Background
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.
Methods
A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.
Results
The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.
Conclusions
In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904
Objective. Gout affects ϳ1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>8.0 mg/dl).Methods. We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28.Results. Greater proportions of febuxostattreated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups.Conclusion. Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.Uric acid is the end product of purine degradation in humans. Hyperuricemia, a serum concentration of urate that exceeds the limit of urate solubility (ϳ7.0 mg/dl), is a common biochemical abnormality (1). Aberrations in any of the multiple mechanisms involved in the production and/or excretion of uric acid may increase serum urate (sUA) concentrations, and persistent hyperuricemia is a marker of monosodium urate (MSU) supersaturation in extracellular fluid (2). As such, hyperuricemia is a necessary (but often not sufficient) risk factor for MSU crystal deposition in tissues, the fundamental pathophysiologic process underlying the clinical manifestations of gout (3). Gout can thus be defined as MSU crystal deposition disease.
To assess the safety, pharmacokinetics, and pharmacodynamics of febuxostat in subjects with normal renal function or renal impairment, febuxostat (80 mg/d) was orally administered for 7 days to subjects with normal renal function (n = 11, CLcr >80 mL/min/1.73 m) or to subjects with mild (n = 6, CLcr 50-80 mL/min/1.73 m), moderate (n = 7, CLcr 30-49 mL/min/1.73 m), or severe renal impairment (n = 7, CLcr 10-29 mL/min/1.73 m). The pharmacokinetics of febuxostat and its active quantifiable metabolites 67M-1, 67M-2, and 67M-4 as well as the pharmacodynamics of uric acid, xanthine, and hypoxanthine were determined in plasma (or serum) and urine. Febuxostat was safe and well tolerated. Regression analyses indicated that febuxostat tmax and Cmax,u values were not affected by CLcr. However, for AUC24,u, CLu/F, and t1/2z, regression analyses indicated a statistically significant relationship with CLcr. With the exception of 67M-1 Cmax, regression analyses for 67M-2 and 67M-4 Cmax, and for AUC24 for all 3 metabolites indicated a statistically significant linear relationship with CLcr. Irrespective of renal function group, the mean serum uric acid concentrations decreased by 55% to 64% by day 7. Although plasma exposure to febuxostat and its metabolites was generally higher in subjects with increasing degrees of renal impairment, the percentages of decrease in serum uric acid were comparable regardless of the renal function group. A once-daily 80-mg dose of febuxostat appears to be safe and well tolerated in different renal function groups and does not appear to require any dose adjustment based on differences in renal function.
Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.
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