The experiences and perspectives of people with gout on urate self-monitoring.

INTRODUCTION: Gout management remains suboptimal despite safe and effective urate-lowering therapy. Self-monitoring of urate may improve gout management, however, the acceptability of urate self-monitoring by people with gout is unknown. The aim of this study was to explore the experiences of urate self-monitoring in people with gout. METHODS: Semistructured interviews were conducted with people taking urate-lowering therapy (N = 30) in a 12-month trial of urate self-monitoring in rural and urban Australia. Interviews covered the experience of monitoring and its effect on gout self-management. Deidentified transcripts were analysed thematically. RESULTS: Participants valued the ability to self-monitor and gain more understanding of urate control compared with the annual monitoring ordered by their doctors. Participants indicated that self-monitoring at home was easy, convenient and informed gout self-management behaviours such as dietary modifications, hydration, exercise and medication routines. Many participants self-monitored to understand urate concentration changes in response to feeling a gout flare was imminent or whether their behaviours, for example, alcohol intake, increased the risk of a gout flare. Urate concentrations were shared with doctors mainly when they were above target to seek management support, and this led to allopurinol dose increases in some cases. CONCLUSION: Urate self-monitoring was viewed by people with gout as convenient and useful for independent management of gout. They believed self-monitoring achieved better gout control with a less restricted lifestyle. Urate data was shared with doctors at the patient's discretion and helped inform clinical decisions, such as allopurinol dose changes. Further research on implementing urate self-monitoring in routine care would enable an evaluation of its impact on medication adherence and clinical outcomes, as well as inform gout management guidelines. PATIENT OR PUBLIC CONTRIBUTION: One person with gout, who was not a participant, was involved in the study design by providing feedback and pilot testing the semistructured interview guide. In response to their feedback, subsequent modifications to the interview guide were made to improve the understandability of the questions from a patient perspective. No additional questions were suggested.

Evaluation of Published Population Pharmacokinetic Models to Inform Tacrolimus Therapy in Adult Lung Transplant Recipients.

BACKGROUND: The applicability of currently available tacrolimus population pharmacokinetic models in guiding dosing for lung transplant recipients is unclear. In this study, the predictive performance of relevant tacrolimus population pharmacokinetic models was evaluated for adult lung transplant recipients. METHODS: Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero. RESULTS: In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33). CONCLUSIONS: Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.

Geographic variation in sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist use in people with type 2 diabetes in New South Wales, Australia.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and cardio-renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio-economic variation in use is not well understood. METHODS: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose-lowering medicines among people with T2D and the prevalence of SGLT2i and GLP-1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose-lowering medicine). We measured the prevalence by small-level geography, stratified by age group, and characterized by remoteness and socio-economic status. RESULTS: The prevalence of SGLT2i (29.7%) and GLP-1RA (8.3%) use in people with T2D aged 40-64 increased with geographic remoteness and in areas of greater socio-economic disadvantage, similar to other glucose-lowering medicines. The prevalence of SGLT2i (55.4%) and GLP-1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP-1RA use (2.5 times the median). Compared with people aged 40-64 years, the prevalence of SGLT2i and GLP-1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. CONCLUSIONS: The prevalence of SGLT2i and GLP-1RA use varied by geography, probably reflecting a combination of system- and prescriber-level factors. Socio-economic variation in GLP-1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.

The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

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.

Patient-Led Urate Self-Monitoring to Improve Clinical Outcomes in People With Gout: A Feasibility Study.

OBJECTIVE: Self-monitored point-of-care urate-measuring devices are an underexplored strategy to improve adherence to urate-lowering therapy and clinical outcomes in gout. This study observed patient-led urate self-monitoring practice and assessed its influence on allopurinol adherence, urate control, and health-related quality of life. METHODS: People with gout (n = 31) and prescribed allopurinol self-monitored their urate concentrations (HumaSens2.0plus) at baseline and thereafter monthly for 12 months (3 months per quarter). Adherence to allopurinol was measured using medication event monitoring technology (Medication Event Monitoring System cap). Time spent below the target urate concentration (<0.36 mmol/L) was determined. Health-related quality of life was measured using a survey (EuroQoL EQ-5D-5L). Gout flares were recorded. Two-tailed Spearman correlation and the Wilcoxon matched-pairs signed-rank test (P < 0.05) were used for statistical comparisons. RESULTS: Most participants were male (94%) and had urate concentrations below the target (74%) at baseline. Overall, seven participants demonstrated repeated periods of "missed doses" (two or fewer allopurinol doses missed consecutively) and "drug holidays" (three or more missed doses). Most participants (94%) persisted with allopurinol. Time spent within the target urate concentration increased 1.3-fold (from 79% to 100%; P = 0.346), and the incidence of gout flares decreased 1.6-fold (from 8 to 5; P = 0.25) in the final quarter compared to that in the first quarter of the study. Health-related quality of life was reduced for participants reporting at least one gout flare (median utility values 0.9309 vs 0.9563, P = 0.04). CONCLUSION: Patient-led urate self-monitoring may support the maintenance of allopurinol adherence and improve urate control, thus reducing the incidence of gout flares. Further research on patient-led urate self-monitoring in a randomized controlled study is warranted.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

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.

