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Objective: We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting. Participants: Six stable patients with end-stage kidney disease. Methods: An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC). Results: Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126–205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135–162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients. Conclusions: The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session. Trial registration: Australasian Clinical Trials Registry Network (ACTRN12616000078459) [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Aim: This research aims to evaluate the predictive performance of a published allopurinol dosing tool. Methods: Allopurinol dose predictions were compared to the actual dose required to achieve serum urate (SU) <0.36 mmol l−1 using mean prediction error. The influence of patient factors on dose predictions was explored using multilinear regression. Results: Allopurinol doses were overpredicted by the dosing tool; however, this was minimal in patients without diuretic therapy (MPE 63 mg day−1, 95% CI 40–87) compared to those receiving diuretics (MPE 295 mg day−1, 95% CI 260–330, P < 0.0001). ABCG2 genotype (rs2231142, G>T) had an important impact on the dose predictions (MPE 201, 107, 15 mg day−1 for GG, GT and TT, respectively, P < 0.0001). Diuretic use and ABCG2 genotype explained 53% of the variability in prediction error (R2 = 0.53, P = 0.0004). Conclusions: The dosing tool produced acceptable maintenance dose predictions for patients not taking diuretics. Inclusion of ABCG2 genotype and a revised adjustment for diuretics would further improve the performance of the dosing tool. [ABSTRACT FROM AUTHOR]

Background and Objectives: 51Cr EDTA clearance (CL) from plasma is used to estimate glomerular filtration rate (GFR). We propose that current methods for analysing the raw 51Cr EDTA measurements over-simplifies the disposition of 51Cr EDTA and therefore could produce biased GFR estimates. The aim of this study was to develop a population pharmacokinetic model for 51Cr EDTA disposition and to compare model-predicted GFR to other methods of estimating renal function.Patients and Methods: Data from 40 individuals who received ~7.4 MBq of 51Cr EDTA, as an intravenous bolus, were available for analysis. Plasma radioactivity (counts/min) was measured from timed collection points at 2, 4, 6 and 24 h after the dose. A population analysis was conducted using NONMEM® version 7.2. Model-predicted GFR was compared with other methods for estimating renal function using mean prediction error (MPE).Results: A two-compartment pharmacokinetic model with first-order elimination best fit the data. Compared with the model predictions, creatinine CL from 24 h urine data was unbiased. The commonly used 'slope-intercept' method for estimating isotopic GFR was positively biased compared with the model (MPE 15.5 mL/min/1.73 m2 [95% confidence interval {CI} 8.9-22.2]. The Cockcroft Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equations led to negatively biased GFR estimates (MPE -19.0 [95% CI -25.4 to -12.7], -20.1 [95% CI -27.2 to -13.1] and -16.5 [95% CI -22.2 to -10.1] mL/min/1.73 m2, respectively).Conclusions: The biased GFR estimates were most obvious in patients with relatively normal renal function. This may lead to inaccurate dosing in patients who are receiving drugs with a narrow therapeutic range where dosing is adjusted according to GFR estimates (e.g. carboplatin).Study Registration: The study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number: ACTRN 12611000035921. [ABSTRACT FROM AUTHOR]

