Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial.

Lancet HIV. 2020 Jan 03;:

Authors: Schürmann D, Rudd DJ, Zhang S, De Lepeleire I, Robberechts M, Friedman E, Keicher C, Hüser A, Hofmann J, Grobler JA, Stoch SA, Iwamoto M, Matthews RP

Abstract
BACKGROUND: Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection.
METHODS: This open-label, consecutive-panel, phase 1b trial was done at Charité Research Organisation (Berlin, Germany) and included men and women (aged 18-60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10 000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of islatravir (0·5-30 mg). The primary outcomes were safety and tolerability of islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28.
FINDINGS: Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78·5-128·0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1·67 log10 copies per mL (95% CI 1·42-1·92) at 10 mg dose to 1·20 log10 copies per mL (0·95-1·46) at 0·5 mg dose. No genetic changes consistent with development of viral resistance were detected.
INTERPRETATION: Single doses of islatravir as low as 0·5 mg significantly suppressed HIV-1 RNA by more than 1·0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of islatravir as a flexible-dose treatment for individuals with HIV-1 infection.
FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, USA.

PMID: 31911147 [PubMed - as supplied by publisher]

Myoclonic status epilepticus induced by cefepime overdose requiring haemodialysis.

BMJ Case Rep. 2019 Jun 06;12(6):

Authors: Garin A, Bavozet F

Abstract
We report a case of cefepime neurotoxicity characterised by myoclonic status epilepticus with coma, in a context of acute renal failure and requiring one discontinuous conventional haemodialysis. Cefepime is a fourth-generation broad-spectrum cephalosporin mainly used to treat hospital-acquired Gram-negative infections. Acute neurotoxicity is an increasingly reported adverse effect which occurs predominantly in patients with renal impairment. Renal replacement therapy has been proposed to treat this condition.

PMID: 31175111 [PubMed - indexed for MEDLINE]

Safety and Immunogenicity of the Quadrivalent HPV Vaccine in Japanese Boys: a Phase 3, Open-Label Study.

Jpn J Infect Dis. 2019 Sep 19;72(5):299-305

Authors: Murata S, Takeuchi Y, Yamanaka K, Hayakawa J, Yoshida M, Yokokawa R, Wakana A, Sawata M, Tanaka Y

Abstract
Human papillomavirus (HPV)-associated disease is common among men with HPV infection. A quadrivalent HPV (qHPV) vaccine has demonstrated 85.9% efficacy against HPV6/11/16/18-related, persistent (≥ 6 month) infection in a study of Japanese men aged 16-26 years old. Here, we report the results of an open-label study of the immunogenicity and tolerability of the qHPV vaccine (NCT02576054), conducted to bridge findings from Japanese men to Japanese boys aged 9-15 years old. A total of 100 boys completed a three-vaccination regimen (Day 1, and Months 2 and 6), and 99 boys were included in the primary analysis population. The rate of seroconversion at one month after vaccine Dose 3 (Month 7) was high for each type of HPV (anti-HPV6/11/16/18 seroconversion rates [95% CI]: 94.9% [85.5%, 98.3%], 99.0% [94.4%, 100.0%], 99.0% [94.5%, 100.0%], and 99.0% [94.4%, 100.0%], respectively). Moreover, anti-HPV6/11/16/18 geometric mean titers were 482.9 mMU/mL, 1052.8 mMU/mL, 3878.3 mMU/mL, and 1114.5 mMU/mL, respectively. Immune responses to the qHPV vaccine were non-inferior among Japanese boys included in the current study and compared with young Japanese men from a separate study. Injection-site reactions were the most common adverse events, and administration of the vaccine was well tolerated in Japanese boys.

PMID: 31155600 [PubMed - indexed for MEDLINE]

Metformin administration increases the survival rate of doxorubicin-treated mice.

