ABSTRACT
BACKGROUND: The CRUCIAL trial (NCT04217421) is investigating the effect of postnatal and perioperative administration of allopurinol on postoperative brain injury in neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) shortly after birth. OBJECTIVE: This study aimed to characterize the pharmacokinetics (PK) of allopurinol and oxypurinol during the preoperative, intraoperative, and postoperative phases in this population, and to evaluate target attainment of the current dosing strategy. METHODS: Nonlinear mixed-effects modeling was used to develop population PK models in 14 neonates from the CRUCIAL trial who received up to five intravenous allopurinol administrations throughout the postnatal and perioperative periods. Target attainment was defined as achieving an allopurinol concentration >2 mg/L in at least two-thirds of the patients during the first 24 h after birth and between the start and 36 h after cardiac surgery with CPB. RESULTS: A two-compartment model for allopurinol was connected to a one-compartment model for oxypurinol with an auto-inhibition effect on the conversion, which best described the PK. In a typical neonate weighing 3.5 kg who underwent cardiac surgery at a postnatal age (PNA) of 5.6 days, the clearance (CL) of allopurinol and oxypurinol at birth was 0.95 L/h (95% confidence interval 0.75-1.2) and 0.21 L/h (0.17-0.27), respectively, which subsequently increased with PNA to 2.97 L/h and 0.41 L/h, respectively, before CPB. During CPB, allopurinol and oxypurinol CL decreased to 1.38 L/h (0.9-1.87) and 0.12 L/h (0.05-0.22), respectively. Post-CPB, allopurinol CL increased to 2.21 L/h (1.74-2.83), while oxypurinol CL dropped to 0.05 L/h (0.01-0.1). Target attainment was 100%, 53.8%, and 100% at 24 h postnatally, 24 h after the start of CPB, and 36 h after the end of cardiac surgery, respectively. The combined concentrations of allopurinol and oxypurinol maintained ≥ 90% inhibition of xanthine oxidase (IC90XO) throughout the postnatal and perioperative period. CONCLUSIONS: The minimal target concentration of allopurinol was not achieved at every predefined time interval in the CRUCIAL trial; however, the dosing strategy used was deemed adequate, since it yielded concentrations well exceeding the IC90XO. The decreased CL of both compounds during CPB suggests influence of the hypothermia, hemofiltration, and the potential sequestration of allopurinol in the circuit. The reduced CL of oxypurinol after CPB is likely attributable to impaired kidney function.
Subject(s)
Allopurinol , Cardiopulmonary Bypass , Heart Defects, Congenital , Models, Biological , Oxypurinol , Humans , Allopurinol/pharmacokinetics , Allopurinol/administration & dosage , Cardiopulmonary Bypass/methods , Infant, Newborn , Heart Defects, Congenital/surgery , Oxypurinol/pharmacokinetics , Male , Female , Cardiac Surgical Procedures/methodsABSTRACT
INTRODUCTION: In addition to the well-established understanding of the pharmacogenetics of drug-metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited. AREAS COVERED: This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol. EXPERT OPINION: Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Allopurinol , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Neoplasm Proteins , Pharmacogenetics , Rosuvastatin Calcium , Humans , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Rosuvastatin Calcium/pharmacokinetics , Rosuvastatin Calcium/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Allopurinol/pharmacokinetics , Allopurinol/administration & dosage , Allopurinol/pharmacology , Polymorphism, Genetic , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Animals , Mutation, MissenseABSTRACT
Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.
Subject(s)
Gout Suppressants , Gout , Oxypurinol , Peritoneal Dialysis , Uric Acid , Humans , Uric Acid/blood , Gout/drug therapy , Gout/blood , Male , Oxypurinol/pharmacokinetics , Gout Suppressants/pharmacokinetics , Gout Suppressants/therapeutic use , Middle Aged , Female , Aged , Allopurinol/therapeutic use , Allopurinol/pharmacokinetics , Renal Elimination , Half-Life , Dialysis Solutions/pharmacokineticsABSTRACT
AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.
