Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.

Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Economic evaluation of personalized vs. standard dosing of 5-fluorouracil in first-line chemotherapy for metastatic colorectal cancer in Australia.

AIMS: Using pharmacokinetics (PK)-guided 5-fluorouracil (5-FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost-effectiveness of PK vs. body surface area (BSA) dosing of 5-FU for patients with mCRC. METHODS: We developed a semi-Markov model with four health states to compare PK-guided dosing within a FOLFOX regimen vs. BSA-guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), and included both one-way and probabilistic sensitivity analyses. RESULTS: BSA-guided FOLFOX provided 1.291 QALYs at a cost of $36 379, compared with PK-guided FOLFOX which delivered 1.751 QALYs at a cost of $32 564. Therefore, PK-guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression-free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables. CONCLUSIONS: PK dose management of 5-FU-based chemotherapy in mCRC patients appears to be a cost-saving strategy in Australia. However, our model estimates are drawn from limited, low-quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK-based to BSA-based dosing across a variety of current regimens, is needed to address our model's uncertainties.

The valley of death: why Australia failed to develop clinically effective drugs in COVID-19.

There is a paucity of public discussion of costs spent on drug trials during coronavirus disease 2019 (COVID-19) and their value, and of large public outlay on research funding for vaccine and drug development that did not deliver medicines nor vaccines for Australians. This oversight left us at the behest of global supply chains, politics and commercial cost-plus pricing for vaccines. It is possible that these outcomes were the result of some major cognitive biases and the failure of a clinical pharmacologist's voice in the leadership teams. Biases included unawareness of the complexities of taking interesting chemicals in vitro to development into therapeutic use that can be tolerated, show efficacy and have appropriate disposition in humans; lack of a systems approach to therapeutic development; and an understanding of the relevance and translatability of pharmacology, physiology and clinical drug development. We believe that reflecting on and addressing these biases will help Australia reposition itself better with a therapeutics and clinical trial strategy for future pandemics, built into the strategy of a Centre for Disease Control.

Efficacy and safety of cannabidivarin treatment of epilepsy in girls with Rett syndrome: A phase 1 clinical trial.

OBJECTIVE: Rett syndrome (RTT), commonly caused by methyl-CpG-binding protein 2 (MECP2) pathogenic variants, has many comorbidities. Fifty to ninety percent of children with RTT have epilepsy, which is often drug-resistant. Cannabidivarin (CBDV), a non-hallucinogenic phytocannabinoid, has shown benefit in MECP2 animal models. This phase 1 trial assessed the safety and tolerability of CBDV in female children with RTT and drug-resistant epilepsy, as well as the effect on mean monthly seizure frequency (MMSF), the electroencephalogram (EEG), and non-epilepsy comorbid symptoms. METHODS: Five female children with drug-resistant epilepsy and a pathogenic MECP2 variant were enrolled. Baseline clinical and laboratory assessments, including monthly seizure frequency, were recorded. CBDV oral solution (50 mg/ml) was prescribed and titrated to 10 mg/kg/day. Data collected included pharmacokinetics, seizure type and frequency, adverse events, EEG, and responses to the Rett Syndrome Behaviour Questionnaire and Rett Syndrome Symptom Severity Index, and were compared to baseline data. RESULTS: All five children reached the maximum CBDV dose of 10 mg/kg/day and had a reduction in MMSF (median = 79% reduction). Three children had MMSF reduction > 75%. This corresponded to an overall reduction in seizure frequency from 32 to 7.2 seizures per month. Ninety-one percent of adverse events were mild or moderate, and none required drug withdrawal. Sixty-two percent were judged to be unrelated to CBDV. Thirty-one percent of adverse events were identified as possibly related, of which nearly all were mild, and the remainder were later assessed as RTT symptoms. Hypersomnolence and drooling were identified as related to CBDV. No serious adverse events reported were related to CBDV. No significant change was noted in EEG or non-epilepsy-related symptoms of RTT. SIGNIFICANCE: A dose of 10 mg/kg/day of CBDV is safe and well tolerated in a pediatric RTT cohort and suggests improved seizure control in children with MECP2-related RTT.

Expert advice for prescribing cannabis medicines for patients with epilepsy-drawn from the Australian clinical experience.

