Drug Labels Research Articles

Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries

The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks.

INSP-17. Augmented Drug Delivery for Pediatric Diffuse Midline Glioma using Convection Enhanced Delivery

Convection enhanced delivery (CED), an alternative to systemic chemotherapy, spans nearly two decades of clinical experience. The application of CED in pediatric neuro-oncology has been mainly used in children with DMG. This exploratory period is highlighted by widely variable features including procedural technique, disease extent, device interface, infusion parameters, and therapeutic agent. This presentation is meant to critically assess if CED for DMG is a logical therapeutic strategy. Most convincing to the perpetuation of this platform is the reproducible demonstration of augmented drug delivery. Post-treatment ratios of intralesional to systemic drug concentrations consistently exceed 1000. CED in the brain stem satisfies a desirable goal of CNS drug delivery: achieving high target tissue drug concentrations while avoiding systemic exposure. Surgical targeting of the brain stem and cannula deployment are solidly established as safe and accurate. Catheter insertion complications such as clinically relevant hemorrhage, CNS infection, and neurological injury are exceptional. Likewise, targeting error is on a millimeter scale with infrequent need for catheter repositioning. The use of intrinsic MRI signals, direct drug labeling, and surrogate tracers have all been used for measuring distribution of the infusion. The experience using a radio-labelled theragnostic agent has provided detailed distribution and dosimetry information. Based on estimates of tumor and hence target volumes, a rationale goal is to reach volumes of distribution in the range of 15-25 cm3. Optimizing this goal has focused on surgical targeting, infusion duration, and multiple treatment plans. Computational predictive modeling is being employed as a preoperative adjunct for maximizing distribution. Experience in DMG thus far has been limited to feasibility and safety studies. There is a paucity of Phase 2 studies and hence outcome has not yet been rigorously tested. Anecdotal increase in survival and long-term survival has been reproducibly reported. Of particular interest are the occasional cases of children exhibiting late out-of-treatment field and even extra-CNS recurrence. Available data is convincing that CED should serve be further explored in future clinical trials designs for children with DMG. Important features of any Phase 2 study design however should include monitoring of drug distribution, measures of tumor coverage, early response monitoring techniques, and possibly combination with whole CNS axis treatment.

Insights of clinical significance from solid tumor profiles with FoundationOneCDx.

3126 Background: FoundationOne CDx (F1CDx) is a US FDA-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. Tumor profiling with F1CDx detects genomic findings with evidence of additional clinical significance. This study analyzes the breadth and impact of clinical decision insights from F1CDx clinical reports across solid tumors. Methods: F1CDx consecutive reports (n = 109,695) were retrospectively analyzed for the type and frequency of clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures in common cancer types and across solid tumors. Predictive markers were defined as therapeutically relevant markers in drug labels or NCCN guidelines or targets of ESCAT evidence Tier I/II (Mateo et al., 2018; PMID: 30137196). Prognostic and diagnostic markers were determined in accordance with NCCN, ESMO, or WHO guidelines. We also describe the frequency and targets of interventional clinical trials with targeted therapies or immune checkpoint inhibitors that were matched to tumor profiles based on clinical or strong preclinical evidence. Results: Predictive genomic findings of clinical significance were identified in more than half of non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC), and melanoma (MEL) tissue samples; over a third of ovarian cancer (OC), urothelial carcinoma (UC), and head and neck squamous cell carcinoma (HNSCC); approximately a fourth of prostate cancer (PC), gastro-esophageal adenocarcinoma (GEA), cholangiocarcinoma (CA), and glioma (GL) samples; and one in 18 pancreatic adenocarcinoma (PA) samples (Table). Prognostic markers were reported for patients with NSCLC (18%), CRC (10%), BC (16%), PC (25%), CA (8.1%), MEL (24%), GL (74%), or HNSCC (7.1%). Diagnostic markers were frequently detected for patients with GL and noted for patients with BC, GEA, or MEL (Table). Interventional clinical trials were evidence-matched to most F1CDx tumor profiles (89%, range 82% in PC to 99% in PA), with the targets of approved therapies accounting for a small subset of targets in clinical development. Conclusions: F1CDx reports support clinical decision making by interpreting predictive, prognostic, and diagnostic markers according to professional guidelines as well as investigational markers for the enrollment in clinical trials. [Table: see text]

Patients Misunderstanding of Dosage Instructions among Patients Attending Kenema Pharmacy: Do Pharmacists Ask ‘Tell me so I know you understand?’

