals, Wilmington, Delaware 19850-5437, USA.
Abstract:
Eight subjects with chronic stable alcoholic cirrhosis and eight matched controls with normal liver function were given an initial 30-minute intravenous infusion of 1 g of meropenem; beginning 24 hours later, they received five additional 1-g doses at 6-hour intervals. No statistically significant differences were found between the first dose and steady state or between groups for any plasma pharmacokinetic parameters-including the highest observed plasma concentrations, plasma concentrations at 6 hours after dosing (C6h), terminal half-life, area under the plasma concentration-time curve (AUC), area under the first moment of the curve, plasma clearance, steady-state volume of distribution, and accumulation ratios-on the basis of either AUC or C6h. There were also no statistically significant differences in any of the measured or calculated pharmacokinetic parameters of the microbiologically inactive metabolite of meropenem (ICI 213,689). A total of 11 adverse experiences (one moderate and 10 mild) were reported by four patients; nine of these experiences, including two in controls, were rated by the investigator as "possibly" drug related. It is concluded that meropenem is well tolerated with repeated intravenous dosing and that dosage adjustments are not necessary for patients with hepatic disease.
Insights
Meropenem dosing in patients with alcoholic cirrhosis showed no significant pharmacokinetic differences compared to healthy controls. Repeated intravenous doses of meropenem are well-tolerated, and dosage adjustments are not needed for hepatic disease.
Area of Science:
- Pharmacology
- Hepatology
- Infectious Diseases
Background:
- Chronic stable alcoholic cirrhosis affects liver function.
- Meropenem is a broad-spectrum carbapenem antibiotic.
- Hepatic impairment can alter drug pharmacokinetics.
Purpose of the Study:
- To evaluate the pharmacokinetics of meropenem in patients with alcoholic cirrhosis.
- To compare meropenem pharmacokinetics between cirrhotic patients and healthy controls.
- To assess the safety and tolerability of repeated meropenem dosing in hepatic disease.
Main Methods:
- Eight subjects with alcoholic cirrhosis and eight healthy controls received meropenem intravenously.
- An initial dose was followed by five additional doses at 6-hour intervals.
- Plasma pharmacokinetic parameters were measured and compared between groups.
Main Results:
- No statistically significant differences in plasma pharmacokinetic parameters (AUC, C6h, half-life, clearance, etc.) were observed between patients with cirrhosis and controls.
- Pharmacokinetics of the meropenem metabolite (ICI 213,689) were also similar between groups.
- Meropenem was well-tolerated, with most adverse experiences reported as mild and possibly drug-related.
Conclusions:
- Meropenem exhibits predictable pharmacokinetics in patients with alcoholic cirrhosis.
- Repeated intravenous dosing of meropenem is safe and well-tolerated in hepatic disease.
- Dosage adjustments for meropenem are not necessary in patients with hepatic impairment.