Effect of Moderate or Severe Hepatic Impairment on Clarithromycin Pharmacokinetics

The pharmacokinetic and safety profiles of clarithromycin (C) and its 14‐hydroxy‐clarithromycin (HC) metabolite were determined after a multiple‐dose oral clarithromycin regimen (250 mg twice daily for five doses) in six healthy subjects and seven patients with moderate or severe hepatic impairment (Pugh grades B and C). Plasma and urine C and HC concentrations were determined using high‐performance liquid chromatography. Hepatic impairment resulted in increased harmonic mean C terminal disposition half‐life and mean ± SD C renal clearance (CLR) compared with normal volunteers (5.0 vs. 3.3 hr and 170 ± 69 vs. 111 ± 17 mL/min, respectively). Hepatic impairment also resulted in decreased metabolite peak plasma concentration and area under the plasma concentration‐versus‐time curve and decreased metabolite/parent concentration ratios compared with normal volunteers. These data suggest that 14‐hydroxylation of C was reduced by moderate to severe hepatic impairment. No adverse events were noted in either study group and there were no study‐related clinically significant changes in laboratory parameters. The decrease in C metabolic clearance appears to be partially offset by an increase in C CLR, resulting in comparable steady‐state concentrations of parent drug. In those indications in which the metabolite may be a necessary element of the antimicrobial activity of C, it would seem prudent to be cautious in using C in patients with moderate to severe hepatic impairment due to reduced production of HC. Otherwise, no dosage adjustment for C appears necessary for subjects with moderate or severe hepatic impairment provided that renal function is not impaired.