Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder.

Ann Clin Transl Neurol. 2021 Feb 04;:

Authors: Devinsky O, King L, Bluvstein J, Friedman D

Abstract
OBJECTIVE: Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD).
METHODS: This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period 1), a 4-week washout, then another 12-week treatment (period 2). The primary outcome was ataluren's safety profile. The secondary outcome measures were (1) changes in convulsive and/or drop seizure frequency and (2) changes in minor seizure types during ataluren treatment compared to placebo. Exploratory objectives assessed changes in cognitive, motor, and behavioral function as well as quality of life during ataluren therapy.
RESULTS: We enrolled seven subjects with DS and eight subjects with CDD. Three treatment-related adverse events (AE) occurred during the blinded phases. Two subjects withdrew due to AE. Ataluren was not effective in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either DS or CDD due to nonsense variants. Limitations included a small sample size and 12-week treatment phase, possibly too short to identify a disease-modifying effect.
SIGNIFICANCE: There was no difference between ataluren and placebo; ataluren is not an effective therapy for seizures or other disorders in children with DS or CDD due to nonsense variants. There were no drug-related serious AE during the double-blind period, consistent with ataluren's favorable safety profile in larger studies. (Funded by Epilepsy Foundation, Dravet Syndrome Foundation, Finding A Cure for Seizures and Epilepsy and PTC Therapeutics, Inc.; ClinicalTrials.gov number, NCT02758626).

PMID: 33538404 [PubMed - as supplied by publisher]

Long-term management of lenvatinib-treated thyroid cancer patients: a real-life experience at a single institution.

Endocrine. 2021 Feb 03;:

Authors: Porcelli T, Luongo C, Sessa F, Klain M, Masone S, Troncone G, Bellevicine C, Schlumberger M, Salvatore D

Abstract
PURPOSE: The efficacy of lenvatinib for advanced and progressive radioactive iodine refractory differentiated thyroid cancer is well established. Herein, we retrospectively evaluated the long-term safety and efficacy of lenvatinib in 23 patients treated at a single Institution.
METHODS: Clinical data of all patients treated for a differentiated thyroid cancer with lenvatinib from April 2015 to September 2020 were retrospectively analyzed.
RESULTS: A total of 23 patients were included. In all, 21 patients received lenvatinib as first-line systemic therapy. Median age at initiation of lenvatinib treatment was 68 (44-90) years. Median duration of the study from initiation of lenvatinib to study end was 23 (2-65) months. The indication for lenvatinib treatment was documented progression of distant metastases in 20 patients and of locally advanced disease in the other 3 and median duration of lenvatinib therapy was 15 (2-64) months. Best treatment responses were: partial response in 6 patients, stable disease in 14, progressive disease in 1, and not evaluable in 2. Median progression-free survival was 25 months (95% CI: 12-40) and median overall survival was 46 months (95% CI: 28-65). Three patients had to discontinue lenvatinib treatment due to serious adverse events and no drug-related death was observed. Ten patients continued lenvatinib for more than 24 months and the only newly registered adverse event after this period of time was one case of G2 proteinuria. Six patients continued lenvatinib treatment beyond documented tumor progression due to oligoprogression or slowly progressive disease (median time 18.5 months, 8-42 months). A total of 14 patients were alive at the end of the study: 11 showed partial response/stable disease on lenvatinib, including 3 who had a stable disease after local ablative therapy for oligoprogressive metastases; 3 had to change treatment, including 2 for lenvatinib-related serious adverse events and 1 for progressive disease.
CONCLUSIONS: Long-term lenvatinib treatment is safe and some patients may experience persistent long-term control of the disease. Late treatment-related AEs rarely occurred. Oligoprogressive and slowly progressive disease can be managed without treatment withdrawal as long as there are some clinical benefits.

PMID: 33537956 [PubMed - as supplied by publisher]

Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study.