There is international interest for consensus advice for prescribers working in the field of drug resistant epilepsy intending to trial potential therapies that are nonregistered or off-label. Cannabinoids are one such therapy. In 2017, the New South Wales State Government (Australia) set up a cannabinoid prescribing guidance service for a wide variety of indications, based on known pharmacology together with the relevant new literature as it became available. Increasing interest in cannabis medicines use outside this State over the following 5 years together with a paucity of registration-standard clinical trials, lack of information around dosing issues, drug interactions and biological plausibility meant there remained a large unmet need for such advice. To address the unmet need in epilepsy, and until medicines were registered or regulator quality data were available, it was agreed to bring together a working group comprising paediatric and adult epilepsy specialists, clinical pharmacists., clinical pharmacologists and cannabis researchers from across Australia to develop interim consensus advice for prescribers. Although interim, this consensus advice addresses much of the current practice gap by providing an informed overview of the different cannabis medicines currently available for use in the treatment of epilepsy in paediatric and adult settings, with information on dose, drug interactions, toxicity, type of seizure and frequency of symptom relief. As such it supplements the limited evidence currently available from clinical trials with experience from front-line practice. It is expected that this consensus advice will be updated as new evidence emerges and will provide guidance for a subsequent Guideline.

Evaluation of pharmacogenomics and hepatic nuclear imaging-related covariates by population pharmacokinetic models of irinotecan and its metabolites.

BACKGROUND: Body surface area (BSA)-based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. METHODS: Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. RESULTS: Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. CONCLUSION: The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.

Complementary and alternative therapies in the palliative setting.

Complementary and alternative medicine (CAM) encompasses a wide range of medication, herbal, dietary and physical therapies that are not usually considered within the realm of conventional therapeutics. Approximately two thirds of the Australian population use CAMs and only around half of this number will discuss their use of these products with their doctor. Clinical use is commonly seen in patients with life-limiting illness, often because they experience a high burden of symptoms. However, it is also the case that many of these therapies do not have demonstrated efficacy, particularly for the often broad list of conditions and symptoms for which they are chosen to be used. Further, depending on whether they are sold as medications, sold as food supplements or imported illegally and distributed via nonstandard therapeutic channels, several products have had reports of toxicity, severe adverse effects, batch irregularities and drug interactions with other therapies. This awareness, together with lack of standardisation of products and lack of interchangeability between brands has made prescribers unwilling to put patients at risk of harm by supporting their use. In this article, we cover general pharmacological principles around use of a small selection of chemicals used in a medical setting to enable some guidance for use.

NSW Cannabis Medicines Advisory Service preliminary survey results: enquirer perceptions and patient outcomes.

BACKGROUND: In 2018, an innovative, State government-funded cannabis medicines drug information service was established for health professionals in New South Wales (NSW). The NSW Cannabis Medicines Advisory Service (CMAS) provides expert clinical guidance and support to medical practitioners considering prescribing a cannabis medicine to their patient(s). AIMS: This research examines quality assurance and patient outcomes related to enquirers' experience with NSW CMAS. METHODS: Data collection involved an online, anonymous survey with two components. Following a health professional enquiry, quality assurance data were collected about the enquirers' experience with NSW CMAS. The second survey focussed on patient outcomes and provides real-world observational data about cannabis medicines safety and effectiveness across a wide range of indications. RESULTS: Data collection occurred between January 2020 and June 2021. Preliminary analyses were based on 68 quality assurance and 50 patient outcomes survey responses. General practitioners represented the highest proportion of survey responses (n = 33; 49%). The most common enquiry involved 'patient-specific advice' (n = 50; 74%). Patient-specific information provided by the service was mainly used for prescribing decision support (n = 45; 90%). CONCLUSIONS: Preliminary findings highlight the impact of an innovative cannabis medicines drug information service in supporting health professional clinical practice in an area of rapid knowledge translation. Quality assurance data indicate that the service is perceived well by the majority of enquirers. Patient outcomes data across a wide range of indications suggest some effectiveness and a reasonable safety profile for prescribed cannabis medicines for most patients.

Aboriginal and Torres Strait Islander patients' cancer care pathways in Queensland: Insights from health professionals.

