Febuxostat Sandoz Mechanism of Action

Pharmacotherapeutic group: Antigout preparations, preparations inhibiting uric acid production. ATC code: M04AA03.
Pharmacology: Pharmacodynamics: Mechanism of action: Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine-xanthine-uric acid. Both steps in the previously mentioned transformations are catalysed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostat has been shown to potently inhibit both the oxidised and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.
Clinical efficacy and safety: The efficacy of febuxostat was demonstrated in three phase 3 pivotal studies (the two pivotal APEX and FACT studies, and the additional CONFIRMS study, described as follows) that were conducted in 4,101 patients with hyperuricaemia and gout. In each phase 3 pivotal study, febuxostat demonstrated superior ability to lower and maintain serum uric acid levels compared to allopurinol. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients whose last 3 monthly serum uric acid levels were <6.0 mg/dl (357 μmol/l). In the additional phase 3 CONFIRMS study, for which results became available after the marketing authorisation for febuxostat was first issued, the primary efficacy endpoint was the proportion of patients whose serum urate level was <6.0 mg/dl at the final visit. No patients with organ transplant have been included in these studies (see Precautions).
Post marketing long term studies: CARES Study was a multicenter, randomized, double-blind, non inferiority trial comparing CV outcomes with febuxostat versus allopurinol in patients with gout and a history of major CV disease including MI, hospitalization for unstable angina, coronary or cerebral revascularization procedure, stroke, hospitalized transient ischemic attack, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease. To achieve sUA less than 6 mg/dL, the dose of febuxostat was titrated from 40 mg up to 80 mg (regardless of renal function) and the dose of allopurinol was titrated in 100 mg increments from 300 to 600 mg in patients with normal renal function and mild renal impairment and from 200 to 400 mg in patients with moderate renal impairment. The primary endpoint in CARES was the time to first occurrence of MACE, a composite of non-fatal MI, non-fatal stroke, CV death and unstable angina with urgent coronary revascularization.
The endpoints (primary and secondary) were analysed according to the intention-to-treat (ITT) analysis including all subjects who were randomized and received at least one dose of double-blind study medication. Overall 56.6% of patients discontinued trial treatment prematurely and 45% of patients did not complete all trial visits. In total, 6,190 patients were followed for a median of 32 months and the median duration of exposure was 728 days for patients in febuxostat group (n 3098) and 719 days in allopurinol group (n 3092). The primary MACE endpoint occurred at similar rates in the febuxostat and allopurinol treatment groups (10.8% vs. 10.4% of patients, respectively; hazard ratio [HR] 1.03; two-sided repeated 95% confidence interval [CI] 0.87-1.23). In the analysis of the individual components of MACE, the rate of CV deaths was higher with febuxostat than allopurinol (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03-1.73). The rates of the 13 other MACE events were similar in the febuxostat and allopurinol groups, i.e. non-fatal MI (3.6% vs. 3.8% of patients; HR 0.93; 95% CI 0.72-1.21), non-fatal stroke (2.3% vs. 2.3% of patients; HR 1.01; 95% CI 0.73-1.41) and urgent revascularization due to unstable angina (1.6% vs. 1.8% of patients; HR 0.86; 95% CI 0.59-1.26). The rate of all-cause mortality was also higher with febuxostat than allopurinol (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01-1.47), which was mainly driven by the higher rate of CV deaths in that group (see Precautions). Rates of adjudicated hospitalization for heart failure, hospital admissions for arrhythmias not associated with ischemia, venous thromboembolic events and hospitalization for transient ischemic attacks were comparable for febuxostat and allopurinol.
FAST study was a prospective, randomised, open-label, blinded endpoint study comparing the CV safety profile of febuxostat versus allopurinol in patients with chronic hyperuricaemia (in conditions where urate deposition had already occurred) and CV risk factors (i.e. patients 60 years or older and with at least one other CV risk factor). Eligible patients received allopurinol treatment prior to randomization, and dose adjustments were required when needed, according to clinical judgement, EULAR recommendations and the approved posology. At the end of the allopurinol lead-in phase, patients with a sUA level of <0.36 mmol/L (<6 mg/dL) or receiving the maximum tolerated dose or the maximum licensed dose of allopurinol were randomised in a 1:1 ratio to receive either febuxostat or allopurinol treatment. The primary endpoint of the study FAST was the time to the first occurrence of any event included in the Antiplatelet Trialists' Collaborative (APTC) composite endpoint, which included: i) hospitalisation for non-fatal MI/biomarker positive acute coronary syndrome (ACS); ii) non-fatal stroke; iii) death due to a CV event. The primary analysis was based on the on-treatment (OT) approach.
