Search

Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model-informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine-treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: "low" (demographic), "medium" (demographic and environmental interaction), and "high" (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R

Background Medical emergency teams use medications to rescue deteriorating patients. Medication management is the system of steps and processes, including prescribing, distribution, administration, and monitoring, to achieve the best outcomes from medication use. Systems or standards for medication management by medical emergency teams have not been defined. Objectives The aim of the study was to propose potential solutions to improve medical emergency team medication management by evaluating medication supply and related medication management practices during medical emergency team activations and understanding clinicians' perceptions about medical emergency team medication management in acute hospitals. Methods A prospective multicentre audit of intensive care unit–equipped hospitals in Victoria, Australia, was conducted. After advertisement and invitation via scheduled email newsletters to hospitals, a representative of the medical emergency team from each hospital self-administered an online audit tool during December 2019 and January 2020. Audit data were analysed descriptively, and perceptions were analysed using content analysis. Results Responses were received from 32 of the 44 (72.7%) eligible hospitals. At 17 of the 32 (53.1%) hospitals, arrest trolleys provided medications for medical emergency team activations, in addition to arrest calls. At 15 of the 32 (46.9%) hospitals, separate, dedicated medical emergency team medication supplies were used to care for deteriorating patients. Dedicated medical emergency team supplies contained a median of 20 (range = 8–37) medications, predominantly cardiovascular (median = 8, mode = 7, range = 4–16) and neurological medications (median and mode = 6, range = 0–11). Variation was observed in all storage and other supply-related medication management practices studied. The four most frequent categories of clinicians' perceptions described systematic challenges with availability of the right medication in the right place at the right time. Conclusions Current supply and related medication management practices and clinicians' perceptions demonstrated further development is necessary for medication management to meet the needs of medical emergency team clinicians and their patients.

In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution. Our model is a valuable addition to the existing meropenem population PK models, and it could be particularly useful during implementation of a therapeutic drug monitoring program combined with Bayesian forecasting. Based on the final model developed, comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 16 different dosing regimens. Simulation results showed that 2 g administered every 8 h with 3-h prolonged infusion (PI) and 4 g/day by continuous infusion (CI) appear to be two empirical dosing regimens that are superior to many other regimens when both target attainment and potential toxicity are considered and renal function information is not available. Following a daily CI dose of 6 g or higher, more than 30% of the population with a creatinine clearance of60 mL/min is predicted to have neurotoxicity. With the availability of institution- and/or unit-specific meropenem susceptibility patterns, as well as an individual patient's renal function, our PTA results may represent useful references for physicians to make dosing decisions.

BACKGROUND: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. INTRODUCTION: Using an opportunistic study design we evaluated the pharmacokinetics (PK) of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. METHODS: A total of 121 adult patients were included. The population PK models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. RESULTS: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the PK of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥65 years of age. CONCLUSION: The simulations suggested that adults ≤50 years of age infected with organisms with higher minimum inhibitory concentrations (MICs) may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT>MIC, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher MICs.

SARS-CoV-2, is the cause of the COVID-19 pandemic which has claimed more than six million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA approved molecules with established safety profiles that have a plausible mechanism for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising repurposable drug candidates that are safe, efficacious, and cost-effective for the treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx, https://www.covirx.org/) that was also developed to enable scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

Frail older people have a high prevalence of drug use and are susceptible to adverse drug reactions. The physiological changes of frailty are likely to affect pharmacokinetics and pharmacodynamics. We reviewed the methods and findings of published studies of pharmacokinetics in frailty. Nine studies describing pharmacokinetics and an additional three of pharmacokinetic pathways in frail older people were identified. Most pharmacokinetic studies investigated a single administration of a medication, dose or formulation, in small populations, often with limited representation of males or females, and applied variable definitions of frailty. Pharmacokinetic sampling designs generally utilised saturated sampling followed by analysis based on the trapezoidal rule for area under the curve, with more recent studies using sparser sampling and more sophisticated modelling to obtain individual and population values of all pharmacokinetic parameters. Overall, the pharmacokinetic studies reported only small changes in some parameters for some drugs with frailty, with the most consistent change reduced hepatic clearance in frail older people. Recommendations for future studies of pharmacokinetics in frailty include (i) standard objective definitions of frailty; (ii) larger studies including people with mild, moderate and severe frailty; (iii) population pharmacokinetic modelling to allow sparser sampling and consideration of multiple influences on pharmacokinetics; (iv) physiologically based modelling as the physiology of frailty emerges and (v) longitudinal pharmacokinetic studies of chronic drug therapy from middle to old age and from robust to pre-frail to frail, including pre-clinical studies. These data, accompanied by pharmacodynamics data in frailty, will inform safe, effective prescribing for frail older people.