Background : Despite the advance in drug development and availability of dozens of drugs in the healthcare system today, knowledge of patients about dispensed medicines is poor to the extent suppositories are being swallowed by patients. The size of commonly used paper envelopes for labeling in Ethiopia doesn't even allow writing the required drug information on it. Methods : Direct observation supported cross-sectional study was conducted to assess the extent of patients' misunderstanding of dosage instructions and associated factors among patients attending Kenema Pharmacy Number 09 at Addis Ababa by using a pre-specified structured interview questionnaire. Result : A total of 398 patients were included in the study and 62.81% were female. Around 34.42% of respondents were found to be in the age range of 25 to 34 years. Two hundred eighty-eight (72.36%) of participants misunderstood one or more dosage regimen instructions, and 269(67.59%) misunderstood the frequency of drug administration. The most commonly misunderstood medications were antibiotics. Moreover, from medication label observations, 273 (68.25%) were dispensed without a medication label. Patient misunderstanding of dosage instructions was significantly associated (p< 0.001) with age, residence, and educational level. Conclusion : A significant number of patients misunderstood dosage regimen instructions. The majority of drugs were dispensed without label information and pharmacists did not practice the 'tell me back if you know, principle to ensure understanding of communicated information. Age, educational status, sex, and residence of patients were significantly associated with patient misunderstanding of dosage instructions. Therefore, pharmacy professionals should appropriately label, and effectively communicate to ensure patient understanding of the dosage instructions for the patient before dispensing. Future studies involving multiple sectors should be done to identify the ranges of associated factors with patients' misunderstanding of dosage instructions and patient–dispenser communication optimization. Keywords: Misunderstanding; Dispensed drug labeling; Dosage instruction; Pharmacy-patient communication; Kenema Pharmacy DOI: 10.7176/JHMN/101-03 Publication date: June 30 th 2022

Safety monitoring practice during the initiation of tyrosine kinase inhibitors (TKIs) for NSCLC treatment.

e21090 Background: TKIs are standard treatment for non-small cell lung cancer (NSCLC) which harbors an actionable mutation. TKIs have a unique toxicity profile, distinct from conventional chemotherapy. Although the manufacturer of each TKI often issues a specific safety precaution on its label, no set schedule has been widely adopted. We surveyed the safety monitoring practice at a large academic institution. Methods: Electronic medical records of patients with ROS1, ALK or EGFR-mutated NSCLC who began a TKI during 2017-2021 were retrospectively reviewed. For each patient, the observation period started from the date of TKI prescription and lasted through day 60. Safety metrics were formulated based on drug label recommendations of each TKI. For each treatment course, the occurrence of 2 index safety monitoring activities (Table) were recorded. Results: Analysis included 130 treatment courses: 82 osimertinib, 20 alectinib, 15 crizotinib and 13 lorlatinib. Median age was 64.3 years, with 66% female, 81% white, 91% ECOG 0/1, 28% zero comorbidity, and 99% non-smoker. For osimertinib, EKG was obtained at baseline (within 30 days of treatment initiation) in 69.5% of observations, and LVEF, in 26.8%. By 60 days, these numbers barely increased (Table). Overall, absence of any index safety monitoring activity occurred in 41 of 130 (32%) treatment courses. Multivariable logistic regression analysis found a trend toward less monitoring among non-white patients: Odds ratio 0.35 (95% CI 0.11-1.09, p = 0.07). No association was found between the number of cardiac risk factors and LVEF monitoring or the use of QT prolonging medication and QTc monitoring. Conclusions: We observed a wide variation in the safety monitoring practice during TKI initiation. Deviation from the manufacturer recommendation was most pronounced for CPK monitoring in alectinib. Future study is needed to define the clinical significance of deviation and to identify barriers to safety monitoring.[Table: see text]

Health Literacy Level and Comprehension of Prescription and Nonprescription Drug Information.

