In the context of the current COVID-19 pandemic, what are the lessons clinical pharmacology could learn to improve our teaching practice and involvement in research and ethics committees to make sure we are better prepared for the next emergency. Is there something in the light of the hydroxychloroquine hype that we as clinical pharmacologists or our professional societies could have done better? We propose updating the way we teach about drug development, rules and ethics of off-label prescribing and critical appraisal of primary sources when guidelines and top-level evidence are not available. Clinical pharmacology should play a leading role in the future re-definition of processes and guidelines for emergencies such as the one we faced in 2020.
Dear editor,Given time, drug discovery programmes will undoubtedly yield highly potent drugs to form the basis of optimised COVID-19 regimens. However, if efficacious therapies can be identified from current medicines, repurposing represents the fastest route to establish deployable interventions and buy time for vaccine and novel drug development. It is important to note that effective medicines were rigorously optimised for the treatment of specific indications. Route of administration, dosage and schedules for existing therapies were optimised to provide adequate plasma/tissue pharmacokinetics and safety for their target disease or condition. These cannot be assumed to be optimal for COVID-19 but are often highly predictable from pre-existing data and clinical experience. For example, hydroxychloroquine and lopinavir/ritonavir recently failed to deliver benefits in RCTs for mild/moderate and severe disease,1, 2 but the clear disconnect between reportedin vitro antiviral activity and known human pharmacokinetics after administration of approved doses was predictable.3Interpretation of laboratory-based antiviral activity assessments is complicated by current uncertainty regarding the appropriateness of the existing model systems. The majority of in vitro antiviral screening assays have utilised Vero cells, which were derived from the kidney of African Green Monkey in the 1970s, and the lack of clinical evidence for which to validate the exposure-response relationship in humans is problematic. Evidence is emerging that the anti-SARS-CoV-2 activity of drugs may be higher in cells derived from humans. However, the question of which cell types are most representative of in vivo performance is yet to be addressed, and all that can really be concluded from current knowledge is that the susceptibility of SARS-CoV-2 to antivirals is cell-type-dependent. The consequences of this in terms of the variety of cell types known to be infected and/or sustain productive infection in vivo is equally uncertain, and further exacerbated by the lack of robustly validated animal models. However, repurposed drugs cannot be assumed to be active against SARS-CoV-2 at a dose that was optimised on the basis of potency for and accumulation at their initial therapeutic target.Nucleoside/nucleotide polymerase inhibitors have proven highly successful for other viruses, but usually require combination with another drug class. Remdesivir and favipiravir have in vitro anti-SARS-CoV-2 activity across multiple studies, and the unprecedented speed at which they have transitioned through COVID-19 RCTs can only be commended.4, 5, 6 Daily IV infusion may make inherent sense for severely ill patients, but a transformational impact for COVID-19 can only be realised if wide compatibility with global healthcare systems and equitable access across all country contexts is achieved. While reduction in symptom duration may mitigate healthcare saturation in high-income countries, the absence of a clear benefit for mortality diminishes game-changing potential. However, the clinical validation of the antiviral activity of such drugs will make them clear candidates for implementation as part of community-based interventions if other challenges are addressed. Importantly, the combination of nucleoside analogues with a secondary target such as the protease has stood the test of time in antiviral pharmacology. The recent reports of low-dose dexamethasone leading to an impact on mortality7 is a significant step forward but long-term mitigation of viral transmission, with subsequent economic and social restrictions, requires antiviral treatment or prevention to minimise hospitalisation through a community-targeted approach.Focussing on existing single drugs, and not appropriately formulated medicines, will require the rethinking of a number of medicine development parameters such as posology, reformulation and therapeutic index (Figure 1); current HIV medicines, for example, are formulated for chronic (life-long) dosing to moderate and control disease but a successful COVID-19 therapy will likely require only a short term acute administration to rapidly cure the patient. Conversely, different considerations are required for longer-term applications in COVID-19 chemoprophylaxis, which could have a dramatic effect on control of the pandemic.Many advanced drug delivery technologies have emerged in recent years. Long-acting drug delivery involving injectable, implantable or microarray patch mediated delivery have attracted enormous recent interest for prevention of other infectious diseases,8, 9 and the ability to deliver potent antiviral combinations for a period of months could play a transformational role in the absence of a safe and efficacious vaccine. The physicochemistry and activity of the polymerase inhibitors, and other drugs with known anti SARS-Cov-2 activity, also warrants investigation of pulmonary delivery via nebuliser or metered dose inhaler for direct dosing to the upper airways to supplement systemic drug delivery as pre- or post-exposure prophylaxis. Several advanced drug delivery strategies can be applied rapidly and do not need to be prohibitively expensive for global community programmes. It seems unlikely that a global pandemic can be ended if effective medicines are only available to the few and equitable access is therefore of benefit to all. Importantly, relying solely upon pre-existing formulations and posologies optimised for other diseases carries inherent risk of rejecting drug candidates with an otherwise high potential for global impact.
