oxypurinol and Renal-Insufficiency

Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative.. A multicenter, open-label, parallel, between-group comparative study was conducted to investigate the effects of renal function on the pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel inhibitor of uric acid synthesis.. Based on creatinine clearance (Ccr), 29 subjects were assigned to 3 groups: normal renal function (Ccr ≥ 80 mL/min), mild renal dysfunction (80 mL/min > Ccr ≥ 50 mL/min), or moderate renal dysfunction (50 mL/min > Ccr ≥ 30 mL/min). Febuxostat was repeatedly orally administered at a dose of 20 mg/d for 7 days.. Impaired renal function caused a slight increase in systemic exposure to unchanged febuxostat and its oxidative metabolites, but the exposure did not increase through repeated administration. Moreover, renal impairment did not markedly reduce the effects of febuxostat on plasma uric acid levels. There were no clinically significant adverse events even in patients with impaired renal function.. Febuxostat is considered an inhibitor of uric acid synthesis that could be used in patients with mild to moderate renal impairment without dose adjustment.

Topics: Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Febuxostat; Female; Follow-Up Studies; Glomerular Filtration Rate; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Oxypurinol; Renal Insufficiency; Thiazoles; Treatment Outcome; Uric Acid; Xanthine Oxidase; Young Adult

Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations.. EMA and FDA bioanalytical method validation guidance have recommended studying matrix effects on quantitation if samples from special patient populations are to be analyzed. In addition to lesinurad (plasma protein binding 98.2%), the matrix effects from special population plasma on the quantitation of verapamil (PPB 89.6%), allopurinol and oxypurinol (PPB negligible) were also investigated.. The plasma from special population patients had no matrix effects on the three quantification methods with stable isotope labeled internal standard, protein precipitation extraction, and LC-MS/MS detection. The validated lesinurad plasma quantification method was successfully applied for the pharmacokinetic evaluations to support the clinical studies in renal impaired patients.. Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations.

Topics: Allopurinol; Calibration; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Hepatic Insufficiency; Humans; Kidney; Liver; Oxypurinol; Reference Standards; Renal Insufficiency; Renal Reabsorption; Reproducibility of Results; Tandem Mass Spectrometry; Thioglycolates; Triazoles; Uricosuric Agents; Verapamil

Topics: Allopurinol; Antigens, Differentiation, T-Lymphocyte; Drug Eruptions; Female; HLA-B Antigens; Humans; Male; Oxypurinol; Renal Insufficiency

Topics: Allopurinol; Antigens, Differentiation, T-Lymphocyte; Drug Eruptions; Female; HLA-B Antigens; Humans; Male; Oxypurinol; Renal Insufficiency

Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR.. We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined.. In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05).. Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Antigens, Differentiation, T-Lymphocyte; Drug Eruptions; Female; Follow-Up Studies; HLA-B Antigens; Humans; Male; Middle Aged; Oxypurinol; Prognosis; Prospective Studies; Renal Insufficiency; Survival Rate; Taiwan; Young Adult

Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.. Non-linear mixed effects modelling was applied to concentration-time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.. A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration-time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/F(m)) from 65% to 29%. CL/F(m) for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h(-1), respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.. In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.

Topics: Adult; Aged; Aged, 80 and over; Diuretics; Drug Interactions; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Oxypurinol; Probenecid; Renal Insufficiency; Severity of Illness Index

Allopurinol is used frequently to treat patients with gout and hyperuricemia. However, adverse effects associated with this agent have been reported occasionally, especially among patients with hyperuricemia complicated with renal diseases. A rise in the blood concentration of oxipurinol, the chief active metabolite of allopurinol, has been noted in patients with renal dysfunctions, pointing to an implication of oxipurinol toxicity. It has been reported that monitoring the serum oxipurinol concentration to maintain in level below 15.2 micrograms/ml (= 100 mumol/l: recommended level) is helpful in avoiding toxicity. At Jikei University Hospital, a survey was conducted on 148 hyperuricemic patients who had been treated with allopurinol at the dosages of 50, 100, 200 and 300 mg daily or 100 mg on alternate days for more than one month. Because oxipurinol is an uricosuric substance, the steady-state serum oxipurinol concentration was determined by HPLC; and creatinine clearance (CCr) was calculated for each patient. 1. In the group composed of patients with normal kidney function (CCr > or = 80 ml/min), increase in the dosage of allopurinol was associated with a linear increase in the serum concentration of oxipurinol. 2. Among the patients with varying renal function who were receiving 100 mg of allopurinol daily, the oxipurinol level increased logarithmically as the creatinine clearance decreased. In some of the patients with renal insufficiency (CCr < 30 ml/min), daily administration of 100 mg of allopurinol resulted in a serum concentration of oxipurinol over 15.2 micrograms/ml. 3. For patients with renal insufficiency (CCr < 30 ml/min), administration of allopurinol at the dosage of 50 mg/day is considered adequate to avoid the accumulation of serum oxipurinol.

Topics: Adult; Aged; Allopurinol; Antimetabolites; Drug Administration Schedule; Female; Humans; Kidney; Male; Middle Aged; Oxypurinol; Renal Insufficiency; Uric Acid