OBJECTIVE The aim of this systematic review and meta-analysis was to determine if a combination of analgesics conveys any significant clinical benefit over paracetamol alone in managing acute musculoskeletal injuries. METHODS Two reviewers independently searched MEDLINE (via PubMed), EMBASE and Cochrane electronic databases. Randomised controlled trials comparing paracetamol with paracetamol plus other oral analgesics in managing acute musculoskeletal injuries (e.g. sprains, contusions) were identified. Outcomes were reduction in pain score, adverse events and need for additional analgesia. Studies were critiqued using the Cochrane Risk of Bias Assessment Tool and data analysed using RevMAN meta-analysis software. RESULTS Six studies were included (n = 1254). No paediatric studies were identified. Five studies compared paracetamol to paracetamol plus NSAID. One study also included an opioid in the combination group. There was no clinically important difference between groups for reduction in pain score in the first 2 h, 24 h or 72 h. At 2 h the mean difference in reduction in pain score at rest on 100 mm VAS was 0.72 mm (-1.36, 2.79), P = 0.5. On activity it was -1.79 mm (-4.08, 0.49), P = 0.12. The risk of adverse events in ED was -0.00 (-0.04, 0.03). More patients receiving combination therapy required additional analgesia in the first 2 h: -0.03 (-0.06, -0.01), P = 0.01. CONCLUSION Paracetamol monotherapy is a reasonable first-line analgesic for acute musculoskeletal injuries as combining additional oral agents does not result in any significant additional analgesic effect.

Syndrome Coronavirus 2 (SARS-CoV-2) has led to remarkable efforts by the scientific communities internationally to identify potential pharmacological treatments through the rapid initiation of clinical trials of novel and/or re-purposed regulatory authorityapproved therapies. We greatly welcome the significant global effort to safely expedite trials. However, we are concerned that many studies have not been of high quality to generate clinically meaningful data to enable effective translation to clinical practice. Identifying the “right” drug (or drug combinations) is only the first step. Applying core clinical pharmacology principles at all stages of research will help identify the right dose, the right patient, and the right treatment protocol. We hope that by setting out the principles outlined in this statement, efforts to find a safe and efficacious treatment for COVID-19 will have the best chance of success.

Cognitive enhancers (CEs) such as methylphenidate, dexamphetamine and modafinil are increasingly used beyond their prescribed indications by healthy individuals without medical necessity, in academ...

The use of real-world data in drug repurposing has emerged due to well-established advantages of drug repurposing in supplementing de novo drug discovery and incentives in incorporating real-world evidence in regulatory approvals. We conducted a scoping review to characterize repurposing studies using real-world data and discuss their potential challenges and solutions. A total of 250 studies met the inclusion criteria, of which 36 were original studies on hypothesis generation, 101 on hypothesis validation, and seven on safety assessment. Key challenges that should be addressed for future progress in using real-world data for repurposing include isolated data sources with poor clinical granularity, false-positive signals from data mining, the sensitivity of hypothesis validation to bias and confounding, and the lack of clear regulatory guidance.

To assess the impact of a pathway allowing nurse initiation of first dose intravenous (IV) antibiotics on time to antibiotic administration (TTA) in adult inpatients with febrile neutropenia (FN).This study evaluated the impact on TTA of a clinical pathway (November 2017 to April 2018) allowing nurse initiation of pre-prescribed antibiotics in adult haematology patients with FN, compared with a prior cohort (November 2016 to April 2017) in which antibiotics were only prescribed and administered after medical review. The primary endpoint for comparison was TTA, calculated as the time between the first recorded fever and IV antibiotic administration. Secondary endpoints included appropriateness of initial antibiotic choice, 30-day all-cause mortality and admission to intensive care unit (ICU).Forty-seven eligible FN episodes in 40 patients and 61 episodes in 52 patients were evaluated in the pre- and post-implementation groups, respectively. Baseline characteristics were comparable between groups. Median (IQR) TTA, in the pre-implementation group [66 min (40-100 min)] was significantly prolonged versus post-implementation group [29 min (20-41 min); p 0.001]. A significantly higher proportion of episodes were administered appropriate initial antibiotics in the post-versus pre-implementation groups (100% vs. 89%, p = 0.03). There was no significant change in 30-day all-cause mortality (0% vs. 5%, p = 0.3) or ICU admission within 48 h of fever (0% vs. 2%, p 0.99) between pre- and post-implementation groups, respectively.A pathway allowing nurse initiation of pre-prescribed antibiotic orders for FN significantly reduced TTA from first recorded fever and increased the proportion of appropriate initial antibiotic choices without significantly impacting on patient outcomes.

The contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data.Analysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital.Between January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls.One in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.

Background In hospitals, rapid response systems (RRSs) identify patients who deteriorate and provide critical care at their bedsides to stabilise and escalate care. Medications, including oral and parenteral pharmaceutical preparations, are the most common intervention for hospitalised patients and the most common cause of harm. This connection between clinical deterioration and medication safety is poorly understood. Objectives To inform improvements in prevention and management of clinical deterioration, this review aimed to examine how medications contributed to clinical deterioration and how medications were used in RRSs. Review methods A scoping review was undertaken of medication data reported in studies of clinical deterioration or RRSs in diverse hospital settings between 2005 and 2017. Bibliographic database searches used permutations of “rapid response system,” “medical emergency team,” and keyword searching with medication-related terms. Independent selection, quality assessment, and data extraction informed mapping against four medication themes: causes of deterioration, predictors of deterioration, RRS use, and management. Results Thirty articles were reviewed. Quality was low: limited by small samples, observational, single-centre designs and few primary medication-related outcomes. Adverse drug reactions and potentially preventable medication errors, involving sedatives, analgesics, and cardiovascular agents, contributed to clinical deterioration. While sparsely reported, outcomes included death and escalation of care. In children, administration of antibiotics or nebulised medications appeared to predict subsequent deterioration. Cardiovascular medications, sedatives, and analgesics commonly were used to manage deterioration but further detail was lacking. Despite reported potential for patient harm, evaluation of medication management systems was limited. Conclusions Medications contributed to potentially preventable clinical deterioration, with considerable harm, and were common interventions for its management. When assessing deteriorating patients or caring for patients who require escalation to critical care, clinicians should consider medication errors and adverse reactions. Studies with more specific medication-related, patient-centred end points could reduce medication-related deterioration and refine RRS medication use and management.

Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination. Methods We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration). Results Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid. Conclusion The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.

During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based meta-analysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.

Background: Intramuscular (IM) oxytocin for postpartum haemorrhage (PPH) prevention in resource-poor settings is limited by the need for cold-chain storage and skilled staff for safe injection. We compared the pharmacokinetics (PK) and safety of heat-stable oxytocin inhaled (IH) versus IM administration in women during third stage of labour (TSL). Methods: The phase 1, randomised, open-label clinical study (NCT02999100) was conducted across three centres in the UK and Australia. Participants (Group 1, women in TSL; Group 2, non-pregnant women of childbearing potential) were randomised 1:1 via validated GSK internal software: Group 1, oxytocin 240 IU (400 μg) IH or oxytocin 10 IU (17 μg) IM immediately after delivery; Group 2, intravenous (IV) oxytocin 5 IU (8·5 μg) and oxytocin 240 IU (400 μg) IH at two separate dosing sessions in a cross-over design. Primary endpoints included characterising oxytocin IH PK. The safety population included patients who received ≥1 dose; any PK sample obtained and analysed was included in the PK population. Additional investigations explored the validity of the PK concentration data. Findings: Participants were recruited between November 2016 and March 2019. In Group 1, 29 participants were randomised; 17 received IH (n=9) or IM (n=8) oxytocin. After IH and IM administration most plasma oxytocin concentrations were below quantification limits (2 pg/ml). In Group 2 (n=14), oxytocin IH concentrations remained quantifiable up to 3 hrs post dose. Adverse events were reported for: Group 1, IH n=3 (33%) and IM n=2 (25%); Group 2, n=14 (100%). No deaths were reported. Interpretation: Safety profiles of oxytocin IH and IM were similar; PK profiles could not be defined for oxytocin IH or IM in women in TSL, despite using a highly sensitive assay. Ex vivo investigations suggested oxytocin metabolism occurred in vivo and not during sample collection and processing. Trial Registration: Trial Registration Number, (ClinicalTrials.gov: NCT02999100). The study protocol can be found online (https://clinicaltrials.gov/ProvidedDocs/00/NCT02999100/Prot_000.pdf). Funding: GlaxoSmithKline (GSK 205920; NCT02999100) Declaration of Interest: KG-K, AS-C, KRP, PL, TN, JM, CG, CK and VLO have no conflicts to declare. SK, AC, RAG, SP, IS, AS, KH, MP, ME and SS are employees of and hold stocks in GSK. MPM is an inventor on the patent method and formulation for oxytocin inhalation (WO2013/016754 A1 [PCT/AU2011001430]). Ethical Approval: The study protocol was reviewed and approved by the Office for Research Ethics Committees of Northern Ireland (UK) and the Monash Health Human Research Ethics Committee (Australia) in accordance with Good Clinical Practice (GCP) guidelines.