Understanding of the term ‘Precision Medicine’ is variable. For clinicians, pharmacists and clinical pharmacologists, it refers to the right decision (treat or not), right drug, right combination, right timing and right dose, taking into account the clinical trial data for the patient group being treated, and finessing that to the individual biological and pharmacological variables either evident, or likely to be evident based on knowledge about comorbidity and body size.To scientists, precision medicine can mean either developing a new molecule to fit a specific target or cell of interest, or ‘finding’ based on mathematical and chemical profiling existing drugs that might ‘fit’ the target of interest (1). However, this focus on ‘targets’ as the method to improve precision has seemingly ignored the well-known principles of radiobiology, cancer biology and pharmacology, and has not delivered the improved health outcomes expected (2). Similarly, since 2015, U.S. and other government’s multi-billion-dollar investments into ‘precision’ drugs “delivering the right treatments, at the right time, every time to the right person whilst helpful to understand some aspects of disease pathophysiology, has also fueled this single target focus (3).In this Themed issue discussion on aspects of science and medicine people refer to as precision medicine approach are covered. Although varied, much discussion is related to the importance of understanding the way each individual both handles and responds to a drug, and specific dose. How to implement individualized dosing into practice however can be an even more challenging area, with different levels of precision costing different amounts, with a spectrum of clinical and economic benefits.Added to this difficulty is the systematizing of regimen and dose for specific cancers which have come into oncology practice over the last few years. Moynihan et al argue that the financial dependence of research on industry funding creates a “sponsorship bias” that overplays efficacy and underplays toxicity. This was confirmed in a systematic review comparing industry sponsored with independently funded trials (4).This is not just an issue with interpretation of results but goes back to trial design. The choice of a comparator may make the outcome of the study drug more favorable (4). Over the years in cancer trials, there has certainly been a move from the principle of treating until maximum response and then allowing a patient time without symptoms or side effects of treatment to studies which are designed to continue treatment until relapse or unacceptable toxicity. This maximizes drug use but is there evidence that prolonging use of a drug maximizes outcomes?Maintenance strategies in metastatic disease can be simply continuing the drug used in induction or switching to another drug, which really can be considered as early second line treatment (5). Although established in lymphomas, randomized studies of continuous maintenance therapy in non-small cell lung cancer (NSCLC) led to no improvement in response or survival and similarly for survival in colorectal cancer (5,6). Prolonging first line therapy in breast cancer only showed a marginal survival benefit. There are ongoing studies, but prolonging induction therapy lacks the evidence for widespread adoption. Switching to another drug or targeted therapy, as an early second line treatment, has shown prolonged survival over induction alone in several tumour types (5).The duration of targeted therapies provides examples of how trial design influences practice. The initial studies of trastuzumab in adjuvant breast cancer initially reported at the American Society of Clinical Oncology in 2005 were designed to give 12 months of therapy and that became the standard of care (7). An ongoing study at the time was comparing 12 months with 24 months. (8). However, an independent French group looked at 6 months compared to 12 months and it is only in 2019 that the final analysis could not show non-inferiority of 6 months of treatment (9). Meanwhile the FinHER study in Finland showed the efficacy and cost-effectiveness of only 9 weeks of adjuvant trastuzumab after chemotherapy (10, 11).In terms of the dose given, the current common method of dosing cytotoxic drugs is based on a patient’s body surface area (BSA). This can be inaccurate with considerable variation between patients because patient-related factors such as organ function, age, gender, activity of metabolizing enzymes, drug resistance and concomitant drugs can influence the pharmacokinetics and pharmacodynamics (12). This gives rise to pharmacologically-based dosing being explored to make individual patient dosing more precise.The first step, however, in the treatment of cancer is to select the drug or drugs most likely to be effective. In the era of precision medicine what is being investigated is identifying mutations in genes or changes in the expression of genes or proteins specific to a tumour, which can be targeted by therapeutics (13). Detecting multiple genomic changes has been made possible by technological advances like next generation sequencing (NGS) replacing older single