In humans, exposure (as expressed as area under the plasma concentration-time curve) following intravenous (IV) lobucavir is proportional to dose. The clearance of lobucavir is independent of dose and the total clearance is approximately 700 mL/min. Renal clearance accounts for approximately 80% of total clearance, with resulting high concentrations of lobucavir in urine. The renal clearance of lobucavir exceeds the glomerular filtration rate (GFR), indicating that there is extensive tubular excretion. There is evidence for saturable absorption of lobucavir after oral administration. Mean plasma AUC values increase, nearly in proportion to the dose, up to doses of 3-6 mg/kg (200-400 mg unit dose), but not at higher doses. There is also considerable variability in the absorption of lobucavir. Intra- and inter-subject variabilities in AUC were assessed in HIV and CMV-seropositive subjects comparing the bioavailability of lobucavir as a solution and as capsule (micronized and non-micronized drug product) formulations. In these studies the percent coefficient of variation (% CV) for intra-subject variability ranged from 20 to 34% CV and the inter-subject variability ranged from 27 to 60% CV. The presence of liver disease may alter the pharmacokinetics of drugs which are protein bound, excreted primarily in the bile, or eliminated by oxidative pathways of metabolism in the liver. The degree of impairment of elimination may be variable subject to the degree of hepatic dysfunction and type of liver disease. Lobucavir is not extensively protein bound, is primarily eliminated by renal excretion, and does not appear to undergo extensive metabolism. However, it appears that absorption of some orally administered drugs may be slightly decreased in subjects with hepatic impairment due to underlying cirrhosis. AUC values for the orally administered nucleoside agents stavudine and sorivudine were decreased by approximately 10% in subjects with hepatic impairment. In neither case was the difference statistically significant nor was it clinically significant warranting dose adjustment. With saturable and variable absorption of lobucavir evident in subjects without hepatic disease, it is important to assess absorption and elimination of lobucavir in subjects with hepatic impairment due to underlying cirrhosis, not least because one of the disease targets of lobucavir is hepatitis B.
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