Subject(s)
Allopurinol , Dose-Response Relationship, Drug , Gout Suppressants , Gout , Models, Biological , Uric Acid , Allopurinol/administration & dosage , Allopurinol/pharmacokinetics , Humans , Gout/drug therapy , Gout/blood , Gout Suppressants/administration & dosage , Gout Suppressants/pharmacokinetics , Uric Acid/blood , Male , Female , Middle Aged , Aged , Adult , Drug Dosage Calculations , Computer SimulationABSTRACT
AIMS: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU). METHODS: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. RESULTS: A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95% CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications. CONCLUSIONS: The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.
Subject(s)
Gout , Hyperuricemia , Organic Anion Transporters , Adult , Humans , Oxypurinol , Allopurinol/pharmacokinetics , Hyperuricemia/drug therapy , Hyperuricemia/genetics , Gout Suppressants/pharmacokinetics , Pharmacogenetics , Gout/drug therapy , Gout/genetics , Organic Anion Transporters/therapeutic use , Organic Cation Transport Proteins/geneticsABSTRACT
The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs.
Subject(s)
Gout , Organic Anion Transporters , Humans , Oxypurinol/pharmacokinetics , Uric Acid , Gout/drug therapy , Gout/genetics , Allopurinol/pharmacokinetics , Organic Anion Transporters/genetics , Organic Cation Transport Proteins/genetics , Glucose Transport Proteins, Facilitative/geneticsABSTRACT
AIMS: This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite. METHODS: Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX). RESULTS: The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113. CONCLUSION: A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.
Subject(s)
Gout , Tool Use Behavior , Humans , Allopurinol/pharmacokinetics , Oxypurinol , Gout Suppressants/pharmacokinetics , Gout/drug therapyABSTRACT
ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Allopurinol , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Allopurinol/analogs & derivatives , Allopurinol/blood , Allopurinol/metabolism , Allopurinol/pharmacokinetics , Cross-Sectional Studies , Humans , Oxypurinol/blood , Oxypurinol/metabolism , Oxypurinol/pharmacokinetics , Ribonucleosides/blood , Ribonucleosides/metabolism , Ribonucleosides/pharmacokinetics , Uric Acid/bloodABSTRACT
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.
Subject(s)
Allopurinol/pharmacokinetics , Gout Suppressants/pharmacokinetics , Methylcellulose/analogs & derivatives , Administration, Oral , Allopurinol/adverse effects , Allopurinol/blood , Allopurinol/chemistry , Animals , Antineoplastic Agents , Blood Urea Nitrogen , Cisplatin , Creatinine/blood , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Drug Liberation , Gout Suppressants/adverse effects , Gout Suppressants/blood , Gout Suppressants/chemistry , Half-Life , Kidney/drug effects , Kidney Diseases/chemically induced , Kidney Diseases/metabolism , Male , Methylcellulose/chemistry , Methylcellulose/pharmacokinetics , Rats, Sprague-DawleyABSTRACT
The Bayesian decision-analytic approach to trial design uses prior distributions for treatment effects, updated with likelihoods for proposed trial data. Prior distributions for treatment effects based on previous trial results risks sample selection bias and difficulties when a proposed trial differs in terms of patient characteristics, medication adherence, or treatment doses and regimens. The aim of this study was to demonstrate the utility of using pharmacometric-based clinical trial simulation (CTS) to generate prior distributions for use in Bayesian decision-theoretic trial design. The methods consisted of four principal stages: a CTS to predict the distribution of treatment response for a range of trial designs; Bayesian updating for a proposed sample size; a pharmacoeconomic model to represent the perspective of a reimbursement authority in which price is contingent on trial outcome; and a model of the pharmaceutical company return on investment linking drug prices to sales revenue. We used a case study of febuxostat versus allopurinol for the treatment of hyperuricemia in patients with gout. Trial design scenarios studied included alternative treatment doses, inclusion criteria, input uncertainty, and sample size. Optimal trial sample sizes varied depending on the uncertainty of model inputs, trial inclusion criteria, and treatment doses. This interdisciplinary framework for trial design and sample size calculation may have value in supporting decisions during later phases of drug development and in identifying costly sources of uncertainty, and thus inform future research and development strategies.