Aim Oral flucloxacillin may be co-administered with probenecid to increase flucloxacillin concentrations and increase attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets. The aims of this study were to describe outcomes of patients treated with oral flucloxacillin plus probenecid as follow-on therapy from initial intravenous treatment, and to identify optimal dosing regimens when treating infections caused by susceptible Gram-positive organisms. Methods We performed a prospective observational study of adults treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly (with food) for proven or probable staphylococcal infections. We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, in order to estimate probability of PK-PD target attainment (fT>MIC), and used Monte Carlo simulation to explore optimal dosing regimens. Results The 45 patients (73% male) had a median (range) age of 49 years (20 – 74), weight of 90 kg (59 – 167), fat free mass (Janmahasatian) of 65 kg (38 – 89) and eGFR (CKD-EPI) of 89 mL/min/1.73m2 (41 – 124). The most common infections were osteomyelitis (n=18, 40%) and septic arthritis (n=12, 27%). Forty patients (89%) were cured 30 days after completion of therapy. 10 (22%) experienced nausea which did not require treatment alternation. Free flucloxacillin clearance depended on allometrically-scaled fat free mass, and increased by 1% for each unit increase in eGFR. Conclusion Oral flucloxacillin and probenecid was well-tolerated and efficacious. Patients with higher fat free mass and eGFR may require four times daily dosing and/or therapeutic drug monitoring to ensure PK-PD target attainment.

Objective: To investigate whether integrating pharmacists into general practices reduces the number of unplanned re-admissions of patients recently discharged from hospital. Design, setting: Stepped wedge, cluster randomised trial in 14 general practices in southeast Queensland. Participants: Adults discharged from one of seven study hospitals during the seven days preceding recruitment (22 May 2017 ‒ 14 March 2018) and prescribed five or more long term medicines, or having a primary discharge diagnosis of congestive heart failure or exacerbation of chronic obstructive pulmonary disease. Intervention: Comprehensive face-to-face medicine management consultation with an integrated practice pharmacist within seven days of discharge, followed by a consultation with their general practitioner and further pharmacist consultations as needed. Major outcomes: Rates of unplanned, all-cause hospital re-admissions and emergency department (ED) presentations 12 months after hospital discharge; incremental net difference in overall costs. Results: By 12 months, there had been 282 re-admissions among 177 control patients (incidence rate [IR], 1.65 per person-year) and 136 among 129 intervention patients (IR, 1.09 per person-year; fully adjusted IR ratio [IRR], 0.79; 95% CI, 0.52‒1.18). ED presentation incidence (fully adjusted IRR, 0.46; 95% CI, 0.22‒0.94) and combined re-admission and ED presentation incidence (fully adjusted IRR, 0.69; 95% CI, 0.48‒0.99) were significantly lower for intervention patients. The estimated incremental net cost benefit of the intervention was $5072 per patient, with a benefit‒cost ratio of 31:1. Conclusion: A collaborative pharmacist‒GP model of post-hospital discharge medicines management can reduce the incidence of hospital re-admissions and ED presentations, achieving substantial cost savings to the health system. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001627448 (prospective).

Background Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

A visual predictive check (VPC) is a common diagnostic procedure for population pharmacometric models. Typically, VPCs are generated by specifying intervals, or "bins", of an independent variable (e.g., time). However, bin specification is not always straightforward and the choice of bins may affect the appearance, and possibly conclusions, of VPCs. The objective of this work was to demonstrate how regression techniques can be used to derive VPCs and prediction-corrected VPCs (pcVPCs) for population pharmacometric models. This alternative approach negates the need for empirical bin selection. The proposed method utilizes local and additive quantile regression. Implementation is straightforward and computationally acceptable. This work provides support for deriving VPCs and pcVPCs via regression techniques.

Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of μ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319–27. ©2018 AACR.

