Multiple-Dose Pharmacokinetics of Pefloxacin in Patients with Hepatocellular Deficiency

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Multiple-dose pharmacokinetics of pefloxacin were evaluated in 25 patients with hepatocellular insufficiency. The severity of liver disease was graded A, B or C according to the Child-Pugh classification. Pharmacokinetic parameters evaluated in patients on day 1 of treatment were compared with those computed in 11 healthy volunteers (the control group) after a single dose. Blood samples were taken at frequent intervals after drug administration and assayed by high performance liquid chromatography. The mean age of patients with liver impairment was slightly greater (59.5 years, range 33 to 81 years) than that of the control group (46.7 years, range 42 to 51 years).

In the patients with liver disease, the mean (± SD) half-life of elimination, although highly variable, was significantly longer (46.3 ± 42.5 hours) than in the control group (11.3 ± 3.5 hours, p < 0.001). The total clearance was significantly decreased (1.76 ± 1.31 L/h vs 6.03 ± 2.99 L/h in the control group). In groups B and C of the Child-Pugh classification, total body clearance was about 30% of normal values. Elimination half-life increased by 200% in group B and 373% in group C compared with values in healthy volunteers. Intergroup differences (group B vs group C of the Child-Pugh classification) were not statistically significant.

The minimum concentrations inhibiting 90% of Gram-negative strains (MIC90) were exceeded by plasma pefloxacin concentrations throughout treatment. For most patients, trough plasma concentrations were above 2 mg/L and peak plasma concentrations averaged 8.5 mg/L. Large inter- and intraindividual variations in the elimination half-life, total clearance and volume of distribution were observed. A practical index is proposed for estimating the most likely pharmacokinetic parameters for a given patient, taking into account the values of the Child-Pugh score or the prothrombin time.

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