Pharmazie. 2019 Dec 01;74(12):737-739

Authors: Alhowail A, Almogbel Y

Abstract
Background: The chemotherapeutic agent doxorubicin (DOX), an anthracycline broadly used to treat different types of cancers, induces several side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity, in a time- and dose-dependent manner. Metformin (MET) is an antidiabetic drug used as a first-line treatment for type-2 diabetes, and is reported to work against various various drug-induced toxicities. This study aimed to investigate whether the administration of MET prophylactically suppresses DOX-induced toxicity, and prolongs the survival following DOX treatment. Methods: Fifty mice were divided into four groups, and each group received different treatments. The animals in the control group received a single injection of saline. The animals in the DOX group received a single dose of DOX (25 mg/kg). The animals in the MET group received MET on a daily basis. The animals in the DOX+MET group received only a single dose of DOX and daily doses of MET. The animals were observed on a daily basis for determining their body weight and evaluating the survival rate of the four study groups. Results: DOX accelerated the mortality rate of the animals in the DOX-treated group. Co-administration of MET and DOX increased the survival rate of the mice. Conclusion: The results of this study demonstrated that the administration of MET can reduce DOX-induced toxicity and increase the survival rate among chemotherapy-treated mice.

PMID: 31907113 [PubMed - in process]

How to communicate evidence to patients.

Drug Ther Bull. 2019 08;57(8):119-124

Authors: Freeman ALJ

PMID: 31345957 [PubMed - indexed for MEDLINE]

An adverse drug effect mentions extraction method based on weighted online recurrent extreme learning machine.

Comput Methods Programs Biomed. 2019 Jul;176:33-41

Authors: El-Allaly ED, Sarrouti M, En-Nahnahi N, Ouatik El Alaoui S

Abstract
BACKGROUND AND OBJECTIVE: Automatic extraction of adverse drug effect (ADE) mentions from biomedical texts is a challenging research problem that has attracted significant attention from the pharmacovigilance and biomedical text mining communities. Indeed, deep learning based methods have recently been employed to solve this issue with great success. However, they fail to effectively identify the boundary of mentions. In this paper, we propose a weighted online recurrent extreme learning machine (WOR-ELM) based method to overcome this drawback.
METHODS: The proposed method for ADE mentions extraction from biomedical texts is divided into two stages: span detection and ADE mentions classification. At the first stage, we identify the boundary of the mentions irrespective of their types with a WOR-ELM in a given sentence. At the second stage, another WOR-ELM is used to classify the identified mentions to the appropriate type. Both stages use the concatenation of character-level and word-level embeddings as features. The character-level embedding is obtained using a modified online recurrent extreme learning machine, whereas the word-level embedding is obtained from a pre-trained model.
RESULTS: Several experiments were carried out on a well-known ADE corpus to evaluate the effectiveness and demonstrate the usefulness of the proposed method. The obtained results show that our method achieves an F-score of 87.5%, which outperforms the current state-of-the-art methods.
CONCLUSIONS: Our research results indicate that the proposed method for adverse drug effect mentions extraction from text can significantly improve performance over existing methods. Our experiments show the effectiveness of incorporating word-level and character level embeddings as features for WOR-ELM. They also illustrate the benefits of using IOU segment to represent ADE mentions.

PMID: 31200909 [PubMed - indexed for MEDLINE]

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose Two-Drug Regimen Versus Continuing a Tenofovir Alafenamide-Based Three- or Four-Drug Regimen for Maintenance of Virologic Suppression in Adults With HIV-1: Phase 3, Randomized, Non-inferiority TANGO Study.