gene testing. Use multiple platforms combining sequencing of DNA with RNA sequencing and with the more established techniques such as immunohistochemistry (IHC) maximizes the potential to discover druggable targets (14). IHC detects changes at the protein level that reflect gene amplifications such as HER-2 in breast cancer, gastric and colorectal cancer which can be targeted with trastuzumab. Rearrangements include EML4-ALK translocation in non-small cell lung cancer which can be targeted by drugs such as crizotinib. Now there is testing for biomarkers related to PD-L1 expression in various tumours which can be targeted by checkpoint inhibitors such as atezolizumab.Molecular profiling which allows matching treatments for cancers to their targets has resulted in a boost for new drug development in rare cancers by using drugs targeted to molecular biomarkers that they have in common with more common cancers, in basket trials (15).Limitations of gene expression profiling and IHC can be illustrated in diffuse large B-cell lymphoma (DLBCL) as summarized by Ofori et al in this issue of the Journal (16). Its subtypes defined by the cell of origin can predict survival and response to chemotherapy, and were initially classified by gene expression profiling. However, fresh tissue had to be available and often only major centers had the capability. IHC methods were subject to observer error. The other issue was that serial tumour profiling during treatment may be able to detect emerging resistance but serial biopsies may not be feasible and surveillance post treatment was only available by imaging, which has not been shown to be associated with a survival benefit.Liquid biopsies have the potential for solving these issues. Biomarkers in blood or other body fluids can be identified, including from circulating tumour DNA (ctDNA), circulating tumour cells (CTC) or exosomes. Circulating tumour DNA fragments are shed from tumour cells and show mutations and methylation profiles of the tumour which could be used to identify targets or predict recurrence in tumours such as DLBCL (17).Circulating tumour cells are derived from primary tumours or their metastases and either actively or passively enter the circulation. Their DNA, RNA and proteins could be used to discover the molecular profile of the tumour and their numbers can correlate with treatment outcome (16). De Souza et al have identified technological and interpretive challenges to overcome before CTCs are used routinely in the clinic (18).Exosomes, formed when a cell membrane buds off with contents including protein, nucleic acids, sugars and lipids are taken up by other cells and represent communication between cells. They can circulate in many body fluids. The potential advantage of exomes is their abundance in the fluids and their contents that may reveal multiple biomarkers which in a disease such as DLBCL could be used to subtype and therefore predict prognosis, be used as surveillance during therapy and reveal resistance mechanisms. They could then be used to follow-up post treatment (16).A further tool to guide dosing of anti-cancer drugs and predicting toxicity and response prior to their administration is pharmacogenomics reviewed by Carr et al (19). Examples with the strongest evidence are assaying for dihydropyrimidine dehydrogenase (DPYD) which is the rate limiting enzyme for 5-FU metabolism, encoded by a gene with multiple variants. Identifying the variant alleles of thiopurine methyltransferase (TMPT) can identify a low activity genotype which metabolizes 6-mercaptopurine to an inactive mercaptopurine resulting in less metabolism of 6-MP to toxic thioguanine nucleotide metabolites. There are many other potential applications of pharmacogenomics, but with equivocal or less evidence. The more widespread use of NGS will allow easier identification of rarer mutations associated with adverse drug reactions. The lack of routine use of pharmacogenomics is multifactorial including the expense, accessibility, the time for processing and the complex interactions including between genomics, clinical factors and the microbiome which account for the individual variations (19).Personalised drug dosing is important in oncology to prevent overdosing, which otherwise may only become evident when a patient develops severe side effects, or underdosing resulting in lack of efficacy, which may not be revealed until scans show a lack of tumour response . The evidence for some drugs that drug exposure is related to efficacy and toxicity allows for therapeutic dose monitoring (TDM) such as is used for dosing antimicrobials. Some examples of attempting TDM with cytotoxics illustrate the challenges.For intravenous 5-FU while DPYD genotyping is useful, more precision is needed for bolus and infusional regimens in a variety of cancers, including head and neck and colorectal cancer. In articulating the importance of TDM dosing Schneider JJ et al. in this themed issue, reiterate that 5-FU dosing by BSA only results in 20-30% patients achieving the therapeutic range. Exploring the relationship between 5-FU area under the curve (AUC) and a target dose resulted in the recommendation of a