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 mult iple-dose oral clarithromycin regimen (250 mg twice daily for five dos es) in six healthy subjects and seven patients with moderate or severe hepatic impairment (Pugh grades B and C). Plasma and urine C and HC c oncentrations were determined using high-performance liquid chromatogr aphy. Hepatic impairment resulted in increased harmonic mean C termina l disposition half-life and mean +/- SD C renal clearance (CL(R)) comp ared with normal volunteers (5.0 vs. 3.3 hr and 170 +/- 69 vs. 11 1 +/ - 17 mL/min, respectively). Hepatic impairment also resulted in decrea sed metabolite peak plasma concentration and area under the plasma con centration-versus-time curve and decreased metabolite/parent concentra tion ratios compared with normal volunteers. These data suggest that 1 4-hydroxylation of C was reduced by moderate to severe hepatic impairm ent. No adverse events were noted in either study group and there were no study-related clinically significant changes in laboratory paramet ers. The decrease in C metabolic clearance appears to be partially off set by an increase in C CL(R), resulting in comparable steady-state co ncentrations of parent drug. In those indications in which the metabol ite 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. Otherwi se, no dosage adjustment for C appears necessary for subjects with mod erate or severe hepatic impairment provided that renal function is not impaired.