OBJECTIVE: To identify points for improvements within the health system where Aboriginal and Torres Strait Islander cancer patients may experience a lack of continuity in their cancer care. The optimal care pathway for Aboriginal and Torres Strait Islander people with cancer (OCP) framework was utilised as a tool in this work. METHODS: Semi-structured interviews were conducted with health professionals at the primary health care (PHC) and hospital setting. Data were categorised into six steps using the OCP framework. RESULTS: This study identified multiple time-points in the cancer pathways that could be strengthened to increase the continuity of cancer care for these patients. In addition, the provision of person-centred care and adequate education tailored to patients' and health professionals' needs can help minimise the likelihood of patients experiencing a lack of continuity in their cancer care. Participants were recruited from an urban hospital (n = 9) and from six Aboriginal Community Controlled Health Services (n = 17) across geographical locations in Queensland. The provision of culturally competent care, effective communication, coordination and collaboration between services along the cancer pathway from prevention and early diagnosis through to end-of-life care were highlighted as important to enhance care continuity for Indigenous Australians. CONCLUSION: The implementation of recommendations outlined in the OCP framework may help with improving cancer care continuity for Indigenous patients with cancer. SUMMARY: Aboriginal and Torres Strait Islander people can sometimes find cancer care pathways complex and difficult to navigate. This study identified points in the cancer pathways that could be strengthened to increase the continuity of cancer care for these patients which could potentially lead to improved outcomes.

A pharmacological framework for integrating treating the host, drug repurposing and the damage response framework in COVID-19.

With any new disease a framework for the development of preventative or treatment therapeutics is key; the absence of such in COVID-19 has enabled ineffective and potentially unsafe treatments to be taken up by governments and clinicians desperate to have options for patients. As we still have few therapies and nil vaccines yet available, the void of a clear framework for research and practice is increasingly clear. We describe a framework that has been used to prioritise therapeutic research in previous pandemics which could be used to progress clinical pharmacology and therapeutics research in COVID-19. This is particularly relevant as discussion has already moved on from antiviral therapeutics to delineating the treatment of the host from treatment and elimination of the infective agent. Focussing on the host brings together three concepts: host treatment, the damage response framework and therapeutic repurposing. The integration of these three areas plays to the traditional strength of pharmaceuticals in providing a period of stabilization to permit time for the development of novel antiviral drugs and vaccines. In integrating approaches to repurposing, host treatment and damage response we identified three key properties that a potentially effective repurposed drug must possess by way of a framework. There must be homology, i.e., the same or similar relation with the pathogenesis of the disease, ideally targeted to the conserved pathophysiological outcomes of the viral attack; there must be a defined locus within the spectrum to prevention to severe disease and the framework must draw upon the historical dose and safety experience of the repurposed drug. To illustrate, we have mapped therapeutics that impact upon a key dysregulated pathway in COVID-19 - the renin angiotensin system - using this approach. Collectively this type of analysis reveals the importance of existing data (repurposed information and administrative observational data) and the importance of the details of the known pathophysiological response to viruses in approaches to treating the host.

Overcoming barriers to implementing precision dosing with 5-fluorouracil and capecitabine.

Despite advances in targeted cancer therapy, the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine continue to play an important role in oncology. Historically, dosing of these drugs has been based on body surface area. This approach has been demonstrated to be an imprecise way to determine the optimal dose for a patient. Evidence in the literature has demonstrated that precision dosing approaches, such as DPD enzyme activity testing and, in the case of intravenous 5FU, pharmacokinetic-guided dosing, can reduce toxicity and yield better patient outcomes. However, despite the evidence, there has not been uniform adoption of these approaches in the clinical setting. When a drug such as 5FU has been used clinically for many decades, it may be difficult to change clinical practice. With the aim of facilitating change of practice, issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed.

Vancomycin: Audit of American guideline-based intermittent dose administration with focus on overweight patients.