The aim of this study was to systematically evaluate whether non-weight-based dosing (non-WBD) or weight-based dosing (WBD) of vancomycin leads to a higher proportion of patients achieving the pharmacokinetic/pharmacodynamic target. Studies from January 1985 to February 2017 were identified through Cochrane, MEDLINE and Embase databases. Those conducted in adults with end-stage renal disease receiving high-flux haemodialysis (HD) and intravenous vancomycin were included. The primary outcome was the proportion of patients with a pre-HD vancomycin concentration of 15-20 mg/L and/or an area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) ratio ≥400. Of the 3948 studies screened, 5 met the inclusion criteria. The proportion of patients with pre-HD concentrations between 15-20 mg/L were 35% (non-WBD) and 13% (WBD) post-loading dose. During maintenance dosing, the proportion of patients with pre-HD concentrations between 15-20 mg/L were 37% (non-WBD) and 50-67% (WBD). The proportion of pre-HD concentrations

Background Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia. Objective Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia. Methods A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention. Results A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p Conclusion The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.

Background Research into which medications contribute to polypharmacy and the variability in these medications across long-term care facilities (LTCFs) has been minimal. Objective Our objective was to investigate which medications were more prevalent among residents with polypharmacy and to determine the variability in prescribing of these medications across LTCFs. Methods This was a cross-sectional study of 27 LTCFs in regional and rural Victoria, Australia. An audit of the medication charts and medical records of 754 residents was performed in May 2015. Polypharmacy was defined as nine or more regular medications. Logistic regression was performed to determine the association between medications and resident characteristics with polypharmacy. Analyses were adjusted for age, sex and Charlson’s comorbidity index. Variability in the use of the ten most prevalent medication classes was explored using funnel plots. Characteristics of LTCFs with low (

Seasonal influenza epidemics continue to cause significant morbidity and mortality, especially in high-risk subpopulations. The rise of drug-resistant influenza strains and high rates of vaccine mismatches drives the search for new safe and effective antiviral drugs. The purpose of this review was to summarize how mathematical models―viral kinetic models, in particular―have advanced our understanding of influenza biology and antiviral pharmacology and to explore how these models may be further developed in the future. Viral kinetic models that use a population approach have been helpful in elucidating the major sources of intra- and inter-individual variability. Thus, these models can help explain why some influenza patients become much sicker than others. Linking viral kinetic models to pharmacokinetic/pharmacodynamic models has enabled quantification of drug effects based on their mechanism of action and in silico evaluation of the efficacy of drug combinations. Viral kinetic models have also been applied to optimizing the design of clinical trials. Future directions for viral kinetic models include coupling to epidemiological models to assess the effectiveness of various public health treatment strategies. These models can also inform health economic decision-making. Since the 1970s, the field of viral kinetic modeling of influenza has made great advances in informing our knowledge of this infectious disease. This tool is being coupled to other types of modeling approaches and will continue to be a critical weapon in our infectious disease armamentarium.

The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations.Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC(0-tau), CLR, and CLNR/F.The data (66 patients, 327 observations) were best described by a two-compartment model, and CLCR was a covariate for CLR. Mean CLR was 17 L/h (CV 22%) and mean CLNR/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CLR increased due to improved renal function, AUC(0-tau) decreased proportionally, while CLNR/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CLCR/3 x 100 to obtain median AUC(0-12) of 18-26 mg/L/h for metformin IR and AUC(0-24) of 38-51 mg/L/h for metformin XR, with C-max The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT>MIC) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT>0.1 mg/L) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration–time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20–30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs.

Background: Pharmacist-led medication review is a collaborative service which aims to identify and resolve medication-related problems. Objective: To critically evaluate published systematic reviews relevant to pharmacist-led medication reviews in community settings. Methods: MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Database of Systematic Reviews (CDSR) were searched from 1995 to December 2015. Systematic reviews of all study designs and outcomes were considered. Methodological quality was assessed using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) tool. Systematic reviews of moderate or high quality (AMSTAR ≥ 4) were included in the data synthesis. Data extraction and quality assessment was performed independently by two investigators. Results: Of the 35 relevant systematic reviews identified, 24 were of moderate and seven of high quality and were included in the data synthesis. The largest overall numbers of unique primary research studies with favorable outcomes were for diabetes control (78% of studies reporting the outcome), blood pressure control (74%), cholesterol (63%), medication adherence (56%) and medication management (47%). Significant reductions in medication and/or healthcare costs were reported in 35% of primary research studies. Meta-analysis was performed in 12 systematic reviews. Results from the meta-analyses suggested positive impacts on glycosylated hemoglobin, blood pressure, cholesterol, and number and appropriateness of medications. Conflicting findings were reported in relation to hospitalization. No meta-analyses reported reduced mortality. Conclusion: Moderate and high quality systematic reviews support the value of pharmacist-led medication review for a range of clinical outcomes. Further research including more rigorous cost analyses are required to determine the impact of pharmacist-led medication reviews on humanistic and economic outcomes. Future systematic reviews should consider the inclusion of both qualitative and quantitative studies to comprehensively evaluate medication review. Refereed/Peer-reviewed