Clin Infect Dis. 2020 Jan 06;:

Authors: van Wyk J, Ajana F, Bisshop F, De Wit S, Osiyemi O, Portilla J, Routy JP, Wyen C, Ait-Khaled M, Nascimento MC, Pappa KA, Wang R, Wright J, Tenorio AR, Wynne B, Aboud M, Gartland MJ, Smith KY

Abstract
BACKGROUND: The 2-drug regimen (2DR) dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with HIV-1. We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals.
METHODS: TANGO is an open-label, multicenter, phase III study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to a once-daily DTG/3TC fixed-dose combination or remain on a tenofovir alafenamide (TAF)-based regimen. Primary endpoint was proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (FDA Snapshot algorithm) in the intention-to-treat-exposed population (4% non-inferiority margin).
RESULTS: 743 adults were enrolled and 741 received ≥1 dose of study drug (DTG/3TC, N=369; TAF-based regimen, N=372). At Week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL treated with DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% CI], -0.3 [-1.2, 0.7]), meeting non-inferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at time of failure. Drug-related grade ≥2 adverse events and adverse events leading to study withdrawal were reported in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively.
CONCLUSIONS: The 2DR DTG/3TC was non-inferior in maintaining virologic suppression vs a TAF-based regimen at Week 48, with no virologic failure or emergent resistance reported in the DTG/3TC group, supporting its use as a simplification strategy for virologically suppressed people living with HIV-1.

PMID: 31905383 [PubMed - as supplied by publisher]

Adverse drug reactions in primary care: a scoping review.

BMC Health Serv Res. 2020 Jan 06;20(1):5

Authors: Khalil H, Huang C

Abstract
BACKGROUND: Medication-related adverse events, or adverse drug reactions (ADRs) are harmful events caused by medication. ADRs could have profound effects on the patients' quality of life, as well as creating an increased burden on the healthcare system. ADRs are one of the rising causes of morbidity and mortality internationally, and will continue to be a significant public health issue with the increased complexity in medication, to treat various diseases in an aging society. This scoping review aims to provide a detailed map of the most common adverse drug reactions experienced in primary healthcare setting, the drug classes that are most commonly associated with different levels/types of adverse drug reactions, causes of ADRs, their prevalence and consequences of experiencing ADRs.
METHODS: We systematically reviewed electronic databases Ovid MEDLINE, Embase, CINAHL Plus, Cochrane Central Register of Controlled Trials, PsycINFO and Scopus. In addition, the National Patient Safety Foundation Bibliography and the Agency for Health Care Research and Quality and Patient Safety Net Bibliography were searched. Studies published from 1990 onwards until December 7, 2018 were included as the incidence of reporting drug reactions were not prevalent before 1990. We only include studies published in English.
RESULTS: The final search yielded a total of 19 citations for inclusion published over a 15-year period that primarily focused on investigating the different types of adverse drug reactions in primary healthcare. The most causes of adverse events were related to drug related and allergies. Idiosyncratic adverse reactions were not very commonly reported. The most common adverse drug reactions reported in the studies included in this review were those that are associated with the central nervous system, gastrointestinal system and cardiovascular system. Several classes of medications were reported to be associated with adverse events.
CONCLUSION: This scoping review identified that the most causes of ADRs were drug related and due to allergies. Idiosyncratic adverse reactions were not very commonly reported in the literature. This is mainly because it is hard to predict and these reactions are not associated with drug doses or routes of administration. The most common ADRs reported in the studies included in this review were those that are associated with the central nervous system, gastrointestinal system and cardiovascular system. Several classes of medications were reported to be associated with ADRs.

PMID: 31902367 [PubMed - in process]

Long-Term Kidney Transplant Outcomes: Role of Prolonged-Release Tacrolimus.

