Biopharmaceutical characterization of a novel sustained-release formulation of allopurinol with reduced nephrotoxicity.

The present study was aimed to develop a novel sustained-release formulation for allopurinol (ALP/SR) with the use of a pH-sensitive polymer, hydroxypropyl methylcellulose acetate succinate, to reduce nephrotoxicity. ALP/SR was evaluated in terms of crystallinity, the dissolution profile, pharmacokinetic behavior, and nephrotoxicity in a rat model of nephropathy. Under acidic conditions (pH1.2), sustained release behavior was seen for ALP/SR, although both crystalline ALP and ALP/SR exhibited rapid dissolution at neutral condition. After multiple oral administrations of ALP samples (10 mg-ALP/kg) for 4 days in a rat model of nephropathy, ALP/SR led to a low and sustained plasma concentration of ALP, as evidenced by half the maximum concentration of ALP and a 2.5-fold increase in the half-life of ALP compared with crystalline ALP, possibly due to suppressed dissolution behavior under acidic conditions. Repeated-dosing of ALP/SR resulted in significant reductions in plasma creatinine and blood urea nitrogen levels by 73% and 69%, respectively, in comparison with crystalline ALP, suggesting the low nephrotoxic risk of ALP/SR. From these findings, a strategic SR formulation approach might be an efficacious dosage option for ALP to avoid severe nephrotoxicity in patients with nephropathy.

Painless gouty tophus in the nasal bridge: A case report and literature review.

RATIONALE: A gouty tophus, arising from the deposition of monosodium urate crystals (MSU), rarely occurs in the nasal bridge. There have been only 7 documented cases of a gouty tophus in the nasal bridge from 1978 to 2018 in English-language literature. PATIENT CONCERNS: A 65-year-old male had a chief complaint of a lump in the nasal bridge that was slowly growing for over 1 year. DIAGNOSIS: MSU crystals were confirmed through ultrasonography (US) and pathological examinations. INTERVENTIONS: A cosmetically less destructive method, ultrasound-guided fine needle aspiration cytology (FNAC) was used to approach the mass lesion of nasal bridge. OUTCOMES: The diagnosis was confirmed as a gouty tophus without performing a nasal subdermal exploration. LESSONS: This case report is the first use of US with FNAC to approach and diagnosed a gouty tophus in the nasal bridge.

A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis.

PURPOSE: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. METHODS: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days). RESULTS: The pharmacokinetics of oxypurinol were best described by a one-compartment model with a separate parameter for dialytic clearance. Allopurinol 100 mg daily produced an AUC7days of 279 µmol/L h in dialysis patients, a value 50-75 % lower than the AUC7days predicted for patients with normal renal function taking 200 to 400 mg daily (427-855 µmol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis. CONCLUSIONS: Oxypurinol is efficiently removed by dialysis. The population dialytic and total (non-dialytic) clearance of oxypurinol were found to be 8.23 and 1.23 L/h, standardised to a fat-free mass of 70 kg and creatinine clearance of 6 L/h, respectively. Our results suggest that if the combination of low-dose allopurinol and haemodialysis does not result in sustained urate lowering below treatment targets (serum urate ≤0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.

ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.

Outcome of Treatment in Gouty Arthritis Patients: A Retrospective Study.

BACKGROUND: Effective treatment in gouty arthritis can prevent joint and renal damage. Target serum uric acid levels of < 6 mg/dl and < 5 mg/dl are recommended in gouty arthritis and those with tophi, respectively. OBJECTIVE: To evaluate: (i) whether patients achieved recommended serum uric acid target and assess influencing factors and (ii) renal function between patients who achieved and not achieved the goal. MATERIAL AND METHOD: The medical records of gouty arthritis patients treated in outpatient department at Thammasat University Hospital between January 2013 and December 2013 were reviewed. Patients were divided into adequately (ATG) and inadequately treated groups (ITG) based on the ACR uric acid criteria after six months of treatment. Factors associated with inadequate treatment were explored and post treatment renal function compared between A and ITGs. RESULTS: Of 139 patients, 46 (33%) achieved target serum uric acid concentrations. Alcoholic consumption was the significant factor influencing the outcome. 75.5% of patients were followed-up > 1 month for second evaluation of uric acid and most of them not receiving dosage up-titration even though not achieving the target. Both groups had similar alterations of renal function after treatment (p = 0.68). CONCLUSION: Most patients failed to achieve recommended uric acid targets. Alcohol consumption was identified as a key risk factorfor a suboptimal outcome. The treat-to-target approach should be underlined. Other risk factors should be explored prospectively.