The aim of this study was to investigate the level of misunderstanding of medication information in Korean adults after stratifying by level of health literacy and to identify the factors influencing the misunderstanding of medication information and reading amounts of information on OTC drug labels. A cross-sectional survey was performed with 375 adult participants using the survey instrument. Multiple linear regression analyses were performed to identify factors which influence misunderstanding of medication information. Participants misunderstood 20% of words on OTC drug labels, 9% of prescription drug instructions, and 9% of pictograms. Participants on average read 59% of the overall contents of the OTC drug labels. As prescription drugs’ dosing regimens became more complicated, the level of misunderstanding instructions increased. The level of misunderstanding words on OTC drug labels significantly decreased as participants had adequate health literacy (β = −18.11, p < 0.001) and higher education levels (β = −6.83, p < 0.001), after adjusting for the study variables. The level of misunderstanding instructions for prescription drugs increased as participants became older (β = 8.81, p < 0.001) and had lower education levels (β = −5.05, p < 0.001), after adjusting for the study variables. The level of misunderstanding pictograms was similar to that of misunderstanding instructions for prescription drug labels. The amount of reading information on OTC drug labels significantly increased as respondents had adequate health literacy (β = 9.27, p < 0.001), were older (β = 12.49, p < 0.001), or had chronic diseases (β = 7.49, p = 0.007). Individuals’ health literacy level, reading behaviors, and complexity of medication instructions are associated with misunderstanding of medication information. Appropriate word choices in drug labels and an improved format of medication instructions could increase understanding of medication information and prevent adverse drug reactions.

Knowledge, Attitude, and Perception of the Clinicians, Nurses, Pharmacists, Patients, and Public on Compounding, Dispensing, and Labeling services of Pharmacists in a hospital

Background: A pharmacist is a professional who dispenses medicines, counsels patients, and advises health care stakeholders on the rational use of medicines. The study is therefore an attempt to determine the awareness about the pharmacy profession among stakeholders. Material methods: This is an exploratory and descriptive study, designed to describe and explore the Knowledge, Attitude, and Perception (KAP) of the role of a pharmacist in the compounding, dispensing, and labeling of drugs. The statements included in the questionnaire were largely based on the guidelines issued by the Pharmacy Council of India (PCI). Questionnaires were randomly provided to clinicians, pharmacists, nurses, public, and patients. The questionnaire was then taken back and kept for analysis of response. 514 stakeholders participated in the study. The results are expressed as percentages and frequencies. Results: All stakeholders agreed that during compounding, dispensing, and labeling, pharmacists ensure that drug products should match the prescription and appropriately compounded, packed, and labeled. All stakeholders except nurse (99%) agreed that during compounding, dispensing and labeling pharmacist ensure that drug product is within the expiry date. 34.9% of patients agreed that while dispensing the drug to the patient/attendants, appropriate information on drugs is given by the pharmacist. Conclusion: The present study reveals that clinicians and nurses do not have sufficient confidence on the supportive role of a pharmacist in the health care team for better patient care. The pharmacist also needs to work proactively and through his knowledge, expertise and skills generate confidence amongst the patient and health workers that he can perform his expanded role effectively and thus promote patient health

Evaluation of the Effect of Food on the Pharmacokinetics of SHR6390, An Oral CDK4/6 Inhibitor, in Healthy Volunteers.

