Liver Disease and Dose Changes for Anti-HIV Drugs

Abacavir Dose Decrease if Mild Liver Disease

Francois Raffi, MD from France and Dr. G. Yuen of Glaxo Wellcome presented a study showing that the dose of abacavir (Ziagen) should be decreased in patients with mild liver disease.  The researchers defined ìmildî liver disease as a ìChild-Pughî score of five on liver biopsy samples.  The study of HIV positive patients included 9 with mild liver disease and 9 ìcontrolî patients without liver disease matched for age and weight.  Women represented 22% of both groups, while all of those with liver disease were Caucasian.  The cause of liver disease was not reported.  After one dose of abacavir 600 mg, blood and urine tests were sampled for up to 24 hours.  The results showed that the blood concentrations of abacavir were higher among those with liver disease.  This included the highest blood concentration (maximum) and the total concentration (ìarea-under-the-curveî or ìAUC.î  The maximum level increased by a mean (average) of 26%, while the ìAUCî increased by 89%.  The ìhalf-lifeî (time until half of an original amount remains, due to metabolism) also increased 58% among those with liver disease.  There were seven ìemergentî side effects (adverse events) that occurred, and 71% of these were among those with liver disease.  Yet, all but one was mild or moderate and ìnon-serious.î  The authors concluded, ìpatients with mild hepatic [liver] impairment [disease] should receive 150 mg [of] abacavir twice daily,î instead of the usual dose of 300 mg twice daily.

Reference
Raffi F and others.  Pharmacokinetics of, and tolerability to, a single, oral, 600 mg dose of abacavir in HIV-positive subjects with or without liver disease (CNAB1006).  Abstract and poster 1630.

Nelfinavir (Viracept) Levels Increased with Liver Disease

A preliminary study to evaluate blood levels of nelfinavir (Viracept) in patients with varying degrees of liver disease was presented.  Nelfinavir is a protease inhibitor drug.  All of the 24 patients were HIV negative.  One 750 mg dose was used.  The results revealed moderate increases in blood concentrations of the drug.  This included the peak (maximal) concentration and the total drug exposure (ìarea-under-the-curveî).  Also, the ìhalf-lifeî (amount of time until half of an original amount remains, due to metabolism) increased.  As a result of this study, Agouron Pharmaceuticals plans to do a similar study in HIV positive patients with liver disease.  Note that a finite increase in the blood concentration of nelfinavir would likely be a benefit in terms of greater anti-HIV potency.  Therefore, a dose adjustment might not be needed.  This assumes that no increased toxicity or side effects occur when future studies are completed.

Reference
Hsyu PH and others.  Pharmacokinetics of nelfinavir and metabolite M8 in patients with liver impairment after a single oral 750 mg dose.  Abstract 1657.