Therapeutic drug monitoring in rheumatic diseases: utile or futile?

Rapid and effective suppression of inflammation is a primary goal in the treatment of rheumatic diseases. However, the therapeutic effect of most medications may be slow to manifest, in the order of weeks or months in the case of DMARDs. Monitoring of drug concentrations allows the possibility of appropriate dose adjustment or changes in medication to achieve more rapid or better outcomes. We review the evidence for drug concentration monitoring. Despite the theoretical utility for monitoring of MTX polyglutamate concentrations in red blood cells in patients with RA, studies have not shown a clear association between concentrations and either efficacy or toxicity and routine measurement is not yet recommended. Small studies associating disease control with concentrations of anti-TNF therapies and anti-drug antibodies suggest that routine monitoring may be useful in the future. However, the data are not yet sufficient for this recommendation. With the use of allopurinol in gout, there is a putative therapeutic range for the active metabolite oxypurinol; however, adjusting the allopurinol dose to achieve a target urate concentration is likely to be most effective, and measuring oxypurinol may be best suited to assessing drug adherence. Although measuring thiopurine metabolite concentrations with AZA therapy has been shown to be useful in IBD, studies in rheumatic diseases have so far failed to confirm a useful association between concentrations and disease control or drug toxicity. Whole blood concentrations of HCQ have been associated with disease control in SLE and future studies may be able to determine a therapeutic range.

Pharmacokinetics and comparative bioavailability of allopurinol formulations in healthy subjects.

Allopurinol is the most commonly used urate-lowering therapy in gout. This study was undertaken to evaluate the pharmacokinetics and relative bioavailability of two brands of allopurinol tablets. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, Two Way, Cross-Over Study with a washout period of 1 week. Under fasting conditions, 24 healthy male volunteers were randomly allocated to receive a single oral dose (200 mg) of either test and reference formulations. Plasma samples were obtained over a 6-hour interval and analyzed for allopurinol by reversed phase liquid chromatography with ultraviolet detection. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUCt-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two allopurinol formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 200-mg allopurinol and both formulations were well tolerated.

Determination of allopurinol and oxypurinol in human plasma and urine by liquid chromatography-tandem mass spectrometry.

Allopurinol is used widely for the treatment of gout, but its pharmacokinetics is complex and some patients show hypersensitivity, necessitating careful monitoring and improved detection methods. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry method was developed to determine the concentrations of allopurinol and its active metabolite oxypurinol in human plasma and urine using 2,6-dichloropurine as the internal standard (IS). Analytes and the IS were extracted from 0.5ml aliquots of plasma or urine using ethyl acetate and separated on an Agilent Eclipse Plus C18 column using methanol and ammonium formate-formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (95:5, v/v) as the mobile phase (A) for allopurinol or methanol plus 5mM ammonium formate aqueous solution (95:5, v/v) as the mobile phase (B) for oxypurinol. Allopurinol was detected in positive ion mode and the analysis time was about 7min. The calibration curve was linear from 0.05 to 5µg/mL allopurinol in plasma and 0.5-30µg/mL in urine. The lower limit of quantification (LLOQ) was 0.05µg/mL in plasma and 0.5µg/mL in urine. The intra- and inter-day precision and relative errors of quality control (QC) samples were ≤11.1% for plasma and ≤ 8.7% for urine. Oxypurinol was detected in negative mode with an analysis time of about 4min. The calibration curve was linear from 0.05 to 5µg/mL in plasma (LLOQ, 0.05µg/mL) and from 1 to 50µg/mL in urine (LLOQ, 1µg/mL). The intra- and inter-day precision and relative errors were ≤7.0% for plasma and ≤9.6% for urine. This method was then successfully applied to investigate the pharmacokinetics of allopurinol and oxypurinol in humans.