BMJ. 2021 01 29;372:m4931

Authors: Yoon D, Lee JH, Lee H, Shin JY

Abstract
OBJECTIVE: To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea.
DESIGN: Cohort study.
SETTING: A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019.
PARTICIPANTS: 441 399 girls aged 11-14 years who had been vaccinated in 2017: 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV.
MAIN OUTCOME MEASURES: Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV unvaccinated group, and adjusted relative risks were estimated using conditional logistic regression in the secondary analysis.
RESULTS: Among the 33 predefined serious adverse events, no associations were found with HPV vaccination in the cohort analysis, including Hashimoto's thyroiditis (incidence rate per 100 000 person years: 52.7 v 36.3 for the vaccinated and unvaccinated groups; adjusted rate ratio 1.24, 95% confidence interval 0.78 to 1.94) and rheumatoid arthritis (incidence rate per 100 000 person years: 168.1 v 145.4 for the vaccinated and unvaccinated groups; 0.99, 0.79 to 1.25), with the exception of an increased risk observed for migraine (incidence rate per 100 000 person years: 1235.0 v 920.9 for the vaccinated and unvaccinated groups; 1.11, 1.02 to 1.22). Secondary analysis using self-controlled risk intervals confirmed no associations between HPV vaccination and serious adverse events, including migraine (adjusted relative risk 0.67, 95% confidence interval 0.58 to 0.78). Results were robust to varying follow-up periods and for vaccine subtypes.
CONCLUSIONS: In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

PMID: 33514507 [PubMed - indexed for MEDLINE]

Pulmonary Manifestations of Rheumatoid Arthritis.

Sr Care Pharm. 2021 Feb 01;36(2):97-103

Authors: Christensen KJ, Malesker MA, Jagan N, Moore DR

Abstract
OBJECTIVE: To describe the case of an 88-yearold male with rheumatoid arthritis who developed pulmonary manifestations. Treatment for his RA previously included various biologics, while at the time of pulmonary consultation included meloxicam, methotrexate, and abatacept. Following chest scans, bronchoscopy, needle biopsy, pulmonary function testing, and a thoracentesis, the diagnosis of pleural effusion and nodules associated with rheumatoid arthritis was determined. The patient was recommended to follow-up with the pulmonologist but was lost to follow-up because of nonpulmonary and nonrheumatoid arthritis complications.<BR/> SETTINGS: Ambulatory clinic pharmacy practice, Community pharmacy, Consultant pharmacy practice.<BR/> PRACTICE CONSIDERATIONS: Drugs used to treat rheumatoid arthritis may produce pulmonary toxicity similar to what is seen with the disease itself. Drug therapy may require modification if identified as an offending agent causing pulmonary manifestations. If fibrosing interstitial lung disease develops, the addition of nintedanib may need to be considered.<BR/> CONCLUSION: In order for pharmacists to better assist providers and patients and improve therapeutic outcomes, it is important for pharmacists to understand that pulmonary manifestations are common in patients having rheumatoid arthritis as well as with drugs used to treat rheumatoid arthritis.

PMID: 33509333 [PubMed - indexed for MEDLINE]

Sex Differences in Lopinavir Concentrations and Occurrence of Marked QTc Prolongation Episodes in Patients with COVID-19.

Drug Saf. 2021 02;44(2):255-257

Authors: Marzolini C, Stader F, Leuppi-Taegtmeyer A, Stoeckle M, Battegay M, Sendi P

PMID: 33245507 [PubMed - indexed for MEDLINE]

Impact of adverse event reports from marketing authorization holder-sponsored patient support programs on the performance of signal detection in pharmacovigilance.