A Scoping Review of Pharmacogenomic Educational Interventions to Improve Knowledge and Confidence.

OBJECTIVES: Poor knowledge and confidence in pharmacogenomics are key barriers to implementation. Education of future health care professionals is required to enhance appropriate use of pharmacogenomics; however, the optimal education approach is unclear. This systematic scoping review evaluates pharmacogenomic educational interventions to improve knowledge and confidence. FINDINGS: A total of 24 studies were included. Most (90%) studies delivered pharmacogenomic education to pharmacy students and consisted of didactic lectures and workshops with case studies. To supplement case studies, self or class aggregated (52%, 12 of 23), mock (43%, 10 of 23) or faculty member provided (4%, 1 of 23) pharmacogenomic data were used in the case scenarios. All studies used quantitative methods, including student assessments and scaled surveys to assess the impact of the educational intervention on knowledge and/or confidence in pharmacogenomics. On average, the educational interventions improved knowledge acquisition by 21%, confidence in pharmacogenomic data interpretation by 37%, confidence in communication of pharmacogenomic information to patients by 41% and to health care professionals by 44%. Improvement in communication with other health care professionals was greater in students involved in interprofessional learning compared to self-pharmacogenomic testing. SUMMARY: The measures used to determine the effect of educational interventions on student knowledge and confidence varied. Innovative pedagogy, specifically interactive case-based learning and simulation such as interprofessional learning, enhances the knowledge and confidence of students in pharmacogenomics. Course-embedded self-pharmacogenomic testing may offer a supplementary, interactive component to case-based learning by using real-life reports as the foundation of knowledge and confidence acquisition.

The Influence of a Therapeutic Drug Monitoring Service on Vancomycin-Associated Nephrotoxicity.

Vancomycin's widespread use as the mainstay antibiotic against methicillin-resistant Staphylococcus aureus infections is complicated by its narrow therapeutic index. Therapeutic drug monitoring using area under the concentration-time curve (AUC)-guided dosing is recommended to optimize therapy and prevent vancomycin-associated nephrotoxicity (VAN). In 2018, a consultative therapeutic drug monitoring Advisory Service (the Service) was piloted at an Australian hospital to enable AUC-guided vancomycin dosing. This study sought to compare the incidence of VAN pre- and post-Service implementation. A 4-year retrospective observational study of intravenous vancomycin therapy (greater than 48 hours) in adults (aged 18 years or older), spanning 3 years before and 1-year after implementation of the Service was undertaken. Nephrotoxicity was defined as an increase in serum creatinine concentrations of 26.5 µmol/L or greater or 50% or more from baseline, on 2 or more consecutive days. Univariate analysis was performed to compare patients before and after implementation, and with and without VAN. Independent factors associated with VAN were identified using a multivariate model. In total, 971 courses of vancomycin therapy, administered to 781 patients, were included: 764 courses (603 patients) before implementation and 207 courses (163 patients) after implementation. The incidence of VAN decreased by 5% after Service implementation (15% before implementation vs 10% after implementation; P = .075). Independent factors associated with VAN were sepsis, heart failure, solid-organ transplant, concomitant piperacillin-tazobactam, and average vancomycin AUC during therapy. In conclusion, there was a nonsignificant trend toward a reduced incidence of VAN after the Service. Larger prospective studies are needed to confirm the efficacy of the Service.

'We are somehow fixated on this being a diabetes drug': a qualitative study exploring the views of cardiologists and nephrologists about sodium-glucose cotransporter 2 inhibitor initiation.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now indicated for heart failure and chronic kidney disease (CKD), irrespective of the presence of diabetes. Hence, cardiologists and nephrologists have an important role in initiating these drugs. AIMS: To explore cardiologists' and nephrologists' perspectives regarding initiating SGLT2i and their safety monitoring practices when initiating SGLT2i. METHODS: Purposive and snowball approaches were used to recruit participants working in diverse areas in New South Wales, Australia. Semi-structured interviews were conducted with 12 cardiologists and 12 nephrologists. Interviews were conducted until thematic saturation was reached. Emergent themes were identified from transcripts. An iterative general inductive approach was used for data analysis. RESULTS: There was a reluctance amongst most non-heart-failure subspecialist cardiologists to initiate SGLT2i. Reasons included the perception of SGLT2i as diabetes drugs, concern about side effects, lack of experience and issues with follow-up. In contrast, nephrologists reported feeling confident to initiate SGLT2i. Nephrologists varied in their opinions about the severity of CKD at which SGLT2i initiation was reasonable and monitoring of renal function following initiation. Government subsidisation was an important factor in the decision to prescribe SGLT2i to people without diabetes. CONCLUSIONS: Our findings highlight the complex transition from the perception of SGLT2i as diabetes drugs to cardiometabolic and reno-protective agents. Interdisciplinary collaboration may enable greater confidence amongst specialists to initiate SGLT2i, including in patients with CKD. Additionally, there is a need for clear and detailed guidance about SGLT2i prescription in patients with renal dysfunction and renal function monitoring following SGLT2i initiation.