AIMS: Vancomycin dosing and monitoring recommendations are poorly adhered to in many institutions internationally, with concerns of treatment failure and propelling antibiotic resistance. The primary aim of this study was to audit the rate of adherence to American guidelines, with particular interest in loading dose administration. The secondary aims were (i) to determine whether or not guideline adherence results in therapeutic concentrations across body mass index (BMI) groups and (ii) to determine whether or not this was in turn associated with morbidity and hospital mortality. METHOD: Data were collected in a single tertiary hospital on all patients who had two or more serum vancomycin concentrations measured. RESULT: In total, 107 patients met the inclusion criteria. Overall, 38.3% of patients were commenced on guideline adherent vancomycin doses, and 28.3% of overweight patients received an adherent first dose compared to 51.1% of non-overweight people (difference 23%, 95% CI 4% to 41%, P = 0.024). Overweight patients were more frequently underdosed compared to non-overweight patients (P = 0.039). The frequency and proportion of underdosing increased with BMI. Overweight patients spent a smaller fraction of their course within the therapeutic range, although the difference was not statistically significant (difference 7.7%; 95% CI 4% to 19.4%; P = 0.195). The overweight group had longer hospital length of stay (LOS), higher mortality and more treatment failures. CONCLUSION: Adherence to guideline-based prescription is poor, particularly in overweight patients. Patients who are initially underdosed have fewer therapeutic vancomycin days, regardless of BMI. Overweight patients have increased hospital LOS, hospital mortality and treatment failure.

Using Therapeutic Drug Monitoring and Pharmacovigilance to Overcome Some of the Challenges of Developing Medicinal Cannabis from Botanical Origins.

PURPOSE: Plants belonging to the genus Cannabis have been domesticated and used by humans for millennia. Thought to have originated from central Asia, cannabis has been harnessed for its nutritional, therapeutic, and psychoactive properties, and as a source of fiber (Office of Medicinal Cannabis. Analytical Monograph Cannabis Flos. Den Haag, The Netherlands: Office of Medicinal Cannabis; 2014). Human use of cannabis is not novel; however, its medicalization offers a new pharmacotherapeutic frontier. METHODS: The authors recently reported a systematic review of the contaminants of cannabis (National Academies of Sciences Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC; 2017). This article draws on the research limitations identified by that review and examines a collection of the relevant literature to provide an appreciation of the current evidence base. RESULTS: The review explores the current status of cannabis in medical use, the drug development aspects that apply when taking a plant through to pill development, and the roles that therapeutic drug monitoring and pharmacovigilance have to guide practice until the drug development information on medicinal cannabis preparations is complete. CONCLUSIONS: A surge of public and clinical interest in the possible therapeutic applications of constituent cannabinoids has potentiated global legislative and policy reform. However, our understanding of its properties, optimized use, and harmful effects remains incomplete (Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in Australia In: Department of Health Department, editor. Woden ACT Australian Government 2017; Dryburgh LM, Bolan NS, Grof CP, Galettis P, Schneider J, Lucas CJ, et al. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. Brit J Clin Pharm. 2018;84(11):2468-2476). In particular, a comprehensive appreciation of its toxicity profile is lacking.

Translational hurdles with cannabis medicines.

PURPOSE: Internationally, there has been widespread medical use of cannabis medicines before rigorous evaluations in randomised controlled trials (RCTs). Some advocates of medicinal use of cannabis argue that real-world evidence (RWE) can be a substitute for or at least supplement evidence from RCTs. We explore the utility, limitations and impact of RWE in the translation of cannabis medicines research into clinical practice using the established literature. METHODS: A literature search was performed via Embase and Medline using a diverse range of cannabinoid and RWE search terms. The review provides a snapshot of cannabis medicine RWE initiatives from around the world. RESULTS: Diverse and novel sources of real-world data and RWE include international cannabis registries, surveys, post-marketing data collection and use of electronic or digital health records. The strengths and limitations of using RWE in translational research are highlighted, along with the identification of barriers to RCTs involving cannabis medicines. CONCLUSIONS: RWE promises to play a significant role in the evaluation of cannabis medicines around the world. When used appropriately RWE may complement RCT data by providing valuable insights into cannabis medicine safety and effectiveness. TAKE HOME MESSAGES: It is important that real-world evidence (RWE) is used to complement rather than replace randomised controlled trial (RCT) evidence on cannabis medicines. Technological advances have created the opportunity to explore diverse and novel sources of cannabis medicine RWE. Although RWE may be more reflective of real-world clinical practice, it cannot provide conclusive evidence of the safety and efficacy of cannabis medicines. While acknowledging its limitations, RWE may nonetheless provide some guidance on safety and adverse events of cannabis medicines. RWE has already had a significant impact on the regulation of cannabis medicines.

Model-based analysis on systemic availability of co-administered cannabinoids after controlled vaporised administration.