Background: Polypharmacy is highly prevalent in residential aged care facilities (RACFs). Although polypharmacy is sometimes unavoidable, polypharmacy has been associated with increased morbidity and mortality. Objective: To identify and prioritize a range of potential interventions to manage polypharmacy in RACFs from the perspectives of health care professionals, health policy and consumer representatives. Methods: Two nominal group technique (NGT) sessions were convened in August 2015. A purposive sample (n = 19) of clinicians, researchers, managers and representatives of consumer, professional and health policy organizations were asked to nominate interventions to address the prevalence and appropriateness of medication use. Participants were then asked to prioritize five interventions suitable for possible implementation at the system level. Results: Six of 16 potential interventions were prioritized highest for possible implementation in clinical practice, with two interventions prioritized as second highest. The top interventions in rank order were 'implementation of a pharmacist-led medication reconciliation service for new residents,' 'conduct facility-level audits and feedback to staff and health care professionals,' 'develop deprescribing scripts to assist clinician-resident discussion,' 'develop or revise prescribing guidelines specific to older people with multimorbidity in RACFs,' 'implement electronic medication charts and records' and 'better support Medication Advisory Committees (MACs) to address medication appropriateness.'. . Conclusion: This study prioritized a range of potential interventions that may be used to assist clinicians and policy makers develop a comprehensive strategy to manage polypharmacy in RACFs. Refereed/Peer-reviewed

Aims A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. Methods The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration–time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R0), a measure of transmissibility, was linked by reduction of viral shedding duration. The number of infected patients per population of 100 000 susceptible individuals was simulated for a series of pandemic scenarios, varying oseltamivir dose, R0 (1.9 vs. 2.7), and drug uptake (25%, 50%, and 80%). The number of infected patients for each scenario was entered into the health economics module, a decision analytic model populated with branch probabilities, disease utility, costs of hospitalized patients developing complications, and case-fatality rates. Change in quality-adjusted life years was determined relative to base case. Results Oseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios. Conclusion This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework.

Objective To investigate administration of pro re nata (PRN) medications and nurse-initiated medications (NIMs) in Australian aged care services over a 12-month period. Design Twelve-month longitudinal audit of medication administrations. Setting and participants Three hundred ninety-two residents of 10 aged care services in regional Victoria, Australia. Methods Records of PRN and NIM administration were extracted from electronic and hard copy medication charts. Descriptive statistics were used to calculate medication administration per person-month. Poisson regression was used to estimate predictors of PRN administration. Results Over a median follow-up of 12 months (interquartile range 10–12 months), 93% of residents were administered a PRN medication and 41% of residents an NIM on 21,147 and 552 occasions, respectively. The mean number of any PRN administration was 5.85 per person-month. The most frequently administered PRN medications per person-month were opioids 1.54, laxatives 0.96, benzodiazepines 0.72, antipsychotics 0.48, paracetamol 0.46, and topical preparations 0.42. Three-quarters of residents prescribed a PRN opioid or PRN benzodiazepine and two-thirds of residents prescribed a PRN antipsychotic had the medication administered on 1 or more occasions over the follow-up. Conclusions and Implications Most residents were administered PRN medications. Administration was in line with Australian regulations and institutional protocols. However, the high frequency of PRN analgesic, laxative, and psychotropic medication administration highlights the need for regular clinical review to ensure ongoing safe and appropriate use.

Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM). Pharmacokinetic profiles representing substantial ARC (creatinine clearance of 250 ml/min) were generated in the HFIM for meropenem (1 g or 2 g administered every 8 h as 30-min infusion and 3 g/day or 6 g/day as continuous infusion [CI]) and tobramycin (7 mg/kg of body weight every 24 h as 30-min infusion) regimens. The time courses of total and less-susceptible bacterial populations and MICs were determined for the monotherapies and all four combination regimens. Mechanism-based mathematical modeling (MBM) was performed. In the HFIM, maximum bacterial killing with any meropenem monotherapy was ∼3 log(10) CFU/ml at 7 h, followed by rapid regrowth with increases in resistant populations by 24 h (meropenem MIC of up to 128 mg/liter). Tobramycin monotherapy produced extensive initial killing (∼7 log(10) at 4 h) with rapid regrowth by 24 h, including substantial increases in resistant populations (tobramycin MIC of 32 mg/liter). Combination regimens containing meropenem administered intermittently or as a 3-g/day CI suppressed regrowth for ∼1 to 3 days, with rapid regrowth of resistant bacteria. Only a 6-g/day CI of meropenem combined with tobramycin suppressed regrowth and resistance over 7 days. MBM described bacterial killing and regrowth for all regimens well. The mode of meropenem administration was critical for the combination to be maximally effective against carbapenem-resistant P. aeruginosa.