Background: Allopurinol dose reduction proportional to creatinine clearance (CLcr) results in suboptimal urate lowering in patients with gout. Similarly, diuretic therapy reduces oxypurinol clearance but is unexpectedly associated with the need for higher allopurinol doses to achieve the serum urate target (<0.36 mmol/L). The authors aimed to clarify the relationship between oxypurinol exposure and urate-lowering response in patients with gout at different stages of chronic kidney disease and those taking diuretics to determine the implications for maintenance dose selection., Methods: Oxypurinol and urate data from 5 clinical studies were available. Model-derived steady-state oxypurinol areas under the concentration-time curves (AUCss0-tau) were estimated using a Bayesian methodology. The observed response metrics included the percentage reduction in urate from baseline and achievement of the target urate level. Exposure-response was explored graphically and using logistic regression. In addition, the influence of chronic kidney disease and diuretic use on the allopurinol dose and oxypurinol AUCss0-tau requirements to achieve the serum urate target were explored., Results: Data from 258 patients with gout taking allopurinol representing 1288 paired steady-state oxypurinol and serum urate measurements were available. Higher oxypurinol exposure seems to be required for urate-lowering response normalization and achieve the serum urate target in individuals with reduced kidney function and those taking diuretics. However, allopurinol dose requirements were reduced by 2-fold at the extremes of kidney function and unchanged in those taking or not taking diuretics., Conclusions: A lower allopurinol maintenance dose was required in patients with reduced kidney function (CLcr <30 mL/min), but this was not proportional to CLcr. Diuretic therapy did not influence allopurinol dose requirements., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This commentary explores how a change in the professional identity of pharmacists from medicines supplier to clinical decision-maker might take place. Three leverage points are identified that support this change. The first leverage point involves workplace culture. Pharmacists require workplaces that support them to assume direct responsibility for drug therapy decisions that may not have traditionally been part of pharmacy practice. The second leverage point involves terminology. Pharmacists need to be able to name and describe the process they use when making decisions about drug therapy. The third leverage point encompasses pharmacy education. Future pharmacists require a foundation that enables them to mobilize their knowledge and skills about drug therapy to act as clinical decision-makers with patients that require complex care. By acting on multiple leverage points, advocates for change in the pharmacy profession can assist pharmacists to establish themselves as decision-makers about drug therapy, shift their professional identity, and reformulate their view of the profession., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Gout is one of the most common forms of arthritis worldwide. Gout is particularly prevalent in Aotearoa/New Zealand and is estimated to affect 13.1% of Māori men, 22.9% of Pacific men and 7.4% of New Zealand European men. Effective long-term treatment requires lowering serum urate to <0.36 mmol/L. Allopurinol is the most commonly used urate-lowering medication worldwide. Despite its efficacy and safety, the allopurinol dose escalation treat-to-target serum urate strategy is difficult to implement and there are important inequities in allopurinol prescribing in Aotearoa. The escalation strategy is labour intensive, time consuming and costly for people with gout and the healthcare system. An easy and effective way to dose-escalate allopurinol is required, especially as gout disproportionately affects working-age Māori men and Pacific men, who frequently do not receive optimal care., Methods and Analysis: A 12-month non-inferiority randomised controlled trial in people with gout who have a serum urate ≥ 0.36 mmol/l will be undertaken. 380 participants recruited from primary and secondary care will be randomised to one of the two allopurinol dosing strategies: intensive nurse-led treat-to-target serum urate dosing (intensive treat-to-target) or protocol-driven dose escalation based on dose predicted by an allopurinol dosing model (Easy-Allo). The primary endpoint will be the proportion of participants who achieve target serum urate (<0.36 mmol/L) at 12 months., Ethics and Dissemination: The New Zealand Northern B Health and Disability Ethics Committee approved the study (2022 FULL 13478). Results will be disseminated in peer-reviewed journals and to participants., Trial Registration Number: ACTRN12622001279718p., Competing Interests: Competing interests: LS reports research funding from the New Zealand Health Research Council and consulting fees from Pharmac outside the submitted work. LTK reports funding from the New Zealand Health Research Council. DFBW reports consulting fees from Health Research Council's Standing Committee on Therapeutic Trials, Wellington, New Zealand, and Australian Human Research Ethics Committees, Bellberry Limited, Adelaide, Australia. ND has received consulting fees, speaker fees or grants from AstraZeneca, Novartis, Dyve Biosciences, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs and Hikma outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CL R ) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling., Methods: In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CL R and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated., Results: Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CL R and GFR. The relative standard error of estimated parameters were 13-37 and 17-44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13-21%) under the FDA designs., Conclusion: The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision., (© 2020 The British Pharmacological Society.)

Background: Therapeutic decision-making is a core element of pharmacy practice, however, little has been documented about how it is enacted in practice and how it can be theorised., Objective(s): This study aims to contribute to pharmacy education and practice theory by investigating the correspondence between explanations from primary care pharmacists in clinical practice roles about how they make decisions related to medicines therapy and a theoretical model of therapeutic decision-making., Methods: In this qualitative study, interview data from 10 pharmacists in primary care settings were analysed using a general inductive approach. The emergent themes were compared to a theoretical model of therapeutic decision-making., Results: Eight themes were identified from the explanations of how participants were making therapeutic decisions in practice. The themes were found to correspond to at least one of the four steps of therapeutic decision-making in the model. Themes corresponding to the information gathering step were described most vividly, whereas, the themes corresponding to the reasoning, judgement, and decision steps were less well-articulated., Conclusions: These findings suggest that the theoretical model can be useful to interpret empirical data about therapeutic decision-making in practice. These findings might provide a means for pharmacists to adopt language to better describe the steps in their therapeutic decision-making process to others, and especially, their colleagues and patients. Findings can be used by pharmacy educators to design learning opportunities for students about therapeutic decision-making., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health economics, and drug regulations.

The aims of this study were to characterise the population pharmacokinetics of metformin in patients receiving haemodialysis, and to determine the doses that will maintain median metformin plasma concentrations below 5 mg L -1 for a typical individual. Metformin plasma concentrations from 5 patients receiving thrice weekly intermittent haemodialysis followed by metformin 500 mg postdialysis were fitted to a published pharmacokinetic model. Additional models to describe the dialytic pharmacokinetics of metformin were explored. Doses of 250 and 500 postdialysis were simulated from the model for a typical haemodialysis patient. The published 2-compartment pharmacokinetic model with an additional parameter to describe haemodialysis clearance provided a reasonable fit to the data. Deterministic simulations from the model for a typical individual suggest that metformin doses of 250-500 mg postdialysis and 250 mg given once daily should maintain median metformin plasma concentrations below 5 mg L -1 ., (© 2020 The British Pharmacological Society.)