Subject(s)
Clinical Trials, Phase III as Topic , Models, Biological , Models, Economic , Allopurinol/administration & dosage , Allopurinol/economics , Allopurinol/pharmacokinetics , Bayes Theorem , Computer Simulation , Decision Theory , Drug Development , Economics, Pharmaceutical , Febuxostat/administration & dosage , Febuxostat/economics , Febuxostat/pharmacokinetics , Gout/blood , Gout/drug therapy , Gout/economics , Humans , Hyperuricemia/blood , Hyperuricemia/drug therapy , Hyperuricemia/economics , Investments , Reimbursement Mechanisms , Research Design , Sample Size , Uncertainty , Uric Acid/bloodABSTRACT
Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly prescribed in primary care. However, implementation of PGx has generally been limited to a relatively few academic hospital centres, with little adoption in primary care. Despite this, many primary healthcare providers are optimistic about the role of PGx in their future practice. The increasing prevalence of direct-to-consumer genetic testing and primary care PGx studies herald the plausible gradual introduction of PGx into primary care and highlight the changes needed for optimal translation. In this article, the potential utility of PGx in primary care will be explored and on-going barriers to implementation discussed. The evidence base of several drug-gene pairs relevant to primary care will be outlined with a focus on antidepressants, codeine and tramadol, statins, clopidogrel, warfarin, metoprolol and allopurinol. This review is intended to provide both a general introduction to PGx with a more in-depth overview of elements relevant to primary care.
Subject(s)
Analgesics, Opioid , Antidepressive Agents , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Pharmacogenomic Variants , Allopurinol/pharmacokinetics , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/therapeutic use , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/therapeutic use , Clopidogrel/pharmacokinetics , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Metoprolol/pharmacokinetics , Pharmacogenetics , Precision Medicine , Primary Health Care , Warfarin/pharmacokineticsABSTRACT
Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 × 10-5 ) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 µM, whereas allopurinol showed no inhibition with concentrations up to 200 µM. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Febuxostat/pharmacokinetics , Neoplasm Proteins/metabolism , Rosuvastatin Calcium/pharmacokinetics , Administration, Oral , Adult , Allopurinol/administration & dosage , Allopurinol/pharmacokinetics , Area Under Curve , Cross-Over Studies , Drug Interactions , Febuxostat/administration & dosage , Female , Healthy Volunteers , Humans , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Male , Rosuvastatin Calcium/administration & dosage , Young AdultABSTRACT
Allopurinol is the most commonly used drug for the treatment of hyperuricemia in people, and in view of the risks of fatal hypersensitivity in patients with renal dysfunction, doses based on the glomerular filtration rate are proposed. In veterinary medicine, allopurinol is used in the treatment of canine leishmaniasis (CanL) caused by Leishmania infantum owing to the drug action of inhibiting the parasite's RNA synthesis. However, renal dysfunction frequently ensues from disease progression in dogs. The purpose of the present study was to standardize and validate a sensitive high-performance liquid chromatography-mass spectrometric (HPLC-MS/MS) method to determine the concentration of allopurinol and its active metabolite oxypurinol in canine urine for clinical pharmacokinetic investigation. Urine samples of eleven (11) dogs with naturally occurring CanL and in the maintenance phase of the treatment with alopurinol were used. For the chromatographic analysis of urine, the mobile phase consisted of a solution of 0.1 % formic acid (88 %) in 10â¯mM ammonium acetate. Separation of allopurinol and oxypurinol occurred in a flow of 0.8â¯mL/min on a C8 reverse phase column 5⯵m, and acyclovir was the internal standard. The HPLC-MS/MS method was validated by reaching the limits of detection and quantification, reproducibility and linearity. The lower limit of quantification achieved by the method was 10⯵g/mL for both allopurinol and oxypurinol. Calibration curves were prepared in blank urine added with allopurinol at concentrations of 10-1000⯵g/mL, and oxypurinol at 10-200⯵g/mL. Coefficients of variation of less than 15 % between intracurrent and intercurrent accuracy values were observed for both allopurinol and oxypurinol. Urine test samples remained stable after being subjected to freeze-thaw cycles and remaining at room temperature for 4â¯h. The method proved to be adequate to quantify allopurinol and oxypurinol in urine samples from dogs under treatment.