therapeutic exposure range of 20-30mgh/L for 46-hour infusion schedules (20). Unfortunately, data is lacking to apply TDM dosing to the oral prodrug capecitabine, which is just as effective as 5-FU but better tolerated.Other common cytotoxic drugs are more problematic. Muth et al reviewed the taxanes; paclitaxel, docetaxel, nab-paclitaxel and cabazitaxel which illustrate some of the complexities of TDM dosing (21). Paclitaxel which is commonly dosed weekly or 3 weekly has non-linear pharmacokinetics, undergoes hepatic metabolism and biliary excretion and there are interactions with its solvent cremophor, however the time above a plasma concentration of 0.05 µmol/L does predict neutropenia and polyneuropathy and may be associated with a favourable clinical outcome, making TDM dosing desirable. Docetaxel, is also extensively metabolised in the liver, has linear kinetics, but is formulated with polysorbate 80 rather than cremophor. Weekly docetaxel has a more favourable toxicity profile that 3-weekly dosing but it is AUC that predicts febrile neutropenia, mucositis and diarrhoea. Less research has been done than with paclitaxel but a small randomized study of TDM and target concentration intervention (TCI) compared to BSA didn’t show a clear advantage for TDM and TCI for docetaxel (22). Unfortunately, is no prospective TDM data for carbazitaxel or nab-paclitaxel.Early in the development of carboplatin the relationship between drug exposure and efficacy and toxicity was established and dosing was more accurately based on renal function (glomerular filtration rate- GFR) than BSA. However, for specific groups such as infants, anephric patients and those receiving high-dose carboplatin, TDM dosing is more desirable that dosing based on (GFR) as summarized by Barnett S et al (23).For TDM to be translated into clinical practice, the evidence base must expand, and sampling strategies need to be simplified, perhaps by micro sampling such as using dried blood spots or using body fluids other than blood. There must be better access to TDM laboratories, and the provision of clinical decision support for interpreting the results of pharmacometrics which use Bayesian estimations to combine pharmacokinetics, individual patient characteristics and drug concentrations (24).Finally, a barrier which must be addressed to allow clinical translation of TDM is the demonstration of its economic efficacy which Vithanachchi DT et al present in a descriptive review (25). They reviewed 11 studies and noted that only a few drugs have been studied. However, all studies reviewed found TDM to be cost effective, based on established incremental cost-effectiveness ratios. In future newer therapeutics should have an economic analysis of TDM, incorporating the associated clinical evidence, which in the short term is reduced toxicity and the long term, a survival advantage.REFERENCES1. Martin JH, Bowden NA. Drug Repurposing – Overcoming the translational hurdles to clinical use. Pharmacol Res Perspect 2019, Nov 26, https://doi.org/10.1002/prp2.548.2. Fay M, Head R, Martin J. Where is the radiobiology and pharmacology research to improve outcomes on glioblastoma? J Neurooncol 2015, 124: 1-3.3. Obama B. The Precision Medicine Inititive https://obamawhitehouse.archives.gov/precision-medicine [Last Accessed 11 Dec 2020]4. Moynihan R, Beros L, Hill S et al. Pathways to independence: towards producing and using trustworthy evidence. BMJ 2019, Dec 3; 367:16576. Doi: 10.1136/bmj.e3502.5. Rowinski E, Fournel P, Bernichon E, Bouleftour W, Magné N, Mery B. Maintenance therapy in metastatic solid tumours. Innovative strategy or simply second-line treatment? Am J Clin Oncol 2019, 42: 615-623.6. von Plessen C, Bergman B, Anderson O et al. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.Br J Cancer 2006, 95: 966-9737. Perez EA, Romond EH, Suman VJ et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011, 29: 3366-3372.8. Cameron D, Piccart-Gebhart MJ, Gelber RD et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-postive early breast cancer: final analysis of the HERceptin Adjuvant (HERA trial. Lancet 2017, 389: 1195-1205.9. Pivot X, Romieu G, Debled M et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicenter, open-label, phase 3 randomized trial. Lancet 2019, 393: 2591-2598.10. Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl JK Med 2006, 354: 809-820.11. Purmonen TT, Pänkäläinen E,Turunen JH, Asseburg C, Martikainen JA. Short-course adjuvant trastuzumab therapy in early stage breast cancer in Finland: cost-effectiveness and value of information analysis based on the 5-year follow-up results of the FinHer trial. Ann Oncol 2011, 50: 344-352.12. Kaestner SA, Sewell GJ. Chemotherapy dosing part I: scientific basis for current practice and use of body surface are. Clin Oncol (R Coll Radiol) 2007, 19: 23-37.13. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med 2020 12:8 https://doi.org/10.1186/s13073-019-0703-1. [Last accessed Jun 10 2020].14. Zimmer K, Kochner F, Spizzo G, Salem M, Gastl G, Seeber A. Treatment according to molecular profiling in relapsed/refractory cancer patients: a review focusing on latest profiling studies. Comput Struct Biotechnol J 2019, 17: 447-453.15. Wang S, Chen R, Tang Y et al. Comprehensive genomic profiling of rare tumour: routes to targeted therapies. Front Oncol 2020, https://doi.org/10.3389/fonc.2020.00536 [Last accessed 10 Jun 2020]16 Ofori K, Bhagat G, Rai A. Exosomes as liquid biopsy biomarkers in diffuse large B-cell lymphoma (DLBCL) – Current. State-of-the -art and unmet needs. Br J Clin Pharmacol 2020, X: XX-XX17. Roschewski M, Dunleavy K, Pittluga S et al. Circulating DNA and CT monitoring in 124 patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 2015, 16: 541-549.18. De Souza P, Po J, Scott K et al. Can on study changes in circulating tumour cell (CTC) counts be used as a predictive measure for therapeutic efficacy in caner clinical trials? A review of the literature. Br J Clin Pharmacol 2020, X: XX-XX.19 Carr DF, Turner RM, Pirmohamed M et al. Pharmacogenomics of anticancer drugs: personalising the choice and dose to manage drug response. Br J Clin Pharmacol 2020, XX: XX-XX.20. Schneider J, Galettis P, Martin J. Overcoming barriers to implementing precision dosing with 5-Fluorouracil and capecitabine. Br J Clin Pharmacol 2020, X:XX-XX.21 Muth M, Ojara FW, Joerger M. Role of TDM-based dose adjustments for major taxane anticancer drugs. Br J Clin Pharmacol 2020, X: XX-XX.22. Engel FK, Loos WJ, van der Bol JM et al. Therapeutic drug monitoring for the individualization of docetaxel dosing: a randomised pharmacokinetic study. Clin Cancer Res 2011, 17: 353-362.23 Barnett S, Kong J, Makin G, Veal GJ. Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom. Br J Clin Pharmacol 2020, X: XX-XX.24 Menz BD,, Stocker SL, Verougstraete N et al. Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology. Br J Clin Pharmacol 2020, X: XX-XX.25. Vithanachchi D, Maujean A, Downes MJ, Scuffham P. A systematic review of economic evaluations of therapeutic drug monitoring interventions for cancer treatments. Br J Clin Pharm 2020, X: XX-XX.
Clinicians, patients, administrators and researchers have become increasingly frustrated by the lack of indication (i.e. problem) information included in prescriptions, despite the obvious benefit this would provide to patients and other healthcare providers . Medication indications are not routinely documented by prescribers, both in inpatient and outpatient settings.[2, 3] Calls have been made to introduce a sixth ‘right’ into the medication management process, whereby the right patient is given the right drug and dose at the right time via the right route for the right indication . Indications-based prescribing has recently gained traction as a potential way forward to facilitate indication documentation [4, 5]. Indications-based prescribing, not currently supported by most electronic prescribing systems (EPSs), describes the scenario where prescribers initially select an indication, not a medication, and the EPS presents the user with suggested medications for addressing the problem. There are clear advantages with this approach, including those associated with guided prescribing (e.g. more appropriate drug selections) and with indication documentation (e.g. improved communication between providers), prompting work to begin on developing EPS functionality in the US to support indications-based prescribing. In a recent usability evaluation of a prototype of this functionality, indications-based prescribing was more efficient to use, resulted in fewer medication errors and in higher usability scores than the traditional EPS functionality .
Aims In light of the recent safety concerns relating to NSAID use in COVID-19, we sought to evaluate cardiovascular and respiratory complications in patients taking NSAIDs during acute lower respiratory tract infections. Methods We carried out a systematic review and meta-analysis of randomised controlled trials and observational studies. Studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections, were included. Primary outcome was all-cause mortality. Secondary outcomes were cardiovascular, renal and respiratory complications. Results In total, eight studies including two randomised controlled trials, three retrospective and three prospective observational studies enrolling 44140 patients were included. Five of the studies were in patients with pneumonia, two in patients with Influenza, and one in patients with acute bronchitis. There was uncertainty as to the effects on mortality (RR 0.87 [0.63, 1.18]), but pleuro-pulmonary complications were more common with NSAID use (RR 2.62 [1.96, 3.50]). However, all studies exhibited high risks of bias, primarily due to lack of adjustment for confounding variables. Cardiovascular outcomes were not reported by any of the included studies. Conclusion Short-term NSAID use during acute lower respiratory tract infections was associated with more pleuro-pulmonary complications although this may be due to confounding by indication. There remains significant uncertainty on the effects on mortality. Such results should be interpreted cautiously given the very low quality of evidence. Mechanistic and clinical studies addressing the captioned subject are urgently needed, especially in relation to COVID-19.