Clinical decision-making skills are recognized as a central component of professional competency but are under-developed in pharmacy compared to other health professions. There is an urgent need for a comprehensive understanding of how pharmacists can best develop and use therapeutic decision-making skills in clinical practice. The aims of this commentary are to define clinical decision-making in pharmacy practice, and to present a model for clinical decision-making that aligns with a philosophical framework for pharmacy practice. The model has utility in education programs for pharmacists and provides a framework for understanding patient-facing clinical services in practice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Clinical decision-making is arguably the most important and underappreciated skill in pharmacy. It can be described as four discrete steps: information gathering, clinical reasoning and judgement and, the decision process. The information gathering and decision negotiation steps and to some extent clinical reasoning are addressed either implicitly or explicitly by practitioners and educators. Clinical judgement, however, remains a largely unexplored concept for clinical decision-making in healthcare therapeutics. It defines how practitioners arrive at a favourable treatment strategy and, due to the often complicated benefit:risk evaluations, is often linked with concepts relating to ambiguity. In this article, we use game theory to explore the judgement stage of clinical decision-making. Game theory allows us to provide a quantitative evaluation of clinical judgement and explore concepts such as ambiguity and its sources in healthcare. Clarifying the elements involved in the judgement stage of clinical decision-making will enable a better understanding of how pharmacists contribute patient care in healthcare teams., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pharmacy has a long history of providing products and services for healthcare. In the last century, these roles have taken a strong focus on clinical care with the provision of medicines review, medicines optimisation, and prescribing services being at the forefront. The profession, however, is diverse. Pharmacists operate across a wide range of healthcare practices that often embrace both historic and contemporary roles simultaneously. The purpose of this article is to provide an overarching philosophical framework for pharmacy that encompasses roles that the modern pharmacist may assume. In doing this, we explore how pharmacy services align with healthcare and how different services require different approaches to clinical decision making., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Gout is one of the most common forms of arthritis. It is well established that urate-lowering therapy that aims for a serum urate less than at least 0.36 mmol/l (6 mg/dl) is required for the successful management of gout. Allopurinol, a xanthine oxidase (XO) inhibitor, is the most commonly used urate-lowering therapy. However, many patients fail to achieve the target serum urate on allopurinol; these patients can be considered to have "inadequate response" to allopurinol. Herein, we examine the potential mechanisms and implications of inadequate response to allopurinol., Methods: The literature was reviewed for potential causes for failure to reach target serum urate in patients receiving allopurinol., Results: The two most common causes of inadequate response to allopurinol are poor adherence and under-dosing of allopurinol. Adherent patients who fail to achieve target serum urate on standard doses of allopurinol form a group that could be considered to be "partially resistant" to allopurinol. There are four potential mechanisms for partial allopurinol resistance: decreased conversion of allopurinol to oxypurinol; increased renal excretion of oxypurinol; abnormality in XO structure and/or function such that oxypurinol is rendered less effective and/or drug interactions., Conclusions: It is important to determine the reasons for failure to achieve treatment targets with allopurinol, particularly as newer agents become available. The knowledge of the mechanisms for inadequate response may help guide the clinician towards making a therapeutic choice that is more likely to result in achieving the serum urate target., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Gout is a major health problem in Polynesians and allopurinol, the drug of choice for the management gout, appears to be less effective in Polynesian patients. The uricosuric drug benzbromarone is an alternative treatment but CYP2C9 poor metabolisers (PMs) may be at a heightened risk of benzbromarone-induced hepatotoxicity. The objectives of this study were to determine the frequency of the PM alleles CYP2C9*2 and CYP2C9*3 in New Zealand (NZ) Caucasian and Polynesian gout cohorts; and then to test for novel CYP2C9 polymorphisms in Polynesians., Methods: Eight hundred and fifty-two Caucasians (537 controls, 315 gout patients) and 1072 Māori and Pacific Island (Polynesian) people (620 controls, 452 gout patients) were genotyped for CYP2C9*2 and CYP2C9*3. Forty Polynesians were screened for novel CYP2C9 polymorphisms using whole genome sequencing., Results: Frequency of CYP2C9 PM alleles was significantly higher in Caucasians compared to Polynesians (CYP2C9*2: 13.5% versus 3.1%; CYP2C9*3: 5.5% versus 1.6%, P<1.2E-11). Within Polynesians, CYP2C9 PM alleles were rarer in Western Polynesians (Samoa, Tonga) than Eastern Polynesians (NZ and Cook Island Maori; CYP2C9*2: 0.6% versus 2.5%; CYP2C9*3: 0.4% versus 2.0%; P<0.03). A total of 152 SNPs were found by sequencing. None of these variants were predicted by in silico analysis to significantly impact on CYP2C9 expression or activity., Conclusion: Prospective CYP2C9 genotyping of Caucasian gout patients may be warranted for benzbromarone, whereas the low frequencies of CYP2C9 PM alleles in Polynesians suggests that the CYP2C9 polymorphism may be of little or no relevance to benzbromarone prescribing in this population., (Copyright © 2013 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)