Transplant Proc. 2019 Dec 31;:

Authors: Banas B, Krämer BK, Krüger B, Kamar N, Undre N

Abstract
Tacrolimus has significantly improved outcomes for kidney transplant patients and remains the cornerstone of immunosuppressive therapy. While improvements in short-term outcomes in transplantation have been achieved in recent years, maintaining long-term graft survival remains a challenge in kidney transplantation. Minimizing risk factors for poor long-term kidney graft function and survival, and modifying tacrolimus regimens in the early and maintenance phases post-transplantation are essential to maintain long-term kidney transplant outcomes. Tacrolimus has a narrow therapeutic window, resulting in a tightly defined range of optimal drug exposure. Underimmunosuppression is associated with long-term risks, such as the development of donor-specific antibodies and antibody-mediated rejection, with a high possibility of a decline in kidney function and progression to graft failure. Conversely, prolonged overimmunosuppression carries a risk of drug-related adverse events. This review provides an overview of the differences in the formulation, delivery, and pharmacokinetic profiles between immediate- and prolonged-release tacrolimus and evaluates the effect of prolonged-release tacrolimus on the risk factors for poor outcomes in kidney transplantation. Recent evidence is used to provide guidance on target tacrolimus trough levels in the early and maintenance phases post-transplantation, with a view to improving long-term kidney graft function.

PMID: 31901329 [PubMed - as supplied by publisher]

How safe are our studies? Analysis of adverse events in Bayer First-in-Human trials from 2006 to 2016
.

Int J Clin Pharmacol Ther. 2020 Jan;58(1):10-20

Authors: Jung D, Boettcher MF, Wensing G

Abstract
PURPOSE: In regard to the current scientific discussion, this analysis aims to broaden the database for a risk evaluation of First-in-Human (FiH) trials with healthy volunteers.
MATERIALS AND METHODS: Study documents of each FiH study conducted between 2006 and 2016 for Bayer Clinical Pharmacology Cardiovascular were reviewed for inclusion. Study types, treatments, dose steps, study population, number, incidence, and intensity of treatment-emergent adverse events (AEs) were cumulatively analyzed using descriptive statistics. A comparison to a previous similar analysis (period 2000 - 2005) was made.
RESULTS: 22 out of 25 studies were included (20 small molecules, 2 biologics) investigating drugs for cardiovascular (9), hematological (7), pulmonary (3), kidney (2), and metabolic (1) diseases. The mean age of subjects was 34.2 years. 1,250 subjects received treatment (950 active, 300 placebo). 952 AEs occurred (0.76 AEs/treatment, 0.85 AEs/active treatment, 0.49 AEs/placebo treatment). 88.2% (840/952) of AEs were mild, 11.3% (108/952) moderate, and 0.4% (4/952) were severe. 0.4% (5/1250) of subjects had active drug- or procedure-related serious AEs. The most frequent AE was headache (12.9% (123/952)), the mostly affected system organ class was CNS (14.4% of all subjects). The relative risk for an AE was significantly higher under active drug compared to placebo (1.24, 95% LCL >1). The incidence of AEs increased with higher dose steps. A higher incidence of AEs (active and placebo) in recent compared to previous studies was observed.
CONCLUSION: The risk of severe harm for healthy participants was low. The risk to experience any AE was higher under active drug compared to placebo. A trend change towards more frequent reporting of AEs in the recent studies was observed.

PMID: 31746730 [PubMed - indexed for MEDLINE]

Medication prescribing errors among hospitalized pediatric patients at Nekemte Referral Hospital, western Ethiopia: cross-sectional study.

BMC Res Notes. 2019 Jul 16;12(1):421

Authors: Fekadu G, Abdisa E, Fanta K

Abstract
OBJECTIVE: Incidence and clinical outcomes of medication prescribing errors are common and potentially more harmful in the pediatric population than in the adult population. Hence, this study was aimed to assess the prevalence and types of medication prescribing errors in the pediatric wards of Nekemte Referral Hospital (NRH).
RESULTS: Of 384 pediatric patients included in the study, 241 (63%) were males and 116 (30.21%) of them were aged between 1-3 years. About 241 (62.76%) of the patients were treated based on empirical diagnosis and only 10 (2.60%) pediatrics had co-morbid disease. The most category of medication prescribing error was dosing error 251 (48.6%) followed by incorrect drug selection 98 (19.0%). Being critically ill (AOR = 5.31, 95% CI = 1.80-12.31, p = 0.003), route of administration via IV (AOR = 3.98, 95% CI = 1.85-11.15, p = 0.011) and via IV + IM route (AOR = 2.22, 95% CI = 1.05-9.25, p = 0.045) as well as 4-6 medications per patient (AOR = 3.10, 95% CI = 3.43-12.42, p = 0.012) and > 6 medications per patient (AOR = 7.23, 95% CI = 3.91-21.45, p < 0.001) were independent predictors of medication prescribing errors. Antibiotics were the most common classes of drugs responsible for prescribing errors.