Expert Opin Drug Saf. 2020 Oct;19(10):1357-1366

Authors: Lee I, Lee TA, Crawford SY, Kilpatrick RD, Calip GS, Jokinen JD

Abstract
OBJECTIVES: Marketing authorization holder (MAH)-sponsored patient support programs (PSPs) are a major source of adverse event (AE) reports. The impact of reports from PSPs on the ability to detect AE signals is unclear. We compared signal detection performance using data from PSPs vs. non-PSP sources, and between PSPs providing clinical services vs. PSPs not providing clinical services.
METHODS: Data were obtained from an internal safety database for a global pharmaceutical company 2015-2017. We assessed whether signals were detected for the reference drug-AE pairs using data from PSPs vs. non-PSP sources, and among different PSP services. The performance was evaluated by four measures including area under the receiver operating characteristic curve (AUC) and time-to-signal detection.
RESULTS: While the majority of reports were from PSPs, non-PSP sources were better and faster at detecting signals (AUC 0.63 vs. 0.41, p = 0.035; HR 3.52, p = 0.014) compared to PSPs. Within PSPs, PSPs providing clinical services were marginally better at detecting signals (AUC 0.60 vs. 0.41, p = 0.053) but not faster compared to PSPs not providing clinical services.
CONCLUSION: Reports of AEs from PSPs had worse signal detection performance compared to non-PSP sources. Pharmacovigilance experts should be mindful when using databases that contain reports from PSPs for signal detection.

PMID: 32662668 [PubMed - indexed for MEDLINE]

Hyper-progressive disease in a patient with advanced non-small cell lung cancer on immune checkpoint inhibitor therapy: A case report and literature review.

Lung Cancer. 2020 01;139:18-21

Authors: Zhang D, Zhang Y, Huang Y, Kong L, Yu J

Abstract
OBJECTIVES: While immune checkpoint inhibitor (ICI) therapy has excellent efficacy in treating multiple cancers, some patients experience accelerated disease progression, defined as hyper-progressive disease (HPD). However, the characteristics of HPD, especially in patients with non-small-cell lung cancer (NSCLC), remain to be elucidated.
MATERIALS AND METHODS: We report about an advanced NSCLC patient with striking disease progression, defined as HPD by existing standards, after the administration of pembrolizumab. We also reviewed related studies to discuss the definition, relative factors, and prognosis of HPD.
RESULTS AND CONCLUSION: This case of NSCLC with HPD had a series of characteristics not widely described in HPD cases previously reported, suggesting the potential complexity of this phenomenon and the necessity to study its characteristics and to more closely monitor patients who are administered ICIs.

PMID: 31704279 [PubMed - indexed for MEDLINE]

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020 Dec;32(12):1526-1529. doi: 10.3760/cma.j.cn121430-20201018-00676.

ABSTRACT

Colchicine is mainly used in the treatment of acute gout attack, acute attack of chronic gout and other diseases in clinic. But the drug has high toxicity (highly toxic), the therapeutic dose is very close to the toxic dose, and there is no special effect after poisoning drug detoxification. The clinical manifestations of early patients after poisoning are not specific, which brings some difficulties and challenges in clinical diagnosis and treatment, and virtually increases the probability of death from drug poisoning. The drug poisoning is still sporadic reports. On September 1, 2020, a patient with acute colchicine poisoning was admitted to People's Hospital of Songtao Miao Autonomous County. This patient is the one with the longest poisoning time that can be retrieved by authoritative medical journals. After treatment, the patient was cured and discharged. This article reported the experience of diagnosis and treatment.

PMID:33541510 | DOI:10.3760/cma.j.cn121430-20201018-00676

A randomized, controlled, multicenter clinical trial to evaluate the efficacy and safety of oral sitafloxacin versus moxifloxacin in adult patients with community-acquired pneumonia.

Curr Med Res Opin. 2021 Feb 03;:1

Authors: Li Y, Zhu D, Peng Y, Tong Z, Ma Z, Xu J, Sun S, Tang H, Xiu Q, Liang Y, Wang X, Xiaoju L, Dai Y, Zhu Y, Qu Y, Xu K, Huang Y, Wu S, Lai G, Li X, Han X, Yang Z, Sheng J, Liu Z, Li H, Chen Y, Zhu H, Zhang Y