Background and IntroductionSHR6390 is a new developed highly effective and selective small-molecule oral CDK4/6 inhibitor. We aimed to evaluate the effect of food on the pharmacokinetics of SHR6390 tablets.MethodsIn an open-label two-way crossover study, 24 healthy Chinese volunteers were randomly divided into Group A and Group B, and 12 volunteers in each group received a single oral dose of a SHR6390 150-mg tablet under fasting and high-fat conditions. Blood samples were collected and determined for pharmacokinetic analyses. A liquid chromatography-tandem mass spectrometry method was developed and validated for determining the SHR6390 concentration.ResultsThe time to maximum plasma concentration was not significantly affected by a high-fat diet. Compared with the fasting group, maximum plasma concentration, i.e., the area under the concentration–time curve (AUC0–t and AUC0–∞) was altered significantly, as evidenced by an increase of 56.9%, 38.6%, and 37.5% respectively. We identified seven metabolites of SHR6390 from the plasma samples, and we found no sex differences in metabolic pathways. All treatment-emergent adverse events were Grade 1 or 2.ConclusionsFood intake increased the maximum plasma concentration, AUC0–t, and AUC0–∞ significantly compared with the fasting condition. Meanwhile, single-dose SHR6390 for two treatment cycles is safe. SHR6390 was administered in a fasting status in the pivotal phase III study (NCT03927456) and chosen for the final drug label.

Pattern of adverse drug effects reported by patients being treated in a tertiary healthcare institution in North India: A retrospective observational study

: Patient safety and well-being is favored by reporting adverse drug effects timely and precisely. Pharmacovigilance contributes to post-marketing surveillance and ensures that necessary changes may be done to the drug labels accordingly.: The study was aimed at observing, analyzing and reporting various adverse effects due to prescribed drug intake for patient conditions and disease being treated at our tertiary healthcare institution.: Study was conducted at Dr. RPGMC, Kangra at Tanda, which is a multi-specialty tertiary healthcare hospital with 700 beds and an ADR monitoring Centre situated in the lap of western Himalayas in North India. Pattern of ADRs reported by the volunteers receiving drug therapy from January to December 2021 was assessed. Data pertaining to age, gender, drug intake, types of ADRs, treatment and outcome of the reactions was collected. Individual assessment was done for each patient. WHO scale was used for causality assessment. ADR profiling was carried out based on site, onset, organ system affected, duration, whether urgent referral was required or not and resolution of signs &amp; symptoms.The data was analyzed using Microsoft excel 2019 and expressed as mean ± standard deviation &amp; percentages.: A total of 83 patients reported ADRs (adverse drug reactions). These were reported to IPC, Ghaziabad through our AMC (Adverse Drug Reaction Monitoring Centre) from 1 January 2021 to 31 December 2021. Gastro-intestinal system related adverse effects (35%) were most common followed by skin (22.9%) and CNS (12%) adverse effects. GI adverse effects included anorexia, dyspepsia, diarrhoea, oral ulcers, nausea, vomiting, weight-loss and raised liver function tests.: ADRs occur commonly but are often undetected. Even if detected they remain underreported as most of the health care professionals are unaware about pharmacovigilance. Therefore, mass sensitization and reward to those who report ADRs vigilantly is the need of the hour to promote patient safety.

Frequently reported adverse events of rebamipide compared to other drugs for peptic ulcer and gastroesophageal reflux disease

This study aimed to detect safety signals of rebamipide and search for adverse events (AEs) of rebamipide that are more common than those of other drugs for peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD) in the elderly population. A total of 101,735 AE reports for drugs used to treat PUD and GERD between 2009 and 2018 from the KIDS-KAERS database (KIDS-KD) were used. Disproportionality analysis was performed to calculate the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). Drug labels in Korea, Japan, and China were reviewed to identify signals that have been listed. AEs frequently reported in the elderly population were also analyzed. Seriousness and median time to AEs were evaluated for statistically significant AEs. A total of 14 signals were detected, and 4 signals (dry mouth, dermatitis, purpura/petechia, and fluid overload) were not listed on drug labels; however, they may be included as part of other listed AEs. In the elderly population, 11 AEs such as dyspepsia/indigestion/gastrointestinal distress, somnolence, dry mouth, and edema were common. These AEs were not serious and occurred within 2–9 days. This study identified possible AEs of rebamipide, a relatively safe drug.

