Fullerene C60 nanoparticles ameliorated cyclophosphamide-induced acute hepatotoxicity in rats.

Biomed Pharmacother. 2018 Jan;97:53-59

Authors: Elshater AA, Haridy MAM, Salman MMA, Fayyad AS, Hammad S

Abstract
Cyclophosphamide (CP), a chemotherapeutic agent, induces hepatotoxicity as one of its side effects. Therefore, the aim of the present study is to investigate the potential hepatoprotective effects of fullerene C60 nanoparticles (C60) against the high toxic dose of CP. Twenty five albino rats were randomly assigned to 5 groups (n=5 per group). Group 1 served as a control. Group 2 received 200mg/kg of CP once intraperitoneally, while group 3 treated with the same CP dose plus C60 (4mgkg, orally) daily for 10days. Group 4 exposed CP and ZnCl2 (4mgkg, orally) daily for 10days. Group 5 exposed to CP and co-treated with C60 and ZnCl2. One day after last treatment, blood and livers were collected for hematological, biochemical and histopathological investigations. C60 normalized significantly RBCs, HB, PCV, WBCs and platelets numbers compared to CP-exposed rats. Moreover, liver enzymes namely ALT, AST and ALP revealed that CP elevated their levels and C60 significantly (p<0.05) reduced them to basal levels. The level of oxidative stress marker namely, MDA was elevated upon CP exposure and normalized by C60 treatment. In addition, antioxidant systems e.g. GSH, CAT and SOD were depleted from liver tissue due to CP toxicity these were recovered by C60 administration. The hepatoprotective effects of C60 on tested parameters were comparable with ZnCl2 and neither additive nor synergistic effect was observed. Histopathogically, severe liver degeneration was recorded after CP treatment, however, only mild changes were observed after C60 administration. Our data suggest that C60 improves both blood and hepatic parameters altered by cyclophosphamide-induced toxicities. The current study is of clinical relevance particularly, application of C60 as a monotherapy or in combination to ameliorate the CP side effects in cancer-treated patients.

PMID: 29080458 [PubMed - indexed for MEDLINE]

A Pilot Phase II Study of Erlotinib for the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia.

Acta Haematol. 2018 Aug 02;140(1):30-39

Authors: Abou Dalle I, Cortes JE, Pinnamaneni P, Lamothe B, Diaz Duque A, Randhawa J, Pemmaraju N, Jabbour E, Ferrajoli A, Wierda WG, Estrov Z, Konopleva M, Ravandi F, Alvarado Y, Borthakur G, Gandhi V, Kantarjian HM

Abstract
Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12-142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3-96.9 weeks) and median event-free survival was 5 weeks (range 1.7-21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.

PMID: 30071517 [PubMed - as supplied by publisher]

Drug-induced hypersensitivity: A 5-year retrospective study in a hospital electronic health records database.

J Clin Pharm Ther. 2018 Aug 01;:

Authors: Mendes D, Alves C, Loureiro M, Fonte A, Batel-Marques F

Abstract
WHAT IS KNOWN AND OBJECTIVE: Hypersensitivity adverse drug reactions (HADRs) are associated with considerable morbidity and mortality. The aim of this study was to identify cases of HADRs within a hospital electronic health records (EHR) database.
METHODS: Data were extracted from EHR through the Portuguese catalogue of allergies and other adverse reactions (CPARA). This registry allows the collection and sharing of information on HADRs in a structured and harmonized way across the healthcare system. This module is used by healthcare professionals to record HADRs within the EHR of each patient. It applies to patients admitted to hospital because of HADRs and also to inpatients developing such reactions during hospitalization. Data recorded from 2013 to 2017 within the Centro Hospitalar de Entre o Douro e Vouga (CHEDV) hospital (397 beds; ≈20 300 inpatients/year) were considered. The MedDRA® classification was used to codify HADRs. The ATC classification system was used to codify drugs. The concept of individual case safety report (ICSR) was considered for performing analyses.
RESULTS AND DISCUSSION: The database contained 464 valid cases (severe, n = 330; 71.1%), corresponding to 380 patients and 559 HADRs. Most patients were female (n = 254; 66.8%); the median age was 55 years. Approximately 0.1% local inhabitants and ≈0.4% inpatients have experienced HADRs over the study period. Most cases (n = 245; 52.8%) were associated with systemic antibacterials. Most HADRs were skin and subcutaneous tissue disorders (n = 266; 47.6%) and immune system disorders (n = 231; 41.3%). The pattern of suspected drugs implicated in anaphylactic reactions was the same as those involved in other HADRs.
WHAT IS NEW AND CONCLUSION: This registry contains HADRs that are relevant for the pharmacovigilance system, but none was spontaneously reported. The responsible authorities should address this problem. The results also reinforce the association between systemic antibacterials and HADRs.

