Drug interactions
Febuxostat is contraindicated with concomitant use of theophylline and chemotherapeutic agents, namely azathioprine and 6-mercaptopurine, because it could increase blood plasma concentrations of these drugs and thereby their toxicity. Pharmacology
Mechanism of action
Febuxostat is a non-purine-selective inhibitor of xanthine oxidase. It works by non-competitively blocking the molybdenum pterin center, which is the active site of xanthine oxidase. Xanthine oxidase is needed to oxidize successively hypoxanthine and xanthine to uric acid. Thus, febuxostat inhibits xanthine oxidase, thereby reducing production of uric acid. Febuxostat inhibits both the oxidized and the reduced forms of xanthine oxidase by virtue of its tight binding to the molybdenum pterin site. Pharmacokinetics
After oral intake, at least 84% of the febuxostat dose is absorbed in the gut, and highest blood plasma concentrations are reached after 60 to 90 minutes. When taken together with a fatty meal, febuxostat reaches lower concentrations in the body; but this is not considered clinically relevant. When in the bloodstream, 99.2% of the substance is bound to the plasma protein albumin, and 82–91% of the active metabolites are bound to plasma proteins. Febuxostat has three active metabolites in humans, which are formed mainly by a number of cytochrome P450 liver enzymes (CYP1A1, 1A2, 2C8, 2C9). One of them is a dicarboxylic acid, the other two are hydroxylated derivatives. These, as well as the original drug, are further glucuronidated, mainly by the enzymes UGT1A1, 1A8, and 1A9.
The target of ravulizumab-cwvz is the same eculizumab (Soliris) with changes to the structure of the antibody resulting in a longer serum half life and therefore reduced dosing regimen. Dialysis
Patients with aHUS who have ESRD are generally consigned to lifelong dialysis, which carries a 5-year survival rate of 34–38%, with infections accounting for 14% of deaths. These patients also remain at ongoing risk of non-kidney systemic complications of the disease. Kidney transplantation
Despite its history of use in patients with aHUS, kidney transplantation does not address the continued and uncontrolled complement activation that leads to progressive, systemic TMA. As many as 90% of patients with aHUS and who are not treated with Soliris or Ultomiris, experience TMA in the transplanted organ, leading to transplant failure. Patients who have undergone kidney transplantation are still at continued risk of neurological, gastrointestinal, and cardiovascular complications and, importantly, premature mortality. Following kidney transplantation, the ongoing, uncontrolled, chronic complement activation associated with aHUS causes graft loss in 66% of children and 55% of adults, as well as continued inflammatory and TMA insult to other organs. Combined liver-kidney transplantation is only available to very few patients, due to the limited supply of solid organs. In addition, there is a substantial near-term risk of mortality, which many physicians and patients consider excessive. In recent years, some transplant centers have begun to administer eculizumab to patients with TMA who receive a kidney transplant. This strategy has been effective in preventing TMA recurrences in these patients.