Aim: We hypothesize that the efficacy of COVID-19 therapeutic candidates will be better predicted by understanding their effects at various points on a viral cell cycle, in particular, the specific rate constants, and that drugs acting independently of these specific discrete sites may not yield expected efficacy. We hypothesize that drugs, or combinations of drugs that act at specific multiple sites on the viral life cycle have the highest probability of success in the treatment of early infection phase in COVID-19 patients. Methods: Using a target cell limited model structure that had been used to characterize viral load dynamics from COVID-19 patients, we performed simulations to show that combinations of therapeutics targeting specific rate constants have greater probability of efficacy and supportive rationale for clinical trial evaluation. Results: Based on the known kinetics of the SARS-CoV-2 life cycle, we rank ordered potential targeted approaches involving repurposed, low-potency agents. We suggest that targeting multiple points central to viral replication within infected host cells or release from those cells is a viable strategy for reducing both viral load and host cell infection. In addition, we observed that the time-window opportunity for a therapeutic intervention to effect duration of viral shedding exceeds the effect on sparing epithelial cells from infection or impact on viral load AUC. Furthermore, the impact on reduction on duration of shedding may extend further in patients who exhibit a prolonged shedder phenotype. Conclusions: Our work highlights the use of model-informed tools to better rationalize effective treatments for COVID-19.
Background Medication harm has negative clinical and economic consequences, contributing to hospitalisation, morbidity and mortality. The incidence ranges from four to 14%, of which up to 50% of events may be preventable. A predictive model for identifying high-risk inpatients can guide a timely and systematic approach to prioritisation. Aim To develop and internally validate a risk prediction model, for prioritisation of hospitalised patients, at risk of medication harm. Methods A retrospective cohort study was conducted in general medical and geriatric specialties at an Australian hospital, over six months. Medication harm was identified using International Classification of Disease (ICD-10) codes and the hospital’s incident database. Sixty-eight variables, including medications and laboratory results, were extracted from the hospital’s databases. Multivariable logistic regression was used to develop the final risk model. Performance was evaluated using area under the receiver operative characteristic curve (AuROC) and clinical utility was determined using decision curve analysis. Results The study cohort included 1982 patients median age 74 years, of which 136 (7%) experienced ≥1 adverse medication event(s). The model included: length of stay, hospital re-admission within 12 months, venous or arterial thrombosis &/or embolism, ≥ 8 medications, serum sodium < 126 mmol/L, INR > 3, anti-psychotic, antiarrhythmic and immunosuppressant medications, and history of medication allergy. Validation gave an AuROC of 0.70 (95% CI: 0.65-0.74). Decision curve analysis identified that the AIME may be clinically useful to help guide decision making in practice. Conclusion We have developed a risk prediction model with reasonable performance. Future steps include external validation.
Problematic polypharmacy is a growing challenge. Medication that is intended to improve patients’ health and wellbeing is instead becoming part of the problem. The way we practice medicine has become one of the drivers for the problems. Dealing with the challenge will need us to think differently about how we do clinical care. A 2013 Kings Fund report stated that tackling problematic polypharmacy requires us to actively build a principle of ‘compromise’ in to the way we use medicines. There are implications for how we consult and make decisions with patients, in how we design health practice and systems to support that decision making, and in our understanding of the process of research – how we generate the knowledge that informs practice. This review considers the current state of play in all three areas and identifies some of the work still need to do in order to generate the practice-based evidence needed to tackle this most challenging problem. Finding a way to redesign practice to address problematic polypharmacy could offer a template for tackling other related complex issues facing medical practice such as multimorbidity, chronic pain and complex mental health.
Diffuse Large B-Cell Lymphoma is the most common type of Non-Hodgkin’s Lymphoma. The disease exhibits significant clinical and biologic heterogeneity. Treatment with standard first line therapy results in cure in about 60% of patients while 30-40%of patients either are refractory to therapy or relapse. Current prognostic scores and biomarkers are unable to accurately predict patients who would relapse or would have refractory disease. A part of the heterogeneity in the behavior of DLBCL is explained by the cell of origin of the tumor. Germinal center type (GCB) DLBCL which is derived from centroblasts are associated with better prognosis compared with activated B-cell type (ABC), which is derived from a B-cell committed to secretory differentiation. While the gold standard for cell of origin determination is gene expression profiling, immunohistochemical methods are routinely used because of more readily available fixed tissue and expertise. Immunohistochemical methods are however associated with a significant degree of discordance with GEP. Within the ABC and GCB types of DLBCL, subgroups of prognostic significance have been identified using various multiple approaches which do not inure themselves to routine practice partly because of limitation of diagnostic material or expertise. Exosomes are a class of membrane bound extracellular vesicles of endosomal origin, produced by multiple cell types. They are involved in intercellular communication and present in abundance in various bodily fluids. Exosomal cargo which includes nucleic acids and proteins can be analyzed, yielding diagnostic and prognostic information in management of DLBCL.