Abstract
OBJECTIVES: To evaluate the efficacy and safety of oral sitafloxacin versus oral moxifloxacin in the treatment of Chinese adults with community-acquired pneumonia (CAP).
PATIENTS AND METHODS: This is a multicenter, randomized, open-label, positive-controlled clinical trial (chinadrugtrials.org.cn identifier: CTR20130046). CAP patients received sitafloxacin tablets 100mg once daily (qd) or 100mg twice daily (bid) to compare with moxifloxacin tablets 400mg qd, for 7-10 days. The primary outcome was non-inferiority of sitafloxacin to moxifloxacin in clinical cure rate at test of cure (TOC) visit in per-protocol set (PPS).
RESULTS: A total of 343 patients were randomized (sitafloxacin 100mg qd, n = 117, sitafloxacin 100mg bid, n = 116, moxifloxacin, n = 110), 291 patients were included in PPS (sitafloxacin 100mg qd, n = 96, sitafloxacin 100mg bid, n = 94, moxifloxacin, n = 101). The clinical cure rate was 94.8% in sitafloxacin 100mg qd group, 96.8% in sitafloxacin 100mg bid group, and 95.0% in moxifloxacin group. At TOC visit, the microbiological success rate was 97.0% (32/33) in sitafloxacin 100mg qd group, 97.1% (34/35) in sitafloxacin 100mg bid group, and 94.9% (37/39) in moxifloxacin group in microbiological evaluable set (MES). The incidence of study drug-related adverse events (AEs) was 23.3% (27/116) in sitafloxacin 100mg qd group, 29.8% (34/114) in sitafloxacin 100mg bid group, and 28.2% (31/110) in moxifloxacin group (P > 0.05). The common AEs related to study drug were dizziness, nausea, diarrhea, increased platelet count, and ALT elevation. All the AEs resolved completely after discontinuation of study drug.
CONCLUSION: Sitafloxacin 100mg qd or 100mg bid for 7-10 days is not inferior to moxifloxacin 400mg qd for 7-10 days in the clinical efficacy for adult CAP patients. Sitafloxacin provides safety profile comparable to moxifloxacin.

PMID: 33534617 [PubMed - as supplied by publisher]

Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Conventional Therapy at Different Periods: A Meta-Analysis of Randomized Controlled Trials.

J Diabetes Res. 2020;2020:9704659

Authors: Huang J, Xiong S, Ding S, Cheng Q, Liu Z

Abstract
Aims: To assess the safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with conventional therapy at different periods.
Methods: We searched PubMed, Embase, and The Cochrane Library from inception to September 23, 2020. A total of six studies involving 4120 patients were included.
Results: Compared with the control group, 15 mg and 5 mg of ertugliflozin were associated with higher risks of genital mycotic infections (GMIs) at 26 weeks (p < 0.0001 and p < 0.0001, respectively), 52 weeks (p < 0.00001 and p < 0.0001, respectively), and 104 weeks (p < 0.00001 and p < 0.0001, respectively). Moreover, females had a higher risk of GMIs than males in the 15 mg group at 26 weeks (p = 0.0008), 52 weeks (p < 0.0001), and 104 weeks (p = 0.02). At 104 weeks, 15 mg and 5 mg of ertugliflozin showed beneficial effects on symptomatic hypoglycemia (p < 0.00001 and p = 0.004, respectively) compared with the effects observed in the control group. Compared with the control group, 15 mg and 5 mg of ertugliflozin were associated with higher risks of drug-related adverse events at 26 weeks (p = 0.002 and p = 0.002, respectively); 15 mg of ertugliflozin was associated with a higher risk of discontinuation related to adverse events at 104 weeks (p = 0.03). No significant differences were found in the remaining safety outcomes.
Conclusion: This meta-analysis of randomized controlled trials indicates that ertugliflozin is tolerated by T2DM, but the risk of GMIs is noteworthy, especially among females in the high-dose group.

PMID: 33532502 [PubMed - in process]

Impact of genetic factors on platinum-induced gastrointestinal toxicity.

Mutat Res. 2020 Oct - Dec;786:108324

Authors: Zheng Y, Deng Z, Tang M, Xiao D, Cai P

Abstract
Severe gastrointestinal (GI) toxicity is a common side effect after platinum-based chemotherapy. The incidence and severity of GI toxicity vary among patients with the same chemotherapy. Genetic factors involved in platinum transport, metabolism, detoxification, DNA repair, cell cycle control, and apoptosis pathways may account for the interindividual difference in GI toxicity. The influence of gene polymorphisms in the platinum pathway on GI toxicity has been extensively analyzed. Variations in study sample size, ethnicity, design, treatment schedule, dosing, endpoint definition, and assessment of toxicity make it difficult to precisely interpret the results. Hence, we conducted a review to summarize the most recent pharmacogenomics studies of GI toxicity in platinum-based chemotherapy and identify the most promising avenues for further research.