Background There is increasing international interest in initiatives to reduce medication-related harm and preventable hospitalizations in residential aged care services (RACS). The Australian Government recommends that RACS establish multidisciplinary Medication Advisory Committees (MACs). No previous research has specifically investigated the structures and functioning of MACs. Objectives To explore the current structures and functioning of MACs, and identify opportunities for MACs to better promote safe and effective medication use. Methods Semi-structured interviews and focus groups were conducted with a maximum variation sample of health professionals (n = 44) across four health services operating across 27 RACS in rural and regional Victoria, Australia. Qualitative data were analyzed using deductive and inductive content analyses. Results were presented to a multidisciplinary expert panel (n = 13) to identify opportunities for improvement. Results Deductively coded themes included composition and functioning of the MAC, education and information needs and support to better manage polypharmacy. Emergent inductively coded themes included general medical practitioner (GP) and pharmacist engagement, collaboration and effectiveness. Participation by GPs and pharmacists was variable, while no MACs involved residents or family carers. Aged care specific and multidisciplinary MACs were generally more proactive in addressing potential medication-related harm. Education to identify and report adverse drug events with high risk medications was identified as a priority. The multidisciplinary panel made 12 recommendations to promote safe and effective medication use. Conclusion Despite all MACs having a strong commitment to medication safety, opportunities exist to improve the composition and structure, proactive identification and response to emerging issues, and systems for staff, resident and family carer training.

The rational use of medicines to achieve better patient outcomes is a global concern. This need has pressured the practice of pharmacy to move away from focusing only on dispensing of the drug product towards the patient's appropriate utilization of the medicine. PharmAlliance, a unique partnership among three leading schools of pharmacy at the University of North Carolina at Chapel Hill (United States), Monash University (Australia), and University College London (United Kingdom), convened a Global Summit of Pharmacy Practice Innovation in November 2017 to bring together the leaders of the professional associations of the three countries to dialogue about how to lead the identified changes. A framework of "One Pharmacy Community" resulted from the discussions and was conceptualized from the overarching theme of the Summit. Recognizing and articulating these similarities into a One Pharmacy Community framework enables the development of a consistent global nomenclature of pharmacy services. The four pillars that resulted from the conversation are education, research, practice, and collaboration. Each of these are essential and dependent on the other in order to enable pharmacy practice to meet the global requirements of patient-focused health care design and delivery. This article describes the framework and each of the pillars.

We compare paracetamol with a combination of paracetamol, ibuprofen, and codeine for pain relief in acute minor musculoskeletal injuries.This was a prospective, double-blind, randomized, active-controlled, parallel-arm study at an urban tertiary hospital emergency department. Participants were aged 18 to 65 years and had acute (48 hours) closed limb or trunk injuries with moderate pain (greater than 3/10). A single dose of 1 g of paracetamol, 400 mg of ibuprofen, and 60 mg of codeine was compared with a single dose of 1 g of paracetamol, placebo ibuprofen, and placebo codeine. The minimum detectable difference in pain was taken as 1.3.Baseline characteristics and pain were similar. There were clinically detectable reductions in pain at rest at 60 minutes for paracetamol: -1.6; 95% confidence interval (CI) -2.2 to -1.1); n=59 and the combination -2.0; 95% CI -2.5 to -1; n=59; difference -0.4; 95% CI -1.1 to 0.29; P=.26. At 120 minutes, the reduction in pain was -2.4; 95% CI -3.2 to -1.6 for paracetamol (n=30) and -2.9; 95% CI -3.7 to -2.2 for the combination (n=35); difference -0.5; 95% CI -1.6 to 0.5; P=.32. Rescue analgesia was required by 4 of 59 patients in the paracetamol group and 5 of 60 in the combination group (P.99). More participants in the combination group had adverse events: 14 of 60 versus 5 of 59 in the paracetamol group, relative risk 2.8; 95% CI 1.1 to 7.2. No adverse events were serious.Combining oral paracetamol, ibuprofen, and codeine as the initial treatment for pain associated with acute musculoskeletal injuries was not superior to paracetamol alone for pain reduction at 60 minutes or need for rescue analgesia, with more adverse events in the combination group.