The population pharmacokinetics of allopurinol and oxypurinol in patients with gout.

PURPOSE: The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics. METHODS: Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent-metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling. RESULTS: Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively. CONCLUSIONS: The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.

Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level.

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.

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.

Facile and rapid high-performance liquid chromatography method for simultaneous determination of allopurinol and oxypurinol in human serum.

OBJECTIVE: To develop a rapid and sensitive assay for the simultaneous determination of allopurinol and oxypurinol in serum. METHOD: High-performance liquid chromatography (HPLC) with UV-detection. Sample preparation consists of protein precipitation by an addition of trichloracetic acid. RESULTS: Percentage recovery and intra-assay coefficient of variation (CV%) for allopurinol were 97.4-101.3 and 0.66-5.13, respectively, in the concentration range 0.5-5.0 microg/mL. For oxypurinol, the percentage recovery and the intra-assay CV% were 93.2-98.1 and 0.88-5.62, respectively, in the concentration ranges 0.4-20 microg/mL. There was no interference of endogenous compounds in this assay. CONCLUSION: This method is useful for routine therapeutic drug monitoring of allopurinol in a clinical setting.

Bioequivalence of allopurinol-containing tablet preparations.

AIM: The study was undertaken to prove the bioequivalence of two allopurinol tablet preparations. SUBJECTS, MATERIALS AND METHODS: The relative bioavailability of allopurinol from two tablet preparations (Uribenz vs. Zyloric 300) was estimated on 18 volunteers of both sexes in an open randomized study by administering one tablet of each preparation at an interval of 2 weeks. The plasma concentrations of allopurinol and its active metabolite oxypurinol were measured over a time-period of 72h by HPLC. RESULTS: While the mean AUC(0-72) values of allopurinol and oxypurinol after the test and reference preparations are entirely identical (5.33 vs. 5.21 and 137.95 vs. 137.96 microg h ml(-1), respectively), the C(max) values of oxypurinol unlike those of allopurinol show small differences (4.59 vs. 4.78 and 1.91 vs. 193 microg/ml, respectively). According to the parametric and non-parametric analysis, the quotients AUC(T)/AUC(R) and C(maxT)/C(maxR) lie within the confidence intervals 0.8 to 1.2 and 0.7 to 1.3 respectively With regard to the t(max) of allopurinol, the differences of test and reference preparations are between 0.10 to 0.05h and of oxypurinol between -0.10 to 0.87h (parametric analysis). Both, Uribenz 300 and Zyloric 300 caused a maximum decrease of the uric acid concentration in the volunteers by 18% after 10 and 24h, respectively. CONCLUSION: Thus the bioequivalence of the allopurinol tablet preparations is demonstrated.

Disposition and uric acid lowering effect of oxipurinol: comparison of different oxipurinol formulations and allopurinol in healthy individuals.

We have investigated the disposition and plasma uric acid lowering effect of oxipurinol in ten healthy individuals following oral administration of three different formulations of oxipurinol and of allopurinol in equimolar doses. The reduction of plasma uric acid was clearcut up to 48 h. As estimated from plasma AUC0-infinity, Cmax, tmax, tlag, and urinary drug excretion, a conventional rapid release preparation of oxipurinol sodium was clearly superior to oxipurinol as free acid and to enteric coated microtablets of oxipurinol sodium. Plasma oxipurinol concentrations following a single dose of the conventional formulation of oxipurinol sodium were approximately 25% lower than those observed after an equimolar dose (300 mg) of allopurinol, but mean Cmax reached the value reported to be necessary for 90% inhibition of xanthine oxidase. Since prolonged administration will result in accumulation of oxipurinol because of its slow elimination, this type of oxipurinol formulation can be expected to meet the therapeutic requirements for a drug to lower plasma uric acid.