PMID: 30069891 [PubMed - as supplied by publisher]

Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress.

Mol Neurobiol. 2018 Aug 01;:

Authors: Montenegro-Burke JR, Woldstad CJ, Fang M, Bade AN, McMillan J, Edagwa B, Boska MD, Gendelman HE, Siuzdak G

Abstract
Antiretroviral therapy (ART) restricts human immunodeficiency virus type one (HIV-1) replication and by so doing, improves the quality and longevity of life for infected people. Nonetheless, treatment can also lead to adverse clinical outcomes such as drug resistance and systemic adverse events. Both could be affected by long-acting slow effective release ART. Indeed, maintenance of sustained plasma drug levels, for weeks or months, after a single high-level dosing, could improve regimen adherence but, at the same time, affect systemic toxicities. Of these, the most troubling are those that affect the central nervous system (CNS). To address this, dolutegravir (Tivicay, DTG), a potent and durable HIV integrase inhibitor used effectively in combination ART was tested. Rodents were administered parenteral 45-mg/kg doses. DTG-associated changes in CNS homeostasis were assessed by measuring brain metabolic activities. After antiretroviral treatment, brain subregions were dissected and screened by mass spectrometry-based metabolomics. Metabolic drug-related dysregulation of energy and oxidative stress were readily observed within the cerebellum and frontal cortex following native drug administrations. Each was associated with alterations in neural homeostasis and depleted canonical oxidation protection pools that included glutathione and ascorbic acid. Surprisingly, the oxidative stress-related metabolites were completely attenuated when DTG was administered as nanoformulations. These data demonstrate the importance of formulation design in control of DTG or perhaps other antiretroviral drug-associated CNS events.

PMID: 30069830 [PubMed - as supplied by publisher]

The Risks and Benefits of Expedited Drug Reviews.

JAMA. 2018 Jul 17;320(3):225-226

Authors: Frakt AB

PMID: 30027237 [PubMed - indexed for MEDLINE]

Case Study: Continuous Bedside Capnography Monitoring of High-Risk Patients Receiving Opioids.

Biomed Instrum Technol. 2018 May/Jun;52(3):208-217

Authors: Milligan PE, Zhang Y, Graver S

PMID: 29771589 [PubMed - indexed for MEDLINE]

Influence of thiopurine methyltransferase gene polymorphism on Egyptian children with acute lymphoblastic leukaemia.

J Genet. 2017 Dec;96(6):905-910

Authors: Tantawy AAG, Ebeid FSE, Adly AAM, El-Ghoroury E, Mostafa M

Abstract
Thiopurine methyltransferase (TPMT) gene polymorphism regulates thiopurine therapeutic efficacy and toxicity. The aim of this study was to determine the influence of TPMT gene polymorphism in Egyptian children with acute lymphoblastic leukaemia (ALL). Sixty-four patients with ALL, T lineage (27%) and pre-B phenotype (73%), who were treated with BFM 90 or CCG 1991 standard risk protocol, and who also experiencedmyleosuppresion toