Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout.

AIMS: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. METHODS: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. RESULTS: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h-1 , 32.8 l, 19.4 l, 3.6 h-1 and 1.25 l h-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. CONCLUSIONS: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

A pharmacokinetic-pharmacodynamic study of a single dose of febuxostat in healthy subjects.

AIMS: To examine the pharmacokinetic-phamacodynamic (PK-PD) relationships of plasma febuxostat and serum urate and the effect of a single dose of the drug on renal excretion and fractional clearance of urate (FCU). METHODS: Blood and urine samples were collected at baseline and up to 145 hours following administration of febuxostat (80 mg) to healthy subjects (n = 9). Plasma febuxostat and serum and urinary urate and creatinine concentrations were determined. Febuxostat pharmacokinetics were estimated using a two-compartment model with first-order absorption. An Emax PK-PD model was fitted to mean febuxostat and urate concentrations. Urinary urate excretion and FCU were calculated pre- and post-dose. RESULTS: Maximum mean plasma concentration of febuxostat (2.7 mg L-1 ) was observed 1.2 hours after dosage. Febuxostat initial and terminal half-lives were 2.0 ± 1.0 and 14.0 ± 4.7 hours (mean ± SD), respectively. The majority (81%) of the drug was eliminated in the 9 hours after dosing. Serum urate declined slowly achieving mean nadir (0.20 mmol L-1 ) at 24 hours. The IC50 (plasma febuxostat concentration that inhibits urate production by 50%) was 0.11 ± 0.09 mg L-1 (mean ± SD). Urinary urate excretion changed in parallel with serum urate. There was no systematic or significant change in FCU from baseline. CONCLUSION: The PK-PD model could potentially be used to individualise febuxostat treatment and improve clinical outcomes. A single dose of febuxostat does not affect the efficiency of the kidney to excrete urate. Further investigations are required to confirm the present results following multiple dosing with febuxostat.

Determination of febuxostat in human plasma by high performance liquid chromatography (HPLC) with fluorescence-detection.

Febuxostat prevents gout attacks by lowering serum urate. Aspects of the pharmacokinetic-pharmacodynamic relationship of febuxostat concentrations to urate in gout patients need further elucidation. In order to undertake these studies, the assay methodology for febuxostat has been enhanced and validated to meet FDA standards. An HPLC method with fluorescence-detection has been modified to increase sensitivity, reduce complexity, shorten the sample preparation process and improve the inter-day coefficient of variation of the lowest quality control sample (0.03 µg/L). Protein in plasma samples (200 µL) is now precipitated with acetonitrile (400 µL) containing the internal standard (2-naphthoic acid). The supernatant is analysed at excitation and emission wavelengths of 320 and 380 nm, respectively as in the previous method. A Luna C18 column (Phenomenex, Australia) at 40 °C with mobile phase of glacial acetic acid (0.032%) in acetonitrile:water (60:40, v:v), an injection volume of 10 µL and a flow rate of 1.5 mL/min is employed. Analysis time is 8 min. Calibration curves in drug-free plasma range from 0.005 to 10.00 µg/mL. Data points are fitted using linear regression with a weighting factor of 1/concentration. The inter-day accuracy and imprecision of the quality control samples (0.0075, 0.015, 3.00 and 9.80 µg/mL) is 90-115% and ≤ 14.5%, respectively.

Effectiveness of an electronic patient-centred self-management tool for gout sufferers: a cluster randomised controlled trial protocol.

INTRODUCTION: Gout is increasing despite effective therapies to lower serum urate concentrations to 0.36 mmol/L or less, which, if sustained, significantly reduces acute attacks of gout. Adherence to urate-lowering therapy (ULT) is poor, with rates of less than 50% 1 year after initiation of ULT. Attempts to increase adherence in gout patients have been disappointing. We aim to evaluate the effectiveness of use of a personal, self-management, 'smartphone' application (app) to achieve target serum urate concentrations in people with gout. We hypothesise that personalised feedback of serum urate concentrations will improve adherence to ULT. METHODS AND ANALYSIS: Setting and designPrimary care. A prospective, cluster randomised (by general practitioner (GP) practices), controlled trial. PARTICIPANTS: GP practices will be randomised to either intervention or control clusters with their patients allocated to the same cluster. INTERVENTION: The intervention group will have access to the Healthy.me app tailored for the self-management of gout. The control group patients will have access to the same app modified to remove all functions except the Gout Attack Diary. PRIMARY AND SECONDARY OUTCOMES: The proportion of patients whose serum urate concentrations are less than or equal to 0.36 mmol/L after 6 months. Secondary outcomes will be proportions of patients achieving target urate concentrations at 12 months, ULT adherence rates, serum urate concentrations at 6 and 12 months, rates of attacks of gout, quality of life estimations and process and economic evaluations. The study is designed to detect a ≥30% improvement in the intervention group above the expected 50% achievement of target serum urate at 6 months in the control group: power 0.80, significance level 0.05, assumed 'dropout' rate 20%. ETHICS AND DISSEMINATION: This study has been approved by the University of New South Wales Human Research Ethics Committee. Study findings will be disseminated in international conferences and peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12616000455460.

Individualising the dose of allopurinol in patients with gout.

AIMS: The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. METHODS: A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR ), concomitant diuretic use and SU concentrations before (UP ) and during (UT ) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. RESULTS: The final plasma oxypurinol concentration-response relationship (UT = UP - C*(UP - UR )/(ID50 + C), r2  = 0.64) and allopurinol dose-response relationship (UT = UP - D* (UP - UR )/(ID50 + D), r2  = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. CONCLUSIONS: Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP .

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat.

Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss/F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9.4 ± 4.9 h. Febuxostat is administered once daily. The maximum (peak) plasma concentrations are approximately 100-fold greater than the trough concentrations. Consequently, there is no significant accumulation of the drug during multiple dose administration. There are few data on the pharmacokinetics of febuxostat in patients with gout. While the pharmacokinetic parameters are not affected by mild to moderate hepatic impairment, there is no consensus on whether renal impairment has any effect on the pharmacokinetics of febuxostat. Febuxostat is extensively metabolised by oxidation (approximately 35 %) and acyl glucuronidation (up to 40 %); febuxostat acyl glucuronides are cleared by the kidney. In healthy subjects treated with multiple doses of febuxostat 10-240 mg, the concentrations of serum urate are reduced by a maximum of about 80 %. The percentage reduction in the concentrations of serum urate is slightly less in gouty patients than in healthy subjects.

Understanding the dose-response relationship of allopurinol: predicting the optimal dosage.

AIMS: The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. METHODS: Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). RESULTS: Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09). CONCLUSIONS: A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr .

Reactive joint symptoms following an outbreak of Salmonella typhimurium phage type 135a.

OBJECTIVE: To quantify the incidence and clinical features of reactive arthritis (ReA) developing in a cohort exposed to an outbreak of Salmonella typhimurium phage type 135a, and factors affecting host susceptibility to ReA. METHODS: A screening questionnaire was mailed to 493 patients with confirmed Salmonella infection. Musculoskeletal symptoms and extraarticular manifestations of ReA were quantified. Positive responders with joint pain were invited to participate further, with a detailed history, examination, and investigations including HLA-B27 status. RESULTS: A total of 261/461 (57%) subjects responded to the questionnaire, with 23/54 adults (43%) and 41/207 children (20%) reporting joint symptoms. Although joint pains were less common in children compared with adults, those children affected usually had eye (34%) or mucocutaneous (37%) symptoms. The incidence of ReA was 14.6%, with adults more frequently affected (24%) than children (12%). This may be an underestimate given the large proportion of children involved. Associated clinical features were similar to previous studies, with the distribution of arthritis affecting the lower limbs predominantly in an oligoarticular pattern, as were the extraarticular manifestations and enthesopathy. We found 17% of subjects were HLA-B27 positive, and 55% were still symptomatic after 6 months. CONCLUSION: In an Australian cohort study of a S. typhimurium phage type 135a outbreak, joint symptoms were common, affecting 25% of subjects. The incidence of ReA of 14.6% and the clinical features were comparable to previous studies. There was a small effect of HLA-B27 status on the development of ReA.