PMID: 33339576 [PubMed - indexed for MEDLINE]

Interventions to improve spontaneous adverse drug reaction reporting by healthcare professionals and patients: systematic review and meta-analysis.

Expert Opin Drug Saf. 2020 Sep;19(9):1173-1191

Authors: Paudyal V, Al-Hamid A, Bowen M, Hadi MA, Hasan SS, Jalal Z, Stewart D

Abstract
INTRODUCTION: The aim of this study was to evaluate the effectiveness of interventions used for improving ADR reporting by patients and healthcare professionals.
AREAS COVERED: A systematic review of literature was conducted by searching Medline, Embase and Cochrane Central Register of Controlled of Trials. Meta-analysis of randomized controlled trials (RCTs; n = 5) was conducted to estimate the pooled risk ratio for the effectiveness of interventions on ADR reporting rates. Data from observational studies were synthesized using narrative synthesis approach.
EXPERT OPINION: A total of 28 studies were included. All except one study targeted healthcare professionals using educational, technological, policy, financial and/or mixed interventions. The results showed that financial and face-to-face educational interventions improved quality and quantity of ADR reporting when compared with interventions not involving face-to-face interactions. However, the quality of studies was generally low. Meta-analysis showed a statistically significant 3.5-fold overall increase in reporting of ADRs [RR 3.53; 95% CI (1.77,7.06)] in the intervention group compared to the control. There was a lack of consideration of theory and sustainability in the design of the interventions. There is a need to develop and test theory-based interventions and target patient reporting. More research needs to be conducted in the low- and middle-income countries.

PMID: 32755492 [PubMed - indexed for MEDLINE]

Cutaneous Adverse Events in Newly Approved FDA Non-cancer Drugs: A Systematic Review.

Drugs R D. 2020 Sep;20(3):171-187

Authors: Macklis PC, Dulmage B, Evans B, Rosenbach M, Gudjonsson JE, Kaffenberger BH

Abstract
The prevalence of cutaneous adverse events attributable to newly approved anti-cancer drugs has been well reviewed in the dermatologic literature. In contrast, over 75% of US Food and Drug Administration approvals in the past 5 years have been for non-cancer drugs and indications. This represents multiple other categories of approved medications associated with cutaneous adverse reactions. To investigate the cutaneous adverse events associated with these potentially neglected medications, a systematic review was conducted. Two hundred and forty-one medications approved by the Food and Drug Administration between 2013 and 2018 were reviewed and 180 non-oncologic drugs were identified. The prescribing information for each medication was reviewed for the presence of cutaneous adverse events and a supplemental literature search was performed to better characterize any adverse events outlined within the prescribing information. Most reactions were classified as morbilliform, macular, popular, or maculopapular. Fortunately, only a few severe cutaneous adverse reactions were reported, namely in benznidazole, cannabidiol, and sofosbuvir. This review summarizes available data drawn from clinical trials and case reports involving cutaneous adverse events from the 21 non-oncologic medications associated with cutaneous adverse events.

PMID: 32557274 [PubMed - indexed for MEDLINE]

Emerging drugs for the treatment of L-DOPA-induced dyskinesia: an update.