PMID: 31311587 [PubMed - indexed for MEDLINE]

Prevalence and recognition of highly significant medication-smoking cessation interactions in a smoke-free hospital.

Drug Alcohol Depend. 2019 07 01;200:78-81

Authors: Chui CY, Taylor SE, Thomas D, George J

Abstract
BACKGROUND: Some medications are more rapidly metabolized by smokers; upon smoking cessation, medication metabolism may be significantly reduced, resulting in medication-related adverse events. Clozapine, olanzapine and theophylline have been deemed to have potentially highly significant interactions with smoking cessation, which could lead to seizures, extrapyramidal effects and tachycardia, respectively. This study examined the period prevalence and characteristics of patients at risk of highly significant medication-smoking cessation interactions when admitted to a smoke-free hospital.
METHODS: A retrospective cross-sectional study was undertaken in an Australian tertiary-referral hospital with a well-established electronic prescribing system. Smokers prescribed clozapine, olanzapine or theophylline prior to and during a hospital admission in 2015 were included. Length of hospital stay, daily doses, and recognition of the potential interaction by treating clinicians were determined from medical records.
RESULTS: The period prevalence of patients at risk of a potentially highly significant medication-smoking cessation interaction was 23/48 (48%), 66/256 (26%) and 1/16 (6%) amongst smokers prescribed clozapine, olanzapine or theophylline, respectively. These interactions were poorly recognized by healthcare professionals during the admission.
CONCLUSIONS: Up to one in two patients receiving medications that have potentially highly significant interactions with smoking cessation may be experiencing clinically significant potential interactions. Such interactions, however, were commonly overlooked by hospital staff. Interventions to improve awareness of this issue are warranted.

PMID: 31108404 [PubMed - indexed for MEDLINE]

Medications and Vocal Function.

Otolaryngol Clin North Am. 2019 Aug;52(4):693-702

Authors: Bock JM

Abstract
Medications can have innumerable direct and indirect effects on laryngeal hydration, vocal fold mucosal integrity, laryngeal muscle function, and laryngeal sensation. Effects, therefore, can be subtle and slowly progressive over time. This article delineates the general classes of medications that are known to cause alterations of vocal function, highlights medical history symptoms that may help raise suspicion for medication-related vocal changes, and presents recommendations for approaches to treatment of these issues.

PMID: 31076163 [PubMed - indexed for MEDLINE]

Idiosyncratic Drug-Induced Acute Liver Failure: A Challenging and Distressing Scenario.

Curr Drug Saf. 2019;14(2):94-101

Authors: Colaci CS, Mendizabal M, Bessone F

Abstract
BACKGROUND: Idiosyncratic Drug Induced Liver Injury (DILI) is a rare adverse event to drugs that occasionally leads to severe liver damage, being one of the leading causes of Acute Liver Failure (ALF) in developed countries. DILI is largely a diagnosis of exclusion.
DISCUSSION AND CONCLUSION: Careful history of drug taking and ruling out other competing etiologies is mandatory given that DILI can present with an extremely variable phenotype. Several prognostic scores have been developed to promptly identify patients with potential risk of developing ALF. New biomarkers to diagnose and predict DILI evolution are under study and hopefully we will benefit from these novel tools in the near future.

PMID: 30767751 [PubMed - indexed for MEDLINE]

Adverse Drug Reactions to Radiographic Contrast Media in a Teaching Hospital in North India: An Observational Study.