Aim To assess clinical outcomes and adverse drug events in patients hospitalised with COVID -19 treated with off- label hydroxychloroquine and azithromycin. Methods We performed a retrospective analysis of hospitalised COVID-19+ patients who received hydroxychloroquine plus azithromycin over a 2 week period. The primary end point was clinical improvement on day 7 defined as either hospital discharge or an improvement of two points on a six-category ordinal scale. Secondary outcomes evaluated included mortality at day 28, ICU admission, requirement for mechanical ventilation and incidence of adverse drug events. Results Data from a total of 82 patients with laboratory confirmed SARS-CoV-2 infection was evaluated. Clinical improvement was seen in 26.8% of patients at Day 7. 31% of patients were admitted to ICU, 16 (19.5%) underwent mechanical ventilation and Day 28 mortality was 28%. Age over 70, history of cardiovascular disease and 3 or more comorbidities were risk factors for mortality. The incidence of adverse drug events was 42%. No patient experienced a Grade 4 or 5 toxicity. Over a fifth of patients (23) had raised LFTs (65% had raised LFTs at baseline), 11 patients experienced prolonged QT and 1 patient experienced grade 1 hypoglycaemia. Treatment was stopped early in 6(7.3%) patients due to prolonged QT interval or LFT elevations. Conclusion This descriptive study details the clinical outcomes of COVID-19 positive patients treated with these agents and highlights the importance of monitoring all repurposed agents for adverse drug events.
Aims The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the non-clinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the non-clinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013-2018 to identify the approach followed for non-clinical development of these products. Methods The purpose of the in vivo studies was designated to be (a combination of) pharmacology/proof-of-concept, safety, biodistribution and/or tumourigenicity. For biodistribution and tumourigenicity also the need for, type and design of in vitro and in vivo studies were recorded. Results In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) or tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for six (out of 86) products, which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. In vivo tumourigenicity studies were regarded of limited value. Conclusions Compared to more conventional medicinal products, the non-clinical development program for cell-based products was more tailored and focussing on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.
Background Adverse drug reactions (ADRs) constitute major clinical burden of public health concern. Intensive adverse drug reactions monitoring in hospitals, though advocated are rare. Aims Intensive monitoring of medical patients for ADRs to assess incidence, risk factors and fatality of ADRs leading to hospital admission or occurring in the hospital. Research design and methods Prospective cohort study on 1280 adult patients admitted to the six medical wards of a tertiary institution over a 12-month period. Patients were assessed for ADRs during and throughout admission. Causality assessment and preventability of ADRs were assessed. Results Sixty-seven (5.2%) patients had ADRs, which was the cause of admission in 46 (3.6%), and majority 61(91%) of the ADRs were preventable. NSAIDs, 14 (20.3%), antidiabetics, 12 (17.4%) and antibacterial, 11 (15.8%) were the most suspected drugs. Gastrointestinal tract (37%), CNS (30.2%), and skin (24.7%) were the most affected organ/systems, while upper GI bleeding and hypoglycaemia were the most observed ADRs. ADRs led to deaths in 7(10.4%) patients, with overall case fatality rate of 0.5%. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis 3/7(42.9%) had the highest fatality rate. Risk factors, relative risk, 95% confidence interval for ADRs were alcohol intake, 1.7 (1.04, 2.80) and duration of hospital stay, 2.0 (1.16, 3.26). Conclusions Preventable ADRs are common and important cause of hospitalization and inpatients’ morbidity and mortality among medical patients in Nigeria. Upper GI bleeding and hypoglycaemia, resulting from NSAIDs and antidiabetic drugs were the most observed ADRs. Strategic planning for intensive follow up of ADRs in Nigeria is advocated.