A framework for understanding sources of bias in medication adherence research.

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.

Using seconds-resolved pharmacokinetic datasets to assess pharmacokinetic models encompassing time-varying physiology.

AIM: Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench-top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours-scale, time-varying physiological processes. Given the recent advent of in vivo electrochemical aptamer-based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time-dense datasets to describe time-varying pharmacokinetic models with good statistical significance. METHODS: We used seconds-resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one- and two-compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. RESULTS: We found that a modified one-compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two-compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one-compartment, time-varying model was statistically preferred over the standard one-compartment model for 80% of our datasets. CONCLUSIONS: Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high-time resolution EAB sensor measurements to identify such impacts.

The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study.

AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.

Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study.

BACKGROUND: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. METHODS: Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration-time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. RESULTS: Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3-12.1% (amikacin), 16.2-19.0% (tobramycin), 12.2-45.8% (gentamicin), and 9.6-19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). CONCLUSIONS: Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

Effect of Therapeutic Plasma Exchange on Itraconazole Pharmacokinetics: A Case Study.

ABSTRACT: The authors present the case of a 34-year-old male patient who underwent therapeutic plasma exchange (TPE) for amyopathic dermatomyositis. Immunosuppression resulted in Aspergillus lentulus pulmonary infection , requiring treatment with super bioavailable-itraconazole. Therapeutic itraconazole concentrations were attained after 2 weeks of treatment after dose adjustments. Interestingly, a substantial reduction in plasma itraconazole concentration was observed during TPE, which was attributed to an insufficient delay between the dosing of itraconazole and TPE initiation. Furthermore, there was an increase in plasma concentration post-TPE, which presumably reflects the redistribution of itraconazole from peripheral compartments back into plasma. This was confirmed by sampling of the TPE plasmapheresate, which revealed that changes in plasma concentration overestimated itraconazole clearance. These findings highlight that the pharmacokinetics of itraconazole are altered during TPE, which should be considered when timing drug administration and obtaining plasma concentrations.

Optimizing adherence to allopurinol for gout: patients' perspectives.

AIMS: Poor adherence to allopurinol among people with gout contributes to suboptimal gout management. This study sought to understand the facilitators and barriers to allopurinol adherence across the three stages of medication adherence, and patient perspectives on strategies to improve adherence, including self-monitoring urate concentration. METHODS: Semi-structured interviews were conducted with 26 people with gout, previously or currently taking allopurinol. De-identified verbatim transcripts were thematically analysed using an inductive and deductive approach. RESULTS: Facilitators of adherence during allopurinol initiation were motivation to prevent gout flares and trust in the advice of their healthcare professionals (HCPs). Reluctance to commence long-term medication was a barrier to allopurinol initiation. Believing in the effectiveness and necessity of allopurinol and reminder systems were facilitators of implementation. Barriers to implementation included forgetfulness, gout flares and limited feedback on allopurinol's effectiveness. Patients discontinued therapy when allopurinol was perceived as ineffective or unnecessary. Discontinuation coincided with patients experiencing gout flares while adhering to allopurinol and receiving suboptimal advice about gout management. Patients identified receiving accurate advice from HCPs and regular urate monitoring for feedback on allopurinol's effectiveness as potential strategies to improve adherence. Perceived benefits of self-monitoring urate as a strategy to promote adherence included the ability to self-manage gout and make informed decisions about allopurinol therapy with their HCP. CONCLUSION: Patient perceptions of the effectiveness and necessity of allopurinol influenced intentional adherence during medication initiation, implementation and discontinuation. Strategies that inform patients of their urate control and provide accurate medical advice have the potential to improve adherence to allopurinol.

Blood, dose recommendation reports and phone calls: Experiences of a therapeutic drug monitoring advisory service for vancomycin.

Dose-prediction software is recommended to enable area under the curve over 24 h (AUC24 )-guided dosing of the antibiotic vancomycin. However, uncertainty remains about how best to implement software in the clinic. We describe the activity, over 18 months, of a consultative therapeutic drug monitoring Advisory Service (the Service) for vancomycin that used dose-prediction software alongside clinical expertise, identifying factors that influence attainment of therapeutic targets. Of the 408 vancomycin dose reports provided for 182 courses of therapy, most (57%) recommended a dose change. The majority (82.8%, 193/233) of recommended dose adjustments were accepted by treating teams. A dose report was not published for 125 courses of therapy, with reasons including patient in intensive care unit or service error. An estimated 26.6 h of staff time was allocated to Service activities each month. Publication of a dose report facilitated attainment of therapeutic targets (P = .002). Software integration could improve Service outcomes, avoiding errors and reducing staff workload.

The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics.

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.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

AIM: Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. METHODS: Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. RESULTS: Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. CONCLUSION: A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.