Pharmacokinetics considerations for gout treatments

Review

Pharmacokinetics considerations for gout treatments Pascal Richette†, Aline Frazier & Thomas Bardin †

Hoˆpital Lariboisie`re, Fe´de´ration de Rhumatologie, Paris, France

1.

Introduction

2.

Drugs approved and used for the treatment of acute gouty

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arthritis 3.

Urate-lowering therapy

4.

Expert opinion

5.

Conclusion

Introduction: Patients with gout often have comorbid conditions such as renal failure, cardiovascular disease and metabolic syndrome. The presence and required treatment of these conditions can make the treatment of gout challenging. Knowledge of the pharmacokinetics of the available drugs for the management of gout is mandatory. Areas covered: A MEDLINE PubMed search for articles published in English from January 1990 to January 2014 was completed using the terms: pharmacokinetics, colchicine, canakinumab, allopurinol, febuxostat, pegloticase, gout, toxicity, drug interaction. Expert opinion: Colchicine is a drug with a narrow therapeutic-toxicity window. Co-prescription with strong CYP3A4 or P-glycoprotein inhibitors can greatly modify its pharmacokinetics and is to be avoided. Elimination of canakinumab mainly occurs via intracellular catabolism, following receptor mediator endocytosis. Canakinumab appears to be a good alternative for patients with contraindications to colchicine, NSAIDs and corticosteroids. For patients with renal impairment, some authors recommend that the allopurinol maximum dosage should be adjusted to creatinine clearance. If the urate target cannot be achieved, the therapy should be switched to febuxostat, which is appropriate with mild--to-moderate renal failure. Anti-pegloticase antibodies affect the pharmacokinetics of the drug because they increase its clearance, with loss of pegloticase activity. Keywords: allopurinol, colchicine, febuxostat, gout, interleukin 1 blockers, pegloticase, pharmacokinetics, urate-lowering therapy Expert Opin. Drug Metab. Toxicol. [Early Online]

1.

Introduction

Gout is a common arthritis due to the deposition of monosodium urate (MSU) crystals within joints, following chronic hyperuricemia [1]. It affects 1 -- 4% of adults in Western countries, where it is the most common inflammatory arthritis in men [2]. The natural history of articular gout typically consists of three periods: i) asymptomatic hyperuricemia; ii) episodes of acute attacks of gout with asymptomatic intervals; and iii) chronic gouty arthritis [3]. Patients with gout often have comorbid conditions such as cardiovascular disease, renal failure and components of the metabolic syndrome [4,5]. Recent data from a large sample of men and women in the US showed that 74% of gouty patients had hypertension, 71% chronic kidney disease ‡ stage 2, 53% obesity, 26% diabetes and 11% heart failure [6]. In addition to hyperuricemia and the chronic inflammation encountered in severe gout [7], the presence of these associated comorbidities contributes to the overall excessive cardiovascular mortality and morbidity due to myocardial infarction and peripheral arterial disease [8-10]. The presence of all these associated comorbid conditions and their treatments affect the choice of therapeutic agents to manage gout. Therefore, knowledge of the pharmacokinetics of drugs used for the management of gout is essential.

10.1517/17425255.2014.915027 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. . .

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Knowledge of the pharmacokinetics of drugs used for the management of gout is crucial. The drug colchicine has a narrow therapeutic-toxicity window. Co-prescription with strong CYP3A4 or P-glycoprotein inhibitors should be avoided. No dose adjustment of canakinumab is necessary for patients with renal impairment. The dose of febuxostat should not be adjusted to creatinine clearance. Antipegloticase antibodies affect the pharmacokinetics of the drug: they increase its clearance, with loss of pegloticase activity.

This box summarizes key points contained in the article.