BACKGROUND: The most important two medicinal cannabinoids are Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Vaporised administration is superior due to its higher systemic availability, lower individual variability and faster drug delivery. Although it is common THC is co-administered with CBD, the influence of CBD on the pharmacokinetics, especially the systemic availability of THC after vaporised administration, is unknown. AIMS: To investigate the influence of different doses of co-administered CBD on the systemic availability of THC, and to compare the availability of THC and CBD in a sample of frequent and infrequent cannabis users. METHODS: The study used a randomised, double-blind, crossover placebo-controlled design. THC and/or CBD in ethanol was vaporised and inhaled. Plasma concentrations of THC and CBD were analysed. The THC data created in this study were pooled together with published THC pharmacokinetic data in order to cover all the phases of THC disposition. Population pharmacokinetic model of THC was developed based on the pooled data. The model of CBD was developed based on the data created in this study. RESULTS: Population pharmacokinetic models of THC and CBD were developed. With concomitant inhalation of high-dose CBD, the systemic availability of THC decreased significantly. Frequent cannabis users appeared to have higher systemic availability of THC and CBD when high-dose CBD was administered. CONCLUSIONS: The results observed in this study are useful for guiding future pharmacokinetic studies of medicinal cannabinoids, and for development of dosing guidelines for medical use of cannabis in the 'real-world' setting.

Effectiveness of patient-oriented education and medication management intervention in people with decompensated cirrhosis.

People with chronic disease often have poor comprehension of their disease and medications, which can negatively affect health outcomes. In a randomised-controlled trial, we found that patients with decompensated cirrhosis who received a pharmacist-led, patient-oriented education and medication management intervention (n = 57) had greater knowledge of cirrhosis and key self-care tasks compared with usual care (n = 59). Intervention patients also experienced improved quality of life. Dedicated resources are needed to support implementation of evidence-based measures at local centres to improve outcomes.

Vancomycin therapeutic drug monitoring in paediatrics.

AIM: Vancomycin guidelines for therapeutic drug monitoring (TDM) aim to maximise efficacy while minimising toxicity and resistance. Vancomycin is effective against Staphylococcus aureus when it achieves area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) > 400. Studies in children have shown that target trough concentrations poorly correlate to AUC/MIC > 400; however, they are used in practice for clinical convenience. This review in paediatric inpatients aims to audit performance against TDM guidelines and consider what changes are needed to optimise vancomycin monitoring. METHODS: Vancomycin prescriptions in patients younger than 18 years old were collected over a 15-month period. Primary outcome measures were vancomycin initial dose (mg/kg/day) and the timing and result of first trough concentration (mg/L). Secondary outcome measures were the numbers achieving recommended targets and whether appropriate dose adjustments were made in response to TDM. RESULTS: A total of 133 courses reached the time when TDM should occur. Average patient age was 6.5 years, and the average initial dose was 52.55 mg/kg/day (range 19.05-86.54 mg/kg). Only 25% of courses (n = 34) had a trough concentration measured at the recommended time. The mean trough concentration was 11.6 mg/L (range < 2.0-39.7). Of 40 patients with a low trough concentration, 50% continued without dose adjustment. CONCLUSION: As shown in the literature, there is a poor correlation between the vancomycin dose given and the trough concentration achieved. Given that recommendations for trough concentration monitoring are designed to simplify the process yet are poorly adhered to, a strategic plan to address these issues is needed.

The rationale of dose-response curves in selecting cancer drug dosing.

Drug development for cancer chemotherapy has an interesting history. A mix of serendipity, animal, cell line, and standard pharmacological principles of dose, dose-response, dose-concentration, dose intensity and combination therapies have been used to develop optimal dosing schedules. However in practice, significant gaps in the translation of preclinical to clinical dosing schedules persist, and clinical development has instead moved to new drug development. A older chemotherapies are still the backbone of most solid tumour schedules, therapeutic drug monitoring has emerged as a method for optimising the dose for individual patients.

Optimising low-dose methotrexate for rheumatoid arthritis-A review.

Methotrexate at low doses (5-25 mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intrapatient variability in response, with contribution of variability in concentrations of active polyglutamate metabolites, associated with clinical efficacy and toxicity. Prescribing remains heterogeneous across population groups, disease states and regimens. This review examines current knowledge of dose-response of oral methotrexate in the setting of rheumatoid arthritis, and how this could help inform dosage regimens.