Overall, 6,128 patients were randomized, 3063 to febuxostat and 3065 to allopurinol. In the primary OT analysis, febuxostat was non-inferior to allopurinol in the incidence of the primary endpoint, which occurred in 172 patients (1.72/100 patient years) on febuxostat compared to 241 patients (2.05/100 patient years) on allopurinol, with an adjusted HR 0.85 (95% CI: 0.70, 1.03), p<0.001. The OT analysis for the primary endpoint in the subgroup of patients with a history of MI, stroke or ACS showed no significant difference between treatment groups: there were 65 (9.5%) patients with events in the febuxostat group and 83 (11.8%) patients with events in the allopurinol group; adjusted HR 1.02 (95% CI: 0.74-1.42); p=0.202.
Treatment with febuxostat was not associated with an increase in CV death or all-cause death, overall or in the subgroup of patients with a baseline history of MI, stroke or ACS. Overall, there were fewer deaths in the febuxostat group (62 CV deaths and 108 all-cause deaths), than in the allopurinol group (82 CV deaths and 174 all-cause deaths).
There was a greater reduction in uric acid levels on febuxostat treatment compared to allopurinol treatment.
Pharmacokinetics: In healthy subjects, maximum plasma concentrations (C_max) and area under the plasma concentration time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. For doses between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for febuxostat. There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t_½) of approximately 5 to 8 hours.
Population pharmacokinetic/pharmacodynamic analyses were conducted in 211 patients with hyperuricaemia and gout, treated with febuxostat 40-240 mg QD. In general, febuxostat pharmacokinetic parameters estimated by these analyses are consistent with those obtained from healthy subjects, indicating that healthy subjects are representative for pharmacokinetic/pharmacodynamic assessment in the patient population with gout.
Absorption: Febuxostat is rapidly (t_max of 1.0-1.5 h) and well absorbed (at least 84%). After single or multiple oral 80 mg and 120 mg once daily doses, C_max is approximately 2.8-3.2 μg/ml, and 5.0-5.3 μg/ml, respectively. Absolute bioavailability of the febuxostat tablet formulation has not been studied.
Following multiple oral 80 mg once daily doses or a single 120 mg dose with a high fat meal, there was a 49% and 38% decrease in C_max and a 18% and 16% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose). Thus, febuxostat may be taken without regard to food.
Distribution: The apparent steady state volume of distribution (V_ss/F) of febuxostat ranges from 29 to 75 l after oral doses of 10-300 mg. The plasma protein binding of febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 80 mg and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 91%.
Biotransformation: Febuxostat is extensively metabolised by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. In vitro studies with human liver microsomes showed that those oxidative metabolites were formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide was formed mainly by UGT 1A1, 1A8, and 1A9.
Elimination: Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of ¹⁴C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the active substance (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the faeces as the unchanged febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).
Renal impairment: Following multiple doses of 80 mg of febuxostat in patients with mild, moderate or severe renal impairment, the C_max of febuxostat did not change, relative to subjects with normal renal function. The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 μg⋅h/ml in the normal renal function group to 13.2 μg.h/ml in the severe renal dysfunction group. The C_max and AUC of active metabolites increased up to 2- and 4-fold, respectively. However, no dose adjustment is necessary in patients with mild or moderate renal impairment.
Hepatic impairment: Following multiple doses of 80 mg of febuxostat in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, the C_max and AUC of febuxostat and its metabolites did not change significantly compared to subjects with normal hepatic function. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).
Age: There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of febuxostat in elderly as compared to younger healthy subjects.
Gender: Following multiple oral doses of febuxostat, the C_max and AUC were 24% and 12% higher in females than in males, respectively. However, weight-corrected C_max and AUC were similar between the genders. No dose adjustment is needed based on gender.
Toxicology: Preclinical safety data: Effects in non-clinical studies were generally observed at exposures in excess of the maximum human exposure.
Pharmacokinetic modelling and simulation of rat data suggests that, when co-administered with febuxostat, the clinical dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose in order to avoid possible haematological effects (see Precautions and Interactions).
Carcinogenesis, mutagenesis, impairment of fertility: In male rats, a statistically significant increase in urinary bladder tumours (transitional cell papilloma and carcinoma) was found only in association with xanthine calculi in the high dose group, at approximately 11 times human exposure. There was no significant increase in any other tumour type in either male or female mice or rats. These findings are considered a consequence of species specific purine metabolism and urine composition and of no relevance to clinical use.
A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat.
Febuxostat at oral doses up to 48 mg/kg/day was found to have no effect on fertility and reproductive performance of male and female rats.
There was no evidence of impaired fertility, teratogenic effects, or harm to the foetus due to febuxostat. There was high dose maternal toxicity accompanied by a reduction in weaning index and reduced development of offspring in rats at approximately 4.3 times human exposure. Teratology studies, performed in pregnant rats at approximately 4.3 times and pregnant rabbits at approximately 13 times human exposure did not reveal any teratogenic effects.