There are several ways to optimize treatment regimens, including reducing the dose, reducing the frequency or changing the way the drug is taken, such as taking a pill with or without food, which can affect the amount of medication absorbed into the body, says Mark Ratain. medical oncologist and clinical pharmacologist. Ratain presented dose-scaling research at this year`s ASCO Annual Meeting and directs the Center for Personalized Therapeutics at the University of Chicago. He echoed others, praising the FDA`s requirement for pharmaceutical companies to conduct dose-optimization studies in a June 11, 2021 editorial published in The Cancer Letter. Fortunately, there are some general guidelines on this topic. In 2015, the FDA issued guidance that addresses the size, shape, and other physical properties of tablets and capsules. Although the guidelines are not binding and are intended for generic drugs, the intent set out in these guidelines is of considerable value in the development of new dosage forms. According to the guidelines, difficulty swallowing tablets and capsules can be a problem for many people, leading to a variety of adverse events and non-adherence to treatment regimens. It is estimated that more than 16 million people in the United States have difficulty swallowing, also known as dysphagia (FDA, 2015). For these people, swallowing a tablet or capsule can be particularly difficult. Of those who have difficulty swallowing medications, less than one-quarter discuss the problem with a doctor, 8% admit to skipping a dose of prescribed medication, and 4% have stopped treatment because the tablets and/or capsules were difficult to swallow (FDA, 2015). People who have difficulty swallowing tablets and capsules often cite size as the main reason for difficulty swallowing. The size of the tablet or capsule affects esophageal transit, regardless of the patient`s factors and administration techniques (i.e.
the use of fluids, the position of the patient). Smaller tablets generally have significantly faster transit times in these studies. This clearly shows that the size of the dose itself can be an important factor when it comes to patient adherence and acceptance. In this context, is it not essential to design a dosage form of acceptable size for the widest possible patient population? For statins, the reduction in coronary events peaks just above the ED50, while a number of adverse drug reactions (ADRs) continue to increase.8 Lipid guidelines in North America since 2013 have revealed that cholesterol targets have no evidence base,1 but with European guidelines2 promote BAT as a therapeutic target, Although statin adherence associated with side effects is known to be reduced. 9 that have been shown to be dose-dependent.8 The decreased benefit of mortality at higher doses of statins8 suggests that some adverse effects may contribute to mortality, e.g. hepatic impairment, rhabdomyolysis, renal dysfunction in patients with pre-existing renal impairment10 and cerebral haemorrhage, particularly in patients with previous stroke, 11 This is of particular concern to older adults. No dose-limiting toxicity has been reported following repeated intravascular injection at doses of up to 2 × 1012 particles (hepatic artery) [47] and 2 × 1013 particles (intravenously) [48,61]. Fever, chills and asthenia after intravascular injection were more frequent and severe than after intratumoral injections (grade 2-3 fever and chills compared to grade 1).
Dose-dependent transaminitis has been reported rarely. Transaminity was generally transient (<10 days) and low-grade (grade 1-2) and not clinically relevant. At the highest intravenous doses administered, aspartate transaminase/alanine transaminase (AST/ALT) levels were approximately 3 to 5 times the upper limit of normal for the trial; Although the maximum tolerated intravenous dose has not yet been defined, it may be close to this dose. The subsequent increase in dose was limited by the supply of the virus. Only one patient in the hepatic artery study exhibited a pro-inflammatory systemic cytokine response in cycle 4, resulting in transient vascular leakage at tumor sites and metabolic acidosis; abnormally high concentrations of TNF and interferon γ have been associated with idiosyncratic inhibition of IL-10 [47]. Clinical studies show that antidepressants are no better than placebo for mild depression and only slightly better than placebo27 for more severe depression, but are often prescribed multiple times their ED50 (Table 1). It is increasingly recognized that between 20 and 30% of more serious mental illnesses do not respond significantly to pharmacotherapy.31, 32 This has important implications for dosing. With only clinical indicators as a guide, clinicians can further increase the dose in non-reactive patients, hoping for a reaction that may not occur. There is little evidence of greater efficacy at higher doses of antidepressants33 or antipsychotics,34 while adverse effects generally continue to increase with dose.22 Side effects reduce adherence.35 Patients are unlikely to avoid psychotropic medications, especially at higher doses, without study or prescription at lower doses.36 The use of antipsychotics in the elderly and in the Dementia should be carefully considered. in particular, their off-label use in sedation and behavioural disorders.37 Published data show that, compared to placebo, the harms outweigh the benefits and that mortality is higher with antipsychotics.39 In an interview with Cancer Today, Eric P. Winer, a medical oncologist and chief of the division of breast oncology at Boston`s Dana-Farber Cancer Institute, welcomed the decision.
“Just because you have cancer and you`re undergoing treatment doesn`t mean you have to be unhappy,” Winer says. Oncologists might consider starting with a lower dose and increasing it based on the patient`s needs, rather than starting with the highest dose and then reducing the dose due to toxicity, Winer says. Safety concerns in the post-market phase of widely used drugs have led to proactive approaches to drug safety41, such as: Risk Assessment and Risk Reduction Strategies42 and Risk Management Plans (RMPs)43 for new drugs upon market entry (Food and Drug Administration, European Medicines Agency). However, many post-market safety issues cannot be identified or anticipated in RMPs, and almost half of the variations in security aspects of product information are not addressed in the RMP.44 Paradoxically, these approaches can foster a false sense of security and cause physicians to think less critically about dose tempering. For patients, this need is urgent, says Julia Maués, who lives in Washington, D.C., and was diagnosed with metastatic breast cancer in 2013. Maués is a member of the Patient-Centered Posing Initiative (PCDI), a patient-led initiative that encourages oncologists to consider the unique characteristics of the patient and whether the highest possible dose is still needed. “I often talk to patients who are suffering from the side effects of the medications they are taking, and their doctor has never addressed the fact that it`s not always the full dose,” she says. A PCDI-sponsored survey of 1,221 patients with metastatic breast cancer, presented at the 2021 ASCO meeting, showed that of the 556 patients who requested and received a dose reduction, 83% reported feeling better. Antihypertensive drugs are often used at higher doses than in RCTs (Table 1) and target epidemiological targets that do not take into account drug side effects. Heart failure guidelines recommend DMT of angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists and β,3 blockers for example, up to 7 times the ED50 of metoprolol and 16 times the ED50 of candesartan, despite the inevitable increase in adverse effects.
Cross-sectional observational data seem to suggest greater benefit at higher doses, but can be confused by greater tolerance at higher doses in patients with less severe disease. In contrast, no reduction in all-cause mortality that provides a useful summary of efficacy and safety is evident when dose allocations (at higher or lower doses) of statins8 and angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists or β inhibitors have been randomized.20, 21 The highest dose of a drug or treatment that achieves the desired effect without causing unacceptable side effects.