Expert Opin Emerg Drugs. 2020 06;25(2):131-144

Authors: AlShimemeri S, Fox SH, Visanji NP

Abstract
INTRODUCTION: Prolonged treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of uncontrolled movements (L-DOPA-induced dyskinesias (LID)) in Parkinson's disease (PD). There is currently only a single approved drug for the treatment of LID, a long-acting preparation of the NMDA antagonist, amantadine, that has variable benefits and side-effects. Therefore, new treatments for LID remain an unmet in PD.
AREAS COVERED: We review the current strategies for the management of LID; the pathogenic mechanisms underlying the development of LID, which provides the rationale for clinical trials of novel targets for LID and provide a review of phase II/III trials for emerging drugs for LID, with either positive results, or ongoing studies, reported between January 2014 and December 2019.
EXPERT OPINION: There are several ongoing studies for agents that showed possible benefit at phase Ib/IIa for reducing LID. However, there are no new positive phase III double-blind randomized controlled clinical trials (DBRCT) for emerging treatments for LID. Generating better preclinical models, more precise recruitment tools and better outcome measures remain a priority. The pharmacology of drugs investigated for LID may be too selective; therefore, evaluating combinations of drugs is worthy of consideration as is the repurposing of existing drugs with multiple pharmacological targets.

PMID: 32366130 [PubMed - indexed for MEDLINE]

ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature.

Curr Opin Pulm Med. 2020 05;26(3):293-301

Authors: Klay D, Platenburg MGJP, van Rijswijk RHNAJ, Grutters JC, van Moorsel CHM

Abstract
PURPOSE OF REVIEW: The current review aims to recognize the variability in clinical presentation of adult patients with bi-allelic ABCA3 mutations, create more depth in ABCA3 mutations reported and highlight the influence of environmental factors on disease course.
RECENT FINDINGS: Mutations in ABCA3 are predominantly linked to neonatal and pediatric interstitial lung disease (ILD) with a minority surviving beyond puberty. Here, we present three patients with ABCA3 mutations who present with disease at the age of 19, 61 and 77. Moreover, we identified c.4451G>C (p.R1484P), c.1675G>A (p.G559R) and c.4745C>G (p.T1582S) as three novel ABCA3 mutations. In addition, we identified six additional patients with ABCA3 mutations in literature who reached an age above 18. Furthermore, we discuss the influence of infections, drugs and smoking on disease course.
SUMMARY: Although extremely rare, patients with bi-allelic mutations in ABCA3 may present at adulthood. Late onset of disease may be influenced by type of mutation or environmental factors.

PMID: 32238781 [PubMed - indexed for MEDLINE]

Human papillomavirus vaccination and postural tachycardia syndrome, deconditioning and exercise-induced hyperalgesia: An alternate interpretation of the reported adverse reactions.

J Obstet Gynaecol Res. 2020 May;46(5):678-683

Authors: Ishizaki Y, Gomi H

Abstract
Human papillomavirus vaccination (HPVV) was included in the national immunization program in 2013 in Japan. However, the Japanese government suspended proactive recommendations 2 months after this decision because various adverse events following the vaccination were reported by the media. More than 6 years have already passed since the suspension of proactive recommendations of all available vaccines in Japan. Although no causal relationship between the adverse effects and HPVV has been confirmed, the Japanese government has not withdrawn the suspension. Thus, it is important to show various possible causes of the adverse events other than HPVV. It is attempted to describe the possible contribution of the misunderstanding regarding the symptoms of postural tachycardia syndrome, deconditioning, and exercise-induced hyperalgesia as the adverse effects of HPVV in this review article.

PMID: 32153078 [PubMed - indexed for MEDLINE]

Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat.

J Clin Pharmacol. 2020 01;60(1):107-116

Authors: Willis BA, Andersen SW, Ayan-Oshodi M, James DE, Liffick E, Hillgren K, Guo Y, Monk SA