Subject(s)
Allopurinol/urine , Dogs/urine , Drug Monitoring/veterinary , Leishmaniasis/veterinary , Oxypurinol/urine , Administration, Oral , Allopurinol/administration & dosage , Allopurinol/pharmacokinetics , Animals , Chromatography, High Pressure Liquid/methods , Dogs/parasitology , Drug Monitoring/methods , Leishmania infantum/isolation & purification , Leishmaniasis/drug therapy , Leishmaniasis/parasitology , Limit of Detection , Male , Oxypurinol/pharmacokinetics , Reproducibility of Results , Tandem Mass Spectrometry/methodsABSTRACT
The aims of this study were to determine factors that predict serum urate (SU) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and SU was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic (ROC) curves were used to identify a minimum oxypurinol concentration predictive of SU < 6 mg/dL. There was a wide range of SU concentrations for each allopurinol dose. The relationship between sensitivity to allopurinol and allopurinol metabolism for each 100 mg allopurinol dose increase varied between individuals. Body mass index (P = 0.023), creatinine clearance (CrCL; P = 0.037), ABCG2 Q141K (P = 0.019), and SU (P = 0.004) were associated with sensitivity to allopurinol. The minimum oxypurinol concentration for achieving the urate target was found to be about 104 µmol/L, but predictive accuracy was poor (ROC curve area under the curve (AUC) 0.65). The minimum therapeutic oxypurinol concentration was found to increase with decreasing renal function. Although there is a positive relationship between change in oxypurinol and change in SU concentration, a minimum therapeutic oxypurinol is dependent on CrCL and cannot reliably predict SU target. Other variables, including ABCG2 Q141K genotype, impact on sensitivity to allopurinol (ACTRN12611000845932).
Subject(s)
Allopurinol/administration & dosage , Gout Suppressants/administration & dosage , Gout/drug therapy , Oxypurinol/blood , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Aged , Allopurinol/pharmacokinetics , Body Mass Index , Creatinine/blood , Creatinine/metabolism , Dose-Response Relationship, Drug , Female , Gout/blood , Gout/diagnosis , Gout/genetics , Gout Suppressants/pharmacokinetics , Humans , Male , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Oxypurinol/metabolism , ROC Curve , Renal Elimination , Treatment Outcome , Uric Acid/bloodABSTRACT
PURPOSE: The major short coming of conventional therapy system is that they can't deliver the therapeutics specifically to a site within the body without producing nonspecific toxicity. Present research aimed at developing kidney targeted allopurinol (AP) loaded chitosan coated magnetic nanoparticles (A-MNPs) for the management of hyperuricemic nephropathy manifested in the form of nephrolithiasis. METHODS: The work includes preparation of magnetic nanoparticles by chemical co-precipitation method and evaluation of the prepared batches for particle size analysis, Transmission electron microscopy, entrapment efficiency, in-vitro release study etc. Further, FTIR spectroscopy, X-ray diffraction, Differential Scanning Calorimetry, Vibrational sample magnetometer (VSM) and in-vivo animal studies were also performed. RESULTS: VSM analysis demonstrates that the prepared nanoparticles exhibit superparamagnetic magnetic behaviour which was retained even after coating by chitosan. In-vivo studies of A-MNPs showed 19.07-fold increase in kidney uptake of AP as compared to serum post 2 h of administration in mice whereas no drug was detected in kidney and serum post 2 h administration of pure drug (free-form) indicating successful targeting to kidney as well as sustained release of AP from the formulated A-MNPs. The significant (p < 0.01) effectiveness of A-MNPs in management of hyperuricemic nephrolithiasis was observed through estimating pH and uric acid levels in urine and serum samples of mice. These findings were also confirmed by histological examination of isolated kidney samples. CONCLUSION: Present investigation signifies that a simple external magnetic field is enough for targeting allopurinol to kidneys by formulating A-MNPs which further offers an effective approach for management of hyperuricemic nephrolithiasis. Graphical Abstract.