Most commonly prescribed blood pressure lowering drug linked with increased risk of skin cancer.

To the Editor, Hydrochlorothiazide (HCTZ) is the most commonly prescribed antihypertensive drug that belongs to a diuretic class.1 It mainly works by increasing the removal of excess water and salts from the body into the urine and by this function it is most widely used alone or in combination with other medications to treat patients with uncontrolled blood pressure and edema that results from numerous medical conditions like heart, Liver and kidney diseases. It also helps treat other ailments like diabetes insipidus, renal tubular acidosis and reduce the risk of kidney stones in patients with high calcium levels in urine. Despite its various uses and benefits, HCTZ comes with a heavy price of undesirable side effects like fatigue, lethargy, gastrointestinal discomfort and is known to cause hyperuricemia and hypokalemia associated with increased blood glucose.2 Furthermore, HCTZ increases the skin sensitivity to sunlight. However, recent research has revealed a more worrisome side effect of HCTZ that needs to be highlighted. In 2017, a nationwide study conducted in Denmark involving more than 70,000 patients with Basal cell carcinoma and 8000 patients with squamous cell carcinoma found a considerably increased risk of developing Non melanoma skin cancer, particularly among the users of HCTZ.3 A recent study also substantiated that a total of 135 squamous cell carcinoma events per 100,000 person years were reported in new users of HCTZ.4 These alarming figures raise a question mark on the safety of HCTZ use. Moreover, HCTZ is now classified as a carcinogenic agent for humans by the International Agency for Research on Cancer and the U.S. Food and Drug Administration has also permitted changes to the HCTZ drug label to warn the health care workers and patients of the risk of non-melanoma skin cancer. 5, 6 Unfortunately in Pakistan, HCTZ is still heavily used as a diuretic and people are not much aware of this new fact. In view of these findings and the fact that HCTZ is among the most generally prescribed drugs in Pakistan, its potential indication of causing skin cancer would impose a serious public health concern so the responsibility lies on the cardiologists, nephrologists and other medical physicians to be aware of this possible hazardous outcome of HCTZ use and should be cautious while prescribing it to patients who are at risk of developing skin cancer or who have had a history of skin cancer.

MO580: Healthy Plant-Based Diet for Patients With Chronic Kidney Disease (CKD) Through Use of Sodium Zirconium Cyclosilicate (SZC): A Feasibility Study (Helpful)

Abstract BACKGROUND AND AIMS Healthy plant-based diets (HealthyPB diet) may offer metabolic and cardiovascular benefits to patients with CKD. However, the higher potassium (K+) content of these diets is a concern when prescribed to CKD patients with hyperkalemia (HK). Potassium-lowering medication, such as SZC, can be a treatment option to allow better control of plasma K + for those ingesting a HealthyPB diet. We investigated whether patients with CKD stage 4–5 and HK can be safely prescribed a HealthyPB diet with increased K + content by concomitant use of SZC. METHOD This is an ongoing open label feasibility clinical trial that will include 36 patients with CKD stage 4–5 not on dialysis with HK (plasma K+ ≥ 5.1 mmol/L). Patients with plasma K+ &amp;gt; 6.5 mmol/L are excluded. Intervention: Patients are followed for 6 weeks. In the first 3 weeks (stabilization phase), SZC is prescribed according to the drug label to normalize plasma K + while ingesting a low protein diet (0.6–0.8 g/kg/day) with low content of K+ (2.3 g/day) as counselled by a dietitian. After 3 weeks, patients initiate and follow for 3 additional weeks, the HealthyPB diet containing unchanged low amount of protein and K + content of 3.7–4 g/day. In order to increase diet adherence, a food basket (containing fruits, vegetables, whole grains, nuts, whole cereals, white meat, fish or eggs in amounts adequate for the patient and the family) is delivered to patient's home once per week. Serum K is closely monitored and the dose of SZC is adjusted according to the drug label to maintain serum K between 3.5 and 5.0 mmol/L. Adherence to the diet is assessed by 24-h urinary K + excretion, 24-h food record, and a semi-quantitative short food questionnaire at the beginning and end of the stabilization phase and again at the beginning and end of the HealthyPB diet phase. The protocol is registered at www.clinicaltrials.gov (identifier NCT04207203). RESULTS Among 14 patients included so far, 12 completed the study protocol and 2 are being followed. Results in the patients (n = 12; age 56.5 ± 10 years; 66.7% men; eGFR: 16.4 ± 4.6 mL/min/1.73 m2) who completed the follow-up are described in the Table 1. Mean ± SD or median and interquartile range; NA: not assessed. At the end of follow-up three (25%) patients had plasma K + between 5.1 and 5.3 mmol/L. CONCLUSION These preliminary results indicate that patients adhered to the low protein HealthyPB diet with an increase in the intake of fruits, vegetables, whole cereals and nuts. The mean plasma K + was well controlled with SZC and within the normal range after the start of the HealthyPB diet.