The standard oral pharmacological management of acute attacks of gout involves colchicine or NSAIDs or corticosteroids [11-14]. NSAIDs are more commonly used in the US and Northern Europe, with colchicine used in France and some countries of southern Europe [15]. Colchicine and low-dose NSAIDs are also used as prophylactic treatment to prevent flares after the initiation of urate-lowering therapy (ULT) [11,14]. Apart from these drugs, the emerging class of IL-1 blockers to treat MSU crystal-induced inflammation could become an interesting option for patients with gout and intolerance or contraindication to colchicine, NSAIDs or corticosteroids. In addition to symptomatic treatment of acute attacks, nearly all gouty patients require long-term treatment with ULT [11,12,16]. The goal of ULT in patients with chronic gout is to reduce and maintain serum uric acid levels below the physiologic saturation in a subsaturating range (i.e., < 6.0 mg/dl) over the long term, which reduces the frequency of gout flares as well as the size and number of tophi [17]. There are three ways to decrease urate levels in humans: i) decreasing urate production, mainly by inhibiting the enzyme xanthine oxidase (XO), which converts hypoxanthine to xanthine and then xanthine to urate; ii) increasing the renal excretion of uric acid with uricosuric agents; and iii) degrading urate into the more soluble component allantoin with a uricase. Here we provide a global overview of the pharmacokinetics and drug interactions of the main approved anti-inflammatory medications and ULTs used for gout. We do not discuss the pharmacokinetics of NSAIDs and corticosteroids because this is beyond the scope of this paper.

Drugs approved and used for the treatment of acute gouty arthritis 2.

Colchicine The use of colchicine is limited by its toxicity, and colchicine overdose is associated with a high mortality rate [18]. Colchicine is absorbed by the jejunum and ileum and is readily 2.1

2

bioavailable after oral administration. Colchicine is liposoluble and is easily absorbed by multiple cell types, where it binds tubulin. Absolute bioavailability was reported to be approximately 45%. Colchicine is predominantly eliminated via enterohepatic recirculation and biliary excretion, with renal clearance reported to account for about 10 -- 20% of total body clearance. It is not removed by hemodialysis [19-21]. Given these data, the presence or not of kidney or hepatic dysfunction must be checked before prescribing colchicine. Although the summary of product characteristics of Colcrys (colchicine) indicates that adjustment of the recommended dose is not required for treatment of flares in patients with mild-to-moderate renal function impairment [22], its use should be avoided in those patients [12]. Indeed, alternatives that can be given to patients with impaired renal function include a short course of oral corticosteroids [21]. In addition, a treatment course of colchicine should not be repeated more than once every 2 weeks in patients with severe impairment [22], which makes management of colchicine therapy difficult. Of note, treatment of gout flares with colchicine is not recommended in patients with renal impairment who are receiving colchicine for prophylaxis. Two proteins play a key role in the elimination of colchicine: P-glycoprotein (ABCB1) and the CYP3A4. P-glycoprotein is an ATP-dependant phospho-glycoprotein located at the cell membrane and can export various drugs out of the cell. It allows for extrusion of colchicine from cells into the gastrointestinal tract [23]. P-glycoprotein expressed by the biliary ductules in the liver can excrete 15 -- 50% of absorbed colchicine [20]. Change in P-glycoprotein activity, induced by medications that are substrates or modulators, for example, may thus lead to intracellular accumulation of colchicine and thereby increased toxic effect. To a lesser extent, absorbed colchicine can be metabolized by intestinal and hepatic CYP3A4, which catalyses demethylation of colchicine to an inactive metabolite [20,21]. Hepatic demethylation of colchicine dependent on CYP3A4 occurs before hepatobiliary excretion of colchicine. A recent study examined the pharmacokinetics of various inhibitors of CYP3A4 or P-glycoprotein and their effects on colchicine metabolism [24]. Co-administration of such inhibitors, in particular cyclosporine, clarithromycin and azithromycin (but not erythromycin), diltiazem and verapamil, ketoconazole and ritonavir, could increase the Cmax and the area under the receiver operating characteristic curve (AUC) of colchicine. Therefore, concurrent use of P-glycoprotein or strong CYP3A4 inhibitors with colchicine is contraindicated in patients with hepatic or renal impairment. Indeed, lifethreatening and fatal colchicine toxicity has been reported in these patients with colchicine taken even at therapeutic doses [18,19]. A dose reduction or interruption of colchicine therapy should be considered in patients taking those inhibitors who have no renal or hepatic impairment. Other potentially significant drug interactions have been reported with statins and fibrates, resulting in some cases in myopathy and rhabdomyolysis [25-28].