Sinusoidal obstruction syndrome, previously known as veno-occlusive disease (VOD/SOS), is a complication in patients undergoing haemopoietic stem cell transplantation (HSCT). Severe VOD/SOS, including progression to multi-organ failure, has resulted in a mortality of greater than 80%. Defibrotide's varying pharmacological actions, particularly on endothelial cells, make it is a useful agent to consider for prophylaxis and treatment of VOD/SOS. Barriers to its routine use include the high acquisition cost and the fact that neither the oral or parenteral formulations are licensed products in many countries at this time. This review summarises available literature on the use of defibrotide in the management of VOD/SOS. Publications consist predominantly of single centre cohort studies and case series. Available evidence indicates that defibrotide is effective in the management of VOD/SOS. Using defibrotide prophylaxis should also be considered, especially in the paediatric setting, where there are available results from a large, open label, randomized controlled trial. Patient outcome data from the larger studies and compassionate programs can inform consensus recommendations on dosing regimen and criteria for the treatment of VOD/SOS with defibrotide in the adult population. The reviewed literature indicates an effective and safe dose for treatment is 25mg/kg/day, continued for at least 14days or until complete response is achieved. Further studies are required to determine the optimal dose and duration of treatment in both paediatric patients and adults. Recent recommendations and a phase 3 trial using historical controls indicate that defibrotide should be included as a pharmacotherapy option in protocols guiding management of VOD/SOS.

Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients. Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a ≥50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies. When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.

Background Clinical medication review (CMR) is a structured and collaborative service aimed at identifying and resolving medication-related problems (MRPs). This is the first systematic review of CMR research in Australia. Objective To systematically review the processes and outcomes of CMR in community-settings in Australia. Methods MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library and the grey literature were searched from 2000 to February 2015. All study designs were considered. Data extraction and quality assessment were performed independently by two investigators. Results Nine controlled studies, 34 observational and uncontrolled studies, 11 qualitative studies (focus groups and interviews) and nine survey studies were included. The CMRs resulted in identification of MRPs ( n = 15 studies, mean 3.6 MPRs per CMR) and improved adherence ( n = 3). Reductions in numbers of medications prescribed ( n = 3 studies), hospitalizations ( n = 3), potentially inappropriate prescribing ( n = 3) and costs ( n = 6) were demonstrated. Comparisons to a control group, predominately non-recipients of CMR, were made in eleven of 43 studies. Evidence supports additional models that promote interprofessional collaboration and timely referral following hospital discharge. Qualitative research identified low awareness of CMR among eligible non-recipients, while benefits were perceived to outweigh barriers to implementation. Underserved populations include indigenous and culturally and linguistically diverse people, recipients of palliative care, those recently discharged from hospital, people with poor medication adherence, those in rural and remote areas, older males, and younger people with long-term, persistent or serious health problems. Conclusion The available evidence suggests CMR is beneficial in improving the quality use of medications and health outcomes. However, lack of comparator groups in many observational studies limited the strength of conclusions in relation to the impact on clinical outcomes. Addressing access gaps for underserved populations, implementing additional referral pathways, and facilitating greater collaboration between the health professionals represent opportunities for further improvement.

Introduction and aims The non-medical use of prescription stimulants such as methylphenidate, dexamphetamine and modafinil is increasing in popularity within tertiary academic settings. There is a paucity of information on awareness, attitudes, and acceptability by professionals of use in this context. This study aimed to investigate professionals’ knowledge of and attitudes towards the use of cognitive enhancers (CEs) in academic settings, and their willingness to use a hypothetical CE. Design and methods A mail survey was sent to doctors, pharmacists, nurses, accountants and lawyers in New Zealand. These disciplines were chosen as they require professional registration to practice. The questionnaire comprised four sections: (1) demographics, (2) knowledge of CEs, (3) attitudes towards the use of CEs, and (4) willingness to use hypothetical CEs. Results The response rate was 34.5% (414/1200). Overall, participants strongly disagreed that it was fair to allow university students to use CEs for cognitive enhancement (Mdn = 1, IQR: 1,3), or that it is ethical for students without a prescription to use cognitive enhancers for any reason (Mdn = 1, IQR: 1,2). Professions differed in their attitudes towards whether it is ethical for students without a prescription to use CEs for any reason (p = 0.001, H 31.527). Discussion and conclusion Divergent views and lack of clear consensus within professions and between professionals on the use of CEs have the potential to influence both professionals and students as future professionals. These divergent views may stem from differences in the core values of self-identity as well as extrinsic factors of acceptability within the profession in balancing the elements of opportunity, fairness and authenticity in cognitive enhancement. Further research is required to inform the development of policy and guidelines that are congruent with all professions.