Prediction of CYP‐mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator

Physiologically‐based pharmacokinetic (PBPK) modeling is being increasingly used in drug development to avoid unnecessary clinical drug–drug interaction (DDI) studies and inform drug labels. Thus, regulatory agencies are recommending, or indeed requesting, more rigorous demonstration of the prediction accuracy of PBPK platforms in the area of their intended use. We describe a framework for qualification of the Simcyp Simulator with respect to competitive and mechanism‐based inhibition (MBI) of CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. Initially, a DDI matrix, consisting of a range of weak, moderate, and strong inhibitors and substrates with varying fraction metabolized by specific CYP enzymes that were susceptible to different degrees of inhibition, were identified. Simulations were run with 123 clinical DDI studies involving competitive inhibition and 78 clinical DDI studies involving MBI. For competitive inhibition, the overall prediction accuracy was good with an average fold error (AFE) of 0.91 and 0.92 for changes in the maximum plasma concentration (Cmax) and area under the plasma concentration (AUC) time profile, respectively, as a consequence of the DDI. For MBI, an AFE of 1.03 was determined for both Cmax and AUC. The prediction accuracy was generally comparable across all CYP enzymes, irrespective of the isozyme and mechanism of inhibition. These findings provide confidence in application of the Simcyp Simulator (V19 R1) for assessment of the DDI potential of drugs in development either as inhibitors or victim drugs of CYP‐mediated interactions. The approach described herein and the identified DDI matrix can be used to qualify subsequent versions of the platform.

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Use of Extrapolation in New Drug Approvals by the US Food and Drug Administration

The US Food and Drug Administration (FDA)-approved indications can be factors in prescribing practices and insurance coverage, yet the frequency with which the extrapolation of clinical characteristics from pivotal trial data to the final approved indication occurs is not well understood. To evaluate the frequency of extrapolation beyond pivotal trial data into approved indications in relation to disease severity, disease subtype, and concomitant medication use. In a cross-sectional study, the characteristics of patients in pivotal trials of 105 novel drug approvals from 2015 to 2017 were identified and compared with the FDA-approved indications for the drugs. Main sources analyzed included FDA reviews, published material describing the pivotal trials, and the original drug labeling. The study was conducted from July 4, 2019, to June 1, 2021. Clinical characteristics of pivotal trials used in FDA approval. Main outcomes included the nature and frequency of extrapolation from study populations to the final indications. Extrapolation was defined as the granting of an indication for use in a broader population than was included in the pivotal trials on the basis of disease severity, disease subtype, or concomitant medication use. Among the 105 novel FDA drug approvals studied, 23 extrapolations of trial population characteristics to the approved indication were identified in 21 drugs (20%): 12 times (29%) in 2015, 3 times (15%) in 2016, and 6 times (14%) in 2017. Extrapolation of trial findings to patients with greater disease severity was most common (n = 14 drugs), followed by differences in disease subtype (n = 6) and concomitant medication use (n = 3). The findings of this study suggest that extrapolation from pivotal trial data to FDA-approved indications is common. Although extrapolations may be grounded in reasonable clinical predictions, they can limit the generalizability of such indications to specific prescribing decisions; these findings suggest a greater need for close postapproval monitoring to determine whether new safety issues arise, or effectiveness differs from expectations when these medications are used in broader real-world populations.