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2.2

Canakinumab

Canakinumab has been approved by the European Medicines Agency for the symptomatic treatment of frequent acute flares in patients in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate. It is a high-affinity human anti-IL-1b monoclonal antibody that neutralizes the bioactivity of the proinflammatory cytokine [29,30]. This activity inhibits the urate crystal-induced IL-1 signaling pathway [31] that occurs via activation of the NALP3 inflammasome [32]. Canakinumab is administered as a single 150-mg dose subcutaneously for gouty arthritis. The absolute bioavailability of subcutaneous canakinumab in gouty arthritis was estimated to be approximately 60%. Serum canakinumab Cmax occurred approximately 7 days after subcutaneous administration of a single dose. The halflife is 25.6 days. Canakinumab has low serum clearance (0.214 l/day), low steady-state volume of distribution (7.44 lL) and approximately 60% subcutaneous absolute bioavailability in a typical 93-kg patient [33]. Because canakinumab is a human IgG with a large molecular size, little renal excretion is expected because little intact immunoglobulin can be filtered by the kidney [34]. Indeed, most of the IgG elimination occurs via intracellular catabolism, following receptor mediator endocytosis [35]. In patients in the Childhood Arthritis Prospective Study (CAPS), creatinine clearance did not have any noticeable effect on the clearance of canakinumab, and therefore, no dose adjustment is required for patients with renal impairment [33,34]. Age and sex do not seem to modify the clearance or volume of distribution of the drug. No study of canakinumab has been performed in patients with impaired hepatic function because most of the IgG elimination occurs via intracellular catabolism [33]. For the same reason, no in vitro metabolism or drug interaction studies have investigated canakinumab, and drugs such as allopurinol, febuxostat or colchicine are not expected to influence its pharmacokinetics. 3.

Urate-lowering therapy

Allopurinol Allopurinol lowers urate levels by inhibiting XO, the enzyme that oxidizes hypoxanthine to xanthine and xanthine to urate [36]. It interacts chemically with the molybdenum center of XO. Allopurinol is an analogue of hypoxanthine and is converted by XO to its active metabolite, oxypurinol, an analogue of xanthine. Allopurinol inhibits XO by two mechanisms [37]: first, as a substrate for XO, and second, oxypurinol can bind strongly to the reduced form of XO and inhibit it. This situation provides the second and probably the most important mechanism of inhibition. It is assumed that of 100 mg allopurinol absorbed, 90 mg is metabolized to oxypurinol [37]. Allopurinol is rapidly metabolized (half-life ~ 1 h) to oxypurinol, which has by far a longer elimination half-life 3.1

(~ 23 h) [38]. During long-term treatment, the plasma concentration of oxypurinol increases with dose of allopurinol [39]. After intravenous or oral administration, 12 and 9%, respectively, of the dose of allopurinol is excreted unchanged in urine, whereas 76% is excreted as oxypurinol [37]. The latter is eliminated almost entirely unchanged in urine, and therefore, the renal clearance of oxypurinol is the most important aspect of the pharmacokinetics of allopurinol. Indeed, the excretion of the active metabolite oxypurinol is significantly reduced in patients with impaired renal function [37,38,40]. Thus, the decrease in renal function leads to higher plasma concentration of oxypurinol but in turn does not lead to greater inhibition of XO. Indeed, greater inhibition of urate synthesis is required to counter the decreased urate clearance associated with renal impairment [41]. Thiazide and loop diuretics are frequently prescribed for patients with gout because of the high frequency of associated cardiovascular comorbidities such as hypertension and heart failure [42]. Both drugs increase urate levels by a combination of volume depletion and increased reabsorption of urate by transporters in the proximal tubules [38]. Although furosemide increases plasma oxypurinol level [38,43,44], the combination of allopurinol and furosemide results in higher urate levels [43], so allopurinol is less effective in patients receiving concomitant furosemide. By contrast, co-administration of allopurinol with probenicid, a uricosuric drug, has a larger hypouricemic effect [45], despite an increased clearance of oxypurinol [45,46] mediated by inhibition of renal transporters [46]. Severe allopurinol-induced hypersensitivity is rare but can be life-threatening, with a mortality rate of approximately 20% [47]. The underlying mechanism of this reaction is not well known but has been attributed in part to cell-mediated immunity to allopurinol and oxypurinol, with renal clearance reduced in patients with substantial renal impairment [48,49]. Allopurinol-induced hypersensitivity develops early and appears to be favored by renal failure [40], high allopurinol doses at initiation [50], co-prescription of diuretics [51], reintroduction of the drug after skin intolerance [1] and the HLA--B*5801 genotype, particularly frequent in some Asian subpopulations [52]. Dose reduction of allopurinol in patients with renal impairment is a matter of debate [53]. It is recommended by some national agencies, the British Society for Rheumatology, the European League Against Rheumatism and others [11,12,54] but not the American College of Rheumatology [16,53]. This recommendation is based on a reported relationship between the dose of allopurinol in patients with renal impairment and the development of allopurinol hypersensitivity [40]. By contrast, some authors proposed that an initial dose of 1.5 mg allopurinol per unit estimated glomerular filtration rate followed by a slow increase in dose to reach the urate target may reduce the risk of severe allergic reaction [50]. Although some studies found that allopurinol does not necessarily induce severe hypersensitivity at higher doses [47,55,56], the relatively low number of patients included in these studies precludes drawing any firm conclusions. The management of