Abstract
Lanabecestat is a human β-site amyloid precursor protein-cleaving enzyme 1 inhibitor in development to slow disease progression in patients with early Alzheimer's disease. The study evaluated the breast cancer resistance protein (BCRP) inhibition potential of lanabecestat on the pharmacokinetics (PK) of rosuvastatin, a probe for BCRP activity, in healthy white subjects who were not carriers of SLCO1B1 (c.521T>C), not homozygotes for ABCG2 (c.421C>A or c.34G>A), and not heterozygotes of ABCG2 (c.421C>A and c.34G>A). The safety of lanabecestat + rosuvastatin, the effects of rosuvastatin on the PK of lanabecestat, and the effects of multiple genetic polymorphisms on rosuvastatin exposure were assessed. Geometric mean ratios of the maximum observed rosuvastatin concentration (Cmax ), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax ) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax at steady state increased 8% in the presence of rosuvastatin. Except for an approximately 80% increase of rosuvastatin AUC (P < .05) in the heterozygotes of ABCG2 c.421C>A relative to the CC genotype, there were no statistically significant associations between rosuvastatin exposure and polymorphisms assessed. Lanabecestat + rosuvastatin was associated with few treatment-emergent adverse events, all of which resolved and were mild. Lanabecestat does not meaningfully impact BCRP activity; therefore, restriction of concomitant administration with BCRP substrates, such as rosuvastatin, may be unnecessary.

PMID: 31378968 [PubMed - indexed for MEDLINE]

Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

J Clin Pharmacol. 2020 01;60(1):125-139

Authors: Darpo B, Benson C, Brown R, Dota C, Ferber G, Ferry J, Jarugula V, Keirns J, Ortemann-Renon C, Pham T, Riley S, Sarapa N, Ticktin M, Zareba W, Couderc JP

Abstract
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.

PMID: 31378962 [PubMed - indexed for MEDLINE]

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1.

HIV Res Clin Pract. 2021 Feb 02;:1-17

Authors: Huhn GD, Wilkin A, Mussini C, Spinner CD, Jezorwski J, El Ghazi M, Van Landuyt E, Lathouwers E, Brown K, Baugh B, AMBER and EMERALD study groups

Abstract
BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917).
OBJECTIVE: To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent).
METHODS: Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials).
RESULTS: D/C/F/TAF demonstrated high Week 96 virologic responses (AMBER: 85% [308/362]; EMERALD: 91% [692/763]) and low VF rates (AMBER: 6% [20/362]; EMERALD: 1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFRcyst and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio.
CONCLUSIONS: D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults.

PMID: 33528318 [PubMed - as supplied by publisher]

Differences in detected safety signals between benzodiazepines and non-benzodiazepine hypnotics: pharmacovigilance study using a spontaneous reporting system.

Int J Med Sci. 2021;18(5):1130-1136

Authors: Toyoshima M, Noguchi Y, Otsubo M, Tachi T, Teramachi H

Abstract
Introduction: In recent years, there has been an increasing number of people who feel sleep-deprived owing to sudden changes in the social environment. Patients prescribed benzodiazepine-based hypnotics (BZ drugs) also develop movement disorder action and memory disorders as adverse events (AEs), and they have further problems such as dependency and tolerance because of long-term use. Therefore, the use of non-benzodiazepine-based hypnotics (Z-drugs) is recommended for patients with insomnia. However, as AEs have also been reported for Z-drugs, it is important to identify these when switching hypnotics. Methods: To understand AEs to be noted when switching from BZ drugs to Z-drugs, we evaluated the differences in AEs developed by both these drugs using volcano plots and safety signals. For this, data registered in the Japanese Adverse Drug Event Report database were used. Results: The volcano plot and safety signals revealed six characteristic Z-drug-induced AEs. Parasomnias (ln odds ratio [OR]: 3.28, -log P: 4.34, proportional reporting ratio [PRR]: 23.47, χ 2: 309.27), Cortical dysfunction NEC (ln OR: 2.76, -log P: 4.34, PRR: 3.62, χ 2: 16.14), and Psychiatric symptoms NEC (ln OR: 2.66, -log P: 2.18, PRR: 2.51, χ 2: 6.63) were detected only in Z-drugs, and safety signals of Suicidal and self-injurious behaviour, Deliria, and Overdoses NEC were also detected with BZ drugs. However, the strength of safety signals was much higher with the Z-drugs. Conclusion: AEs related to falls and bone fractures are expected to be more strongly onset in BZ drugs than in Z-drugs, which are said to have less muscle relaxant action. However, there was no particularly significant difference in this parameter between the two drug classes. Understanding the difference between these AEs of Z-drugs and BZ drugs is important for the proper use of hypnotics.

PMID: 33526972 [PubMed - in process]