Guide to development of compound files for PBPK modeling in the Simcyp population-based simulator.

The Simcyp Simulator is a software platform for population physiologically‐based pharmacokinetic (PBPK) modeling and simulation. It links in vitro data to in vivo absorption, distribution, metabolism, excretion and pharmacokinetic/pharmacodynamic outcomes to explore clinical scenarios and support drug development decisions, including regulatory submissions and drug labels. This tutorial describes the different input parameters required, as well as the considerations needed when developing a PBPK model within the Simulator, for a small molecule intended for oral administration. A case study showing the development and application of a PBPK model for ondansetron is herein used to aid the understanding of different PBPK model development concepts.

Little impact of studies in pregnancy on drug labelling

Little impact of studies in pregnancy on drug labelling

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Joint pain liniments and gum lotion in the eye - A consecutive case series of mistaken identity.

Purpose:Patient safety errors can arise due to similarity in packaging of medications. We aimed to describe the clinical features of patients presenting with accidental application of joint pain liniments and gum lotion in the eye due to confusion arising from similarity in packaging.Methods:This was a retrospective case series with eight consecutive patients presenting from December 2020 to August 2021 with history of accidental application of joint pain liniments or gum lotion in the eye instead of eye drops. All patients underwent visual acuity assessment and slit-lamp examination with fluorescein staining of the cornea to look for corneal involvement and was reassessed till complete resolution.Results:Of the eight patients, three were males and five were females. Seven had accidentally applied joint pain liniment, while one had applied gum lotion into the eye. Five of them had corneal involvement ranging from punctate erosions to near-total epithelial defects. Two patients needed referral to a tertiary center and hospital admission. Treatment duration ranged from 2 days to 1 month. Two patients were lost to follow-upConclusion:This study highlights patient safety errors arising from confusion of medication due to similar labeling and packaging of different drugs. While there was no permanent morbidity, such confusions lead to needless discomfort and waste of time, money, and effort for the patient as well as the health-care system.

Application of physiologically based pharmacokinetic modelling for the prediction of drug-drug interactions involving anlotinib as a perpetrator of cytochrome P450 enzymes.

Anlotinib is a small molecule of novel tyrosine kinase inhibitor initially approved to treat non-small cell lung cancer in China. Drug-drug interaction (DDI) is an extrinsic factor important for the appropriate use of anlotinib in clinical practice. In vitro experiments demonstrated that anlotinib is a substrate of cytochrome P450 (CYP) enzymes and moderate inhibitor of several common ones; however, no clinical DDI studies have been performed to investigate inhibitory effects of anlotinib on these CYP enzymes. Thus, its drug label recommends avoiding co-administration with substrates of these enzymes, which have narrow therapeutic windows. In this study, we performed a CYP450 inhibition study, followed by gathering in vitro and clinical pharmacokinetic data to build the first physiologically based pharmacokinetic (PBPK) model of anlotinib. The verified model was subsequently used to predict the DDI mediated by anlotinib. As a result, the marginal plasma exposure changes of typical CYP3A and CYP2C9 substrates were less than the bioequivalence threshold, indicating that anlotinib has a very low potential of causing clinically meaningful DDI through the inhibition of several major CYP enzymes. According to the FDA's latest guideline on DDI, the established model with the simulation results may support the revision of anlotinib labelling without further clinical studies, lifting unnecessary restrictions on anlotinib regimens.