Curr Drug Saf. 2019;14(2):122-126

Authors: Chopra D, Jain A, Garg R, Dhingra S

Abstract
BACKGROUND: Radiocontrast media are used extensively nowadays to visualize internal organs. Currently, non-ionic iodinated contrast media are used which are generally considered to be safe but some adverse reactions have been reported. Thus, the present study was carried out to analyze the nature and incidence of adverse drug reactions (ADRs) to radiographic contrast media in a teaching hospital.
METHODS: An observational study carried out for a period of six months in a teaching hospital. Contrast media induced adverse reactions were analyzed in terms of affected organs, rate, causality assessment, severity and preventability. The treatment and outcomes of adverse events were also recorded. Naranjo Probability Scale was used to evaluate the relationship between the contrast agent used and the suspected ADR. The severity of the suspected ADRs was determined using Hartwig Scale and preventability was assessed using modified Schumock and Thornton criterion.
RESULTS: A total of 15 suspected ADRs occurred in 11 patients with an incidence of 1.4%. It included 5 (45.4%) males and 6 (54.5%) females (p < 05). The highest percentage (72.7 %) of ADRs was seen in adult patients, the mean age being 40.8 years. Vomiting (33.3%) was the most common ADR noted followed by severe nausea and rashes. 64.7 % of ADRs were categorized as probable and 35.3 % were possible. Adverse reactions required treatment in 46.6% patients. There was no fatality reported.
CONCLUSION: The reactions observed were mild to moderate in severity and occurred within 30 minutes of the administration of the contrast.

PMID: 30666915 [PubMed - indexed for MEDLINE]

Regorafenib in Chinese patients with metastatic colorectal cancer: subgroup analysis of the phase 3 CONCUR trial.

J Gastroenterol Hepatol. 2020 Jan 03;:

Authors: Xu J, Xu RH, Qin S, Pan H, Bai Y, Chi Y, Wang L, Bi F, Cheng Y, Liu T, Ma D, Shen L, Ba Y, Liang J, Wang X, Yau TCC, Ma BB, Yeh KH, Lin JK, Kappeler C, Shapiro JA, Kalmus J, Li J

Abstract
BACKGROUND AND AIM: In the phase 3 CONCUR trial (NCT01584830), regorafenib improved overall survival (OS) versus placebo in Asian patients with treatment-refractory metastatic colorectal cancer (mCRC). We conducted a post-hoc subgroup analysis of Chinese patients in CONCUR.
METHODS: Adults with mCRC progressing despite at least two prior treatment regimens and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:1 to regorafenib 160 mg once daily or placebo for the first 3 weeks of each 4-week cycle. Dose modifications were permitted. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective overall response, disease control rate, and safety.
RESULTS: A total of 172 Chinese patients were randomized and treated (regorafenib n=112, placebo n=60). OS was significantly improved with regorafenib versus placebo (8.4 vs 6.2 months, respectively; hazard ratio [HR] 0.56, 95% CI 0.39-0.80; one-sided p=0.000632), as was PFS (HR 0.32, 95% CI 0.22-0.47; one-sided p<0.000001). The most common drug-related grade ≥3 treatment-emergent adverse events (TEAEs; regorafenib, placebo) were hand-foot skin reaction (19%, 0%), hypertension (13%, 3%), hypophosphatemia (7%, 0), increased alanine aminotransferase (6%, 0), and increased aspartate aminotransferase (5%, 0). In patients receiving regorafenib and placebo, respectively, TEAEs led to treatment discontinuation in 14% and 7%, dose reduction in 39% and 0%, and dose interruption in 64% and 20%.
CONCLUSIONS: This retrospective analysis showed that regorafenib provided an OS benefit over placebo for Chinese patients with previously treated mCRC. TEAEs were consistent with the regorafenib safety profile and manageable with treatment modifications.

