Christopher Lademacher

Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28‐week, phase III, randomized, double‐blind, parallel‐group trial

OBJECTIVE To compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. METHODS Subjects (n = 1,072) with hyperuricemia (serum urate level > or = 8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to < or = 2.0 mg/dl) renal function were randomized to receive once-daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. RESULTS Significantly (P < or = 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with febuxostat than with allopurinol. CONCLUSION At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.

The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.

IntroductionThe purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.MethodsSubjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.ResultsComorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.ConclusionsUrate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.Clinical Trial RegistrationNCT00430248

Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout.

Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and < 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance. Results. After 1 month initial treatment, > 80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA < 6.0 mg/dl. After ULT reassignment, > 80% of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups. Conclusion. Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time. Registered as NCT00175019.

Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy.

Clinical benefit early in urate-lowering treatment of gout is difficult to document. We examined data from 1,832 gouty subjects treated with either urate-lowering agents or placebo to identify determinants of gout flare incidence and tophus size during year 1 of treatment. Reductions from pretreatment serum urate levels influenced flare frequency and tophus size, but the effect of urate level on flare incidence was biphasic. Lower urate levels were associated with higher flare incidence early in treatment but lower incidence by one year. The complex relationship between urate-lowering and clinical outcome early in treatment has implications for both clinical and investigative approaches to urate-lowering management.

Pharmacokinetic Assessment of Drug-Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults.

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration‐time curves (AUC0–∞) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.

Pharmacokinetic Evaluation of CYP3A4‐Mediated Drug‐Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazoles effects on CYP3A4‐mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration‐time curve (AUCτ) during a dosing interval by 90% and maximum concentration (Cmax) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0‐∞) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0‐∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.

Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non‐purine selective inhibitor of xanthine oxidase

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase. WHAT THIS STUDY ADDS Co-administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat. Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide. AIM This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat. METHODS Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed. RESULTS Mean febuxostat C(max), AUC((0-t)), AUC((0-infinity)), t(1/2,z), CL/F and V(ss)/F values for regimens co-administration/febuxostat alone were 2.9/2.9 microg ml(-1), 9.3/9.1 microg ml(-1) h, 9.6/9.3 microg ml(-1) h, 6.5/6.1 h, 8.8/9.3 l h(-1) and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C(max), AUC((0-t)), and AUC((0-infinity)) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C(mean,24h), C(mean,48h) and CL(R) for both regimens co-administration/febuxostat alone were 216/203 micromol l(-1), 218/202 micromol l(-1) and 9.1/10.1 ml min(-1), respectively. Although serum uric acid C(mean,24h) and C(mean,48h) values were higher and CL(R) values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%-9.5%) was considered clinically significant. CONCLUSION Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.

Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein‐1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion‐transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P‐glycoprotein (P‐gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P‐gp substrate), digoxin (0.5 mg; P‐gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration‐time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134),  and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P‐gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.

Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects

This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration‐time curves (AUC∞) and maximum concentrations (Cmax) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R‐methadone, AUC∞ reduced 10%, Cmax increased 3%; S‐methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2‐, CYP2C8‐, or CYP2D6‐mediated metabolism.

Pharmacokinetic and Pharmacodynamic Evaluation of the Drug-Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects.

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration‐time curves from time 0 to infinity of S‐ and R‐warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S‐ and R‐warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment‐emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.