Subject(s)
Allopurinol/administration & dosage , Chitosan/chemistry , Kidney/chemistry , Nephrolithiasis/drug therapy , Administration, Oral , Allopurinol/chemistry , Allopurinol/pharmacokinetics , Animals , Chemical Precipitation , Disease Models, Animal , Drug Delivery Systems , Magnetite Nanoparticles , Mice , Nanoparticles , Nephrolithiasis/blood , Nephrolithiasis/chemically induced , Nephrolithiasis/urine , Oxonic Acid/adverse effects , Uric Acid/blood , Uric Acid/urineABSTRACT
BACKGROUND: Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Hepatic Insufficiency/metabolism , Renal Insufficiency/metabolism , Thioglycolates/blood , Triazoles/blood , Uricosuric Agents/blood , Allopurinol/pharmacokinetics , Calibration , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Clinical Trials as Topic , Hepatic Insufficiency/blood , Hepatic Insufficiency/physiopathology , Humans , Kidney/metabolism , Kidney/physiopathology , Liver/metabolism , Liver/physiopathology , Oxypurinol/blood , Oxypurinol/pharmacokinetics , Reference Standards , Renal Insufficiency/blood , Renal Insufficiency/physiopathology , Renal Reabsorption , Reproducibility of Results , Tandem Mass Spectrometry/methods , Tandem Mass Spectrometry/standards , Thioglycolates/pharmacokinetics , Triazoles/pharmacokinetics , Uricosuric Agents/pharmacokinetics , Verapamil/blood , Verapamil/pharmacokineticsABSTRACT
Several diseases would benefit from prolonged drug release provided by systems retained in the stomach for extended time periods. Expandable gastroretentive devices are administered in a collapsed configuration enabling swallowing and regain in situ their native shape having larger spatial encumbrance, thus hindering voidance through the wide open pylorus. An expandable system for gastric retention was here proposed relying on the shape memory behavior of pharmaceutical-grade poly(vinyl alcohol). Different original configurations to be recovered upon exposure to aqueous fluids at 37⯰C, potentially enabling gastric retention, were conceived. Prototypes containing allopurinol were directly manufactured by fused deposition modeling or shaped by purposely-designed templates from hot melt extruded rods immediately after production. Various temporary shapes, in principle suitable for administration, were programmed by manual deformation of samples by means of specific templates, under defined temperature conditions. In 0.1â¯N hydrochloric solution at 37⯰C, the prototypes recovered their original shape, reaching the desired spatial encumbrance within few minutes. Release from the samples, although of relatively short duration, was independent of the original shape and processing undergone, and was noticeably slowed down by application of Eudragit® RS/RL-based coatings.