PMID: 31900959 [PubMed - as supplied by publisher]

Real-world study of direct oral anticoagulant dosing patterns in patients with atrial fibrillation.

Pharm Pract (Granada). 2019 Oct-Dec;17(4):1709

Authors: Gustafson WL, Saunders J, Vazquez SR, Jones AE, Witt DM

Abstract
Background: Direct oral anticoagulants (DOACs) are preferred for stroke prevention in atrial fibrillation (AF). However, off-label doses have been associated with increased risk of adverse events.
Objective: The objective of this study was to compare the frequency and outcomes of labeled versus off-label DOAC dosing in patients with AF.
Methods: This retrospective cohort study included adults diagnosed with nonvalvular AF (NVAF), discharged from University of Utah Health on DOAC therapy between 7/1/2017 and 9/30/2017. The primary outcome was off-label DOAC dosing frequency, defined as dosing inconsistent with manufacturer labeling. Secondary outcomes included variables associated with off-label dosing and a composite of adverse events (major bleeding, thromboembolism, and all-cause mortality) in the 90 days following the index hospital discharge.
Results: Of 249 included patients, 16.1% were discharged with off-label dosing. Factors associated with off-label dosing included advanced age, lower body mass index, decreased renal function, use of rivaroxaban, and hepatic impairment. The majority of off-label patients (70%) received lower-than-recommended DOAC dosing. Prescriber rationale for off-label prescribing was documented in 25% of patients and included anti-Xa guided dosing, high risk for bleeding or thromboembolism, and prior history of on-therapy adverse events. The rate of adverse events between labeled and off-label DOAC doses was not statistically different (10.0% vs. 6.7%, p=0.299), although this is likely due to small sample size.
Conclusions: Off-label DOAC prescribing for stroke prevention in NVAF at University of Utah Health was consistent or lower than previously published studies. Off-label dosing most often involved under-dosing of rivaroxaban. Future research should investigate the role of provider rationale and insight in optimizing DOAC therapy outcomes.

PMID: 31897264 [PubMed]

A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer.

Invest New Drugs. 2020 Jan 02;:

Authors: Goyal L, Chaudhary SP, Kwak EL, Abrams TA, Carpenter AN, Wolpin BM, Wadlow RC, Allen JN, Heist R, McCleary NJ, Chan JA, Goessling W, Schrag D, Ng K, Enzinger PC, Ryan DP, Clark JW

Abstract
Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2, MET, or FGFR2 or mutations in PIK3CA, EGFR, or BRAF. Ganetespib which is a novel triazolone heterocyclic inhibitor of HSP90, is a potentially biologically rational treatment strategy for advanced EG cancers with these gene amplification. This multicenter, single-arm phase 2 trial enrolled patients with histologically confirmed advanced EG cancer with progression on at least one line of systemic therapy. Patients received Ganetespib 200 mg/m2 IV on Days 1, 8, and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). Secondary endpoints included: Progression Free Survival (PFS); to correlate the presence of HSP clients with ORR and PFS; evaluating the safety, tolerability and adverse events profile. In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single-agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug.

PMID: 31898183 [PubMed - as supplied by publisher]

Interstitial nephritis associated with nivolumab in a patient with hodgkin lymphoma.

Rev Assoc Med Bras (1992). 2019 08 05;65(7):934-936

Authors: Oliveira DS, Mesquita JL, Garcia YDO, Rosales YMZ, Lemes RPG, Rocha Filho FD, Fernandes PFCBC, Duarte PMA, Pitombeira MDS, Duarte FB

PMID: 31389500 [PubMed - indexed for MEDLINE]

"Top ten": another alert on the prescription of proton-pump inhibitors (PPIs) for the elderly.

Rev Assoc Med Bras (1992). 2019 07 22;65(6):742-743

Authors: Manso MEG, Oliveira HSB

PMID: 31340295 [PubMed - indexed for MEDLINE]