MULTIPLE-DOSE PHARMACOKINETICS OF PEFLOXACIN IN PATIENTS WITH HEPATOCELLULAR DEFICIENCY

Multiple-dose pharmacokinetics of pefloxacin were evaluated in 25 pati ents with hepatocellular insufficiency. The severity of liver disease was graded A, B or C according to the Child-Pugh classification. Pharm acokinetic parameters evaluated in patients on day 1 of treatment were compared with those computed in 11 healthy volunteers (the control gr oup) after a single dose. Blood samples were taken at frequent interva ls after drug administration and assayed by high performance liquid ch romatography. The mean age of patients with liver impairment was sligh tly greater (59.5 years, range 33 to 81 years) than that of the contro l 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 c ontrol 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, t otal body clearance was about 30% of normal values. Elimination half-l ife increased by 200% in group B and 373% in group C compared with val ues 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 (MI C90) were exceeded by plasma pefloxacin concentrations throughout trea tment. 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 clearan ce and volume of distribution were observed. A practical index is prop osed for estimating the most likely pharmacokinetic parameters for a g iven patient, taking into account the values of the Child-Pugh score o r the prothrombin time.