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Table 1. Febuxostat and allopurinol pharmacokinetics.

Structure Inhibitor constant Ki (nM) Enzyme selectivity Clearance

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Half-life (h)

Febuxostat

Allopurinol (oxypurinol)

Nonpurine 0.9 Selective inhibitor of xanthine oxidase Extensively metabolized in the liver and excreted by urine and feces 5 -- 8

Purine 0.5 Nonselective inhibitor of xanthine oxidase Mainly excreted by urine

transplant gout has been made difficult by the dangerous drug interaction between allopurinol and azathioprine because XO is involved in the metabolism of azathioprine and 6-mercaptopurine [57]. Mycophenolate mofetil has no effect on urate levels and can be used in place of cyclosporin or tacrolimus, which both increase the serum urate level. Alternatively, mycophenolate mofetil that is not metabolized by XO may be substituted for azathioprine to ensure the safe use of allopurinol [58]. Febuxostat Unlike allopurinol, febuxostat is a potent, nonpurine, selective inhibitor of XO (Table 1) [59,60]. It interacts with a narrow channel leading to the molybdenum center of the enzyme. By this mechanism, febuxostat is able to inhibit both the reduced and oxidized forms of XO [61]. This ability to inhibit both forms of the enzyme gives febuxostat an advantage over oxypurinol, which binds only weakly to the oxidized form. Both febuxostat and oxypurinol have a close in vitro inhibition constant (Ki), < 1 and 0.5 nM, respectively. Following oral administration, febuxostat is absorbed rapidly, reaching plasma Cmax within 1 h. It has a half-life of 5 -- 8 h. The primary method of clearance is hepatic. Febuxostat is extensively metabolized by conjugation via uridine diphosphonate glucuronosyl-transferase enzymes and by oxidation via CYP enzymes. Only 1 -- 6% of the drug is excreted unchanged in urine [61-64]. The impact of renal function on the pharmacokinetics of febuxostat has been investigated. The mean AUC of unchanged febuxostat was similar in patients with normal or mild renal impairment [63,65]. Therefore, no dose adjustment is necessary for such patients. Of note, the efficacy and safety have not been fully evaluated in patients with severe renal impairment. Age and gender have no significant effect on the pharmacokinetics or pharmacodynamics of febuxostat. Therefore, dose adjustments by age or sex are not required [66]. The effect of hepatic impairment on febuxostat was evaluated in one study [67]. Cmax, AUC and half-life were greater but not significantly for patients with mild or moderate hepatic impairment than normal hepatic function. Therefore, febuxostat does not appear to need dose adjustments for patients with mild-to-moderate hepatic impairment [61]. The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment. 3.2

