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.
Chu
S Y
SY
Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064-3500.
Granneman
G R
GR
Pichotta
P J
PJ
Decourt
J P
JP
Girault
J
J
Fourtillan
J B
JB
D002851:Chromatography, High Pressure Liquid; D017291:Clarithromycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008875:Middle Aged
C056228:14-hydroxyclarithromycin; D017291:Clarithromycin