Subject(s)
Drug Carriers/chemistry , Drug Compounding/methods , Printing, Three-Dimensional , Smart Materials/chemistry , Acrylic Resins/chemistry , Administration, Oral , Allopurinol/administration & dosage , Allopurinol/pharmacokinetics , Capsules , Chemistry, Pharmaceutical , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Drug Liberation , Feasibility Studies , Gastric Mucosa/metabolism , Models, Chemical , Polymers/chemistry , Time FactorsABSTRACT
OBJECTIVES: Gout patients with chronic kidney disease (CKD) accumulate the active allopurinol metabolite oxypurinol, suggesting that allopurinol may promote greater serum urate (sU) lowering in CKD patients. METHODS: We identified all patientswith gout diagnoses on either 100 mg or 300 mg of allopurinol daily, with available pre- and on-treatment sU levels, in our system in a 1-year period. Mean sU decrement by dosing per CKD groups was determined by CKD stage. RESULTS: Of 1,288 subjects with gout, 180 met entry criteria, with 83 subjects receiving 100 mg and 97 receiving 300 mg allopurinol. Subjects with CKD stage 1 experienced less sU lowering with 100 mg than 300 mg of allopurinol. Subjects with stage 4 and 5 CKD had equivalent sU decreases across the 100 mg and 300 mg allopurinol groups. However, the 100 mg group started at a higher pre-treatment sU and ended at a higher final sU than the 300 mg group. CONCLUSIONS: The strategy of titrating allopurinol to sU in patients with kidney impairment may result in greater sU lowering at lower doses than in patients without CKD but may also pose a treatment challenge from a possible drug ceiling effect.
Subject(s)
Allopurinol , Gout , Kidney , Renal Insufficiency, Chronic , Uric Acid/blood , Allopurinol/administration & dosage , Allopurinol/pharmacokinetics , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Gout/blood , Gout/complications , Gout/drug therapy , Gout Suppressants/administration & dosage , Gout Suppressants/pharmacokinetics , Humans , Kidney/metabolism , Kidney/physiopathology , Kidney Function Tests/methods , Male , Middle Aged , New York , Outcome and Process Assessment, Health Care , Patient Acuity , Renal Elimination , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/physiopathology , Retrospective Studies , Veterans Health Services/statistics & numerical dataABSTRACT
A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7µm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats.
Subject(s)
Allopurinol/pharmacokinetics , Chromatography, Liquid/methods , Hydrophobic and Hydrophilic Interactions , Oxypurinol/pharmacokinetics , Tandem Mass Spectrometry/methods , Thioglycolates/pharmacokinetics , Triazoles/pharmacokinetics , Allopurinol/blood , Animals , Oxypurinol/blood , Rats , Reproducibility of Results , Thioglycolates/blood , Tissue Distribution , Triazoles/bloodABSTRACT
BACKGROUND/AIMS: Thiopurines are key drugs in maintenance therapy for treating inflammatory bowel disease (IBD). Time-dependent 5-aminosalicylates (5-ASA) releasing preparations (time-dependent 5-ASA) increase 6-thioguanine nucleotide (6-TGN), an active metabolite of thiopurines. However, the effects of pH-dependent 5-ASA releasing preparations (pH-dependent 5-ASA) on thiopurine metabolism were not reported. METHODS: We conducted a retrospective study of 134 IBD patients who received thiopurine treatment. The 6-methylmercaptopurine (6-MMP)/6-TGN values after taking the same dose of thiopurine preparations for at least 28 days were included. RESULTS: There was a significant decrease in the 6-MMP/6-TGN ratio in time-dependent 5-ASA compared with group without 5-ASA preparations and the pH-dependent 5-ASA group (p = 0.008 and < 0.001 respectively). Spearman's rank correlation coefficient indicated a negative relationship between the daily oral dose of time-dependent 5-ASA and the 6-MMP/6-TGN ratio (r = -0.362, p = 0.003). Multivariate logistic regression analysis was performed in the groups with 6-MMP/6-TGN ratios of 1 or more and less than 1. The use of time-dependent 5-ASA and concomitant allopurinol negatively affected the independent 6-MMP/6-TGN ratio (p = 0.006 and 0.007 respectively). CONCLUSION: Our study revealed that time-dependent but not pH-dependent 5-ASA decreases the 6-MMP/6-TGN ratio. We also confirmed that concomitant allopurinol results in a low 6-MMP/6TGN ratio.