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As for allopurinol, the effect of a diuretic on the pharmacokinetics and pharmacodynamics of febuxostat has been examined. The authors found that the rate and extent of absorption of a single dose of febuxostat, 80 mg, was not affected by co-administration with a single dose of hydrochlorothiazide, 50 mg, in healthy subjects. Also, this co-administration had no clinically significant effect on the pharmacodynamics of febuxostat, so dose adjustment of this XO inhibitor is not required when administered with hydrochlorothiazide [68]. The effect of food and antiacids on febuxostat was investigated in a crossover study [69]: both reduced the absorption rate of febuxostat, with no significant change in urate levels. Therefore, febuxostat can be administered regardless of food or antiacid intake. In a recent study, only small, clinically insignificant increases in febuxostat plasma concentrations were noted with combined therapy with lesinurad, 400 or 600 mg/day, a novel selective uric acid reabsorption inhibitor that inhibits URAT1, similar to the clinically unimportant effect of naproxen on febuxostat [70]. Indeed, several studies found that febuxostat did not affect the pharmacokinetics of indomethacin, naproxen or colchicine, nor did these drugs significantly affect the pharmacokinetics of febuxostat [61,71]. Finally, as for allopurinol, febuxostat impairs the XOdependent metabolism of azathioprine, and therefore, their concurrent use must be avoided [72]. Pegloticase Pegloticase is a recombinant mammalian uricase (porcine/ baboon variant) produced in Escherichia coli and is a tetrameric enzyme. Each subunit is conjugated with several strands of a 10-kDa monomethoxy PEG (mPEG) [73]. The rationale for the addition of mPEG to this molecule was to reduce the potential for immunogenicity and increase circulation half-life as compared with the non-PEGylated porcine enzyme [74-76]. Pegloticase has no known secondary pharmacodynamic activities besides its capacity for oxidating uric acid. In a Phase I study of a single perfusion of pegloticase, 4 -- 8 mg, mean urate levels decreased from 11.1 ± 0.6 mg/dl at baseline to 2 mg/dl within 24 h and to a nadir of 1.0 ± 0.5 mg/dl within 48 to 72 h postinfusion. Moreover, at 6 h after pegloticase perfusion, the urate level was 6 mg/dl [77]. Thus, the onset of pegloticase activity is rapid. In addition, 3.3

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Pharmacokinetics considerations for gout treatments

maximum serum concentrations of pegloticase, based on measurements of plasma uricase activity, were dose-proportional after a single infusion of pegloticase [77]. The uricase activity of pegloticase is maintained for several weeks after one infusion. The mean half-life of uricase activity is 9.2 ± 3.2 days (range 6.4 -- 13.8 days), whereas the intravenous pegloticase half-life is about 14 days (range 7 -- 44 days) [78,79]. In a Phase II open-label study of the pharmacodynamics and pharmacokinetics of pegloticase in 41 patients with refractory gout, the mean half-maximal inhibitory concentration and 90% inhibitory concentration was 0.10 and 0.93 µg/ml, respectively. Thus, low levels of pegloticase are sufficient to provide 50 and 90% of the maximal suppressive effect of pegloticase [78]. The clearance and volume of distribution of pegloticase (about 5 -- 10 l) are influenced by body surface area, but its pharmacokinetics profile is not affected by age, sex, body weight or creatinine clearance [77]. No dose adjustment is required for patients with renal impairment. By contrast, the pharmacokinetics of pegloticase can be changed by the presence of antipegloticase antibodies, frequent in patients receiving pegloticase. The frequency was 89% in a Phase III randomized controlled trial [80], between 63 and 86% in the Phase II multidose study [79] and 41% in the intravenous Phase I study [77]. Antibodies were directed more often against the mPEG component than the recombinant uricase [76]. Much of the immunogenicity of pegloticase--protein conjugates made with mPEG is due to the methoxy groups [81]. The presence of antipegloticase antibodies is associated with decreased pegloticase half-life as compared with no antipegloticase antibodies (11.0 [range 4 -- 21] days vs 16.1 [range 4 -- 22] days) because of increased clearance of the drug, a lower proportion of responders than nonresponders and a lower proportion of time with urate levels < 6 mg/dl during treatment [73,80]. Moreover, high titers of antipegloticase antibodies were associated with infusionrelated reaction and loss of urate-lowering efficacy. The effect of antipegloticase antibodies on other pegylated therapeutic agents is unknown.

4.

Expert opinion

The links between the myriad comorbidities often encountered in patients with gout and hyperuricemia are complex. Indeed, some of the comorbidities, such as renal failure or insulin resistance, can increase urate blood level and thus contribute to the development of gout, whereas hyperuricemia per se might contribute to the development of hypertension, metabolic syndrome and renal failure. These complex interactions might represent a vicious circle whereby some comorbidities could become both a cause and an effect of elevated urate levels. Most of all, presence of these comorbidities and their treatments might render the management of gout challenging. Indeed, because of the need to adapt the posology or avoid