Aims: Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing of propofol in this population. Methods: A non-linear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants. Results: 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from three studies. Body weight (BW) of the pooled study population was 3.050 (0.580 – 11.440) kg, postmenstrual age (PMA) was 36.56 (27.00 – 43.00) weeks and postnatal age (PNA) was 1.14 (0 – 104.00) weeks (median and range). A three compartment structural model was identified and the effect of BW was modeled using fixed allometric exponents. Elimination clearance maturation was modeled accounting for the maturational effect on elimination clearance until birth (by GA) and postpartum (by PNA/GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.63 L min-1) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume (V1) in function of PNA improved the model fit. Conclusions: It is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio-anatomical changes may explain the changes in V1. The developed model may serve as a prior for propofol dose finding in (preterm) neonates.
AIM: The main objective was to determine the prevalence of prescribing issues in HIV-infected subjects ≥65 years according to the Beers and STOPP/START criteria and drug-drug interactions (Liverpool website). Secondary objectives were to assess the concordance between Beers and STOPP/START criteria in our population, and to identify the drugs most frequently involved in the prescribing issues. METHODS: Cross-sectional cohort study based on a systematic review of the electronic drug prescriptions of 91 HIV-infected patients aged ≥65 years. Discrepancies between prescription criteria were assessed using crosstabs and compared using the Chi-square test or Fisher exact test. RESULTS: The mean age was 72.1 (5.6) years, 75.8% had ≥3 comorbidities, and 59.3% polypharmacy. Prescribing issues were identified in 87.9%; 71.4% by STOPP/START and 45.1% by Beers. Comparing both criteria, 56.9% of prescribing issues by STOPP/START were detected by Beers, while 92.5% of those detected by the Beers criteria were detected by STOPP/START (p<0.001). Orange/red flag interactions were found in 45.1%: 3 severe (red) in 2 patients (2.2%). The most frequent drugs involved in prescribing issues were benzodiazepines (>30%). Cobicistat was the drug most frequently involved in interactions (42.9%). CONCLUSIONS: The prevalence of prescribing issues among older HIV-infected persons gives cause for concern, as it is almost 90%. Optimization strategies, including a critical review of the treatment plan, should be implemented in clinical routine by a multidisciplinary team, in particular in patients with multiple comorbidities and polypharmacy. The STOPP/START criteria should be recommended for European populations, since they seem to better detect prescribing issues.
Aims: The investigation regarding the clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is rare. This study evaluated safety and efficacy of PD-1 with Toripalimab, Camrelizumab or Sintilimab for Chinese Hepatocellular carcinoma (HCC) patients in a real-life cohort. Methods: We retrospectively analyzed HBV associated HCC patients treated with Toripalimab, Camrelizumab or Sintilimab in a retrospective cohort from Nov 2018 to Dec 2019. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP) and overall survival (OS). Results: Seventy eight patients were finally included in the analysis: 26 for Toripalimab, 36 for Camrelizumab, and 16 for Sintilimab. Mean duration of follow-up was 22.7 ± 12.6 weeks and the mean Cycles of PD-1 at cut-off were 4.8 ± 2.7 for all patients. The ORR and DCR for the whole cohort were 17.9% and 73.1%, respectively. Overall, 21 (26.9%) patients had radiological disease progression and 6 (7.7%) patients died during follow-up. Median PFS was 40.7 (95% CI, 34.7-46.7) weeks, median TTP was 45.7 (95% CI, 40.5-60.0) weeks, and median OS was 51.1 (95% CI, 46.4-55.9) weeks. Most frequent drug-related AEs were Rash (19.2%), Hypertension (15.4%), Fatigue (12.8%), Paraesthesia (12.8%), and Diarrhoea (10.3%). Conclusions: Our findings suggest that: 1. PD-1-targeted immunotherapy with Toripalimab, Camrelizumab or Sintilimab yielded a promising outcome in Chinese HBV patients with HCC; 2. Immunotherapy was well tolerated generally and had manageable side effects, which is worth of popularization and application in clinical practice.
Aims This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised dosing regimen for patients with liver dysfunction. Methods The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic (ROC) curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by TBIL (TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed. Results ROC curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance (CL), the volume of distribution (V) and oral bioavailability (F) were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole CL was significantly associated with total bilirubin (TBIL) and platelet count. The V increased with weight. Patients with TBIL-1 could be treated with loading dose of 400 mg every 12 hours (q12h) for first day and maintenance dose of 100 mg q12h intravenously or orally. TBIL-2 and TBIL-3 patients could be treated with loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily (qd) and 50 mg qd orally or intravenously, respectively. Conclusions TBIL-based dosing regimens provide a practical strategy for voriconazole maximizing treatment outcomes.