some drugs in patients with renal impairment combined with putative drug interactions, effective treatment can be difficult. This situation has been well highlighted in a study finding that the presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. Of note, patients were frequently prescribed medications for which they had contraindications: in one study, about 30% of patients were prescribed colchicine despite having at least one strong contraindication [82]. This latter point is crucial because colchicine is effective for the treatment of gout attacks [83] but has a narrow therapeutic-toxicity window, with important variability in tolerance between subjects. This characteristic might limit its use for acute attacks, particularly in patients with renal failure, in whom doses should be reduced. In addition, physicians should be aware of some potential drug--drug interactions that can be life-threatening. The US FDA has analyzed the safety data for colchicine-related deaths described in the literature: 169 deaths were associated with the use of oral colchicine; 117 patients were taking colchicine within the therapeutic range of £ 2 mg/day. In all, 60 of the 117 reported deaths (51%) involved patients who were concomitantly receiving clarithromycin [19]. In a retrospective study of 116 patients prescribed clarithromycin and colchicine, 9 of the 88 patients (10.2%) who received the two drugs concomitantly died. The independent factors associated with death in the patients who had received clarithromycin and colchicine were long overlapped therapy, the presence of baseline renal impairment and the development of pancytopenia [84]. Alternatives to colchicine include classical NSAIDs or coxibs, which are widely used as first-line therapy for acute flares [14]. However, their widespread utility is limited in some patients by gastrointestinal tolerability. Furthermore, these medications may impair renal function and are contraindicated in cases of prior peptic ulcer disease, heart failure or coronary heart disease. Corticosteroid therapy can also be used for acute gouty arthritis attacks because it is as effective as NSAIDs [85]. However, its use might be limited in patients with diabetes, hypertension or heart failure. Another alternative in patients with severe renal failure or with comorbidities that contraindicate the use of NSAIDs is IL-1 blockers. The pharmacokinetics of IL-1 blockers allows their use in patients with renal impairment, and no drug--drug interaction is expected with these molecules. ULT is the standard of care for the treatment of chronic gout because this therapy can cure gout by dissolving all accumulated crystals [86]. Because of the pharmacokinetics of allopurinol, renal function is an important determinant for its efficacy and safety. Dose adjustment of allopurinol according to creatinine clearance is controversial. It often does not allow for reaching the recommended urate target of 6 mg/dl [41,87]. In this case, the patient should be switched to another ULT, such as febuxostat. The latter has the advantage of not being excreted by kidneys, so it can be used for patients

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P. Richette et al.

with mild-to-moderate renal failure. Because of its ability to inhibit both isoforms of XO, febuxostat is a more potent ULT than allopurinol. Animal studies have demonstrated that the potency is 10 -- 30 times greater than that of allopurinol [88], and pivotal trials [89,90] have shown that febuxostat, 80 -- 120 mg, is more effective than allopurinol, 300 mg, in reducing uric acid levels. Pegloticase is indicated for chronic gout in adults with disease refractory to conventional therapy (i.e., patients with abnormal urate levels and signs and symptoms inadequately controlled by XO inhibitors at the maximal medically appropriate dose or for whom these drugs are contraindicated). As discussed above, antipegloticase antibodies affect the pharmacokinetics of recombinant uricase. Indeed, antibodies lead to increase clearance of the drug, with resulting loss of uric acid response. Monitoring uric acid level is a good surrogate for measuring the development of antipegloticase antibodies. Therefore, oral ULT should be discontinued or not instituted in patients receiving pegloticase. Indeed, concomitant use of ULT may mask the increase in uric acid associated with the loss of response to pegloticase because of the development of antipegloticase antibodies.

5.

Conclusion

The management of gout includes therapy of acute flares and long-term preventive therapy via adequate urate lowering. A number of therapies are available, and in all cases, the presence of comorbidities, particularly renal dysfunction, and their treatments due to putative drug--drug interaction need to be considered when choosing the most appropriate therapy. Knowledge of the pharmacokinetics of the available drugs for the management of gout is mandatory.

Declaration of interest P Richette has received consulting fees, advisory board compensation, and lecture fees from Me´narini, Ipsen, Savient, Sanofi, Novartis, Astra Zeneca. T Bardin has received consultancy and/or speaker fees from Ardea Biosciences, Biocryst, Ipsen, Menarini, Novartis and Savient. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Pascal Richette†1,2 MD PhD, Aline Frazier1,2 MD & Thomas Bardin1,2 MD † Authors for correspondence 1 Universite´ Paris Diderot, Sorbonne Paris Cite´, UFR de Me´decine, F-75205 Paris, France 2 AP-HP, Hoˆpital Lariboisie`re, Service de Rhumatologie, Poˆle Appareil Locomoteur, 2 Rue Ambroise Pare´, 75475 Paris cedex 10, France Tel: +33 1 49 95 62 90; Fax: +33 1 49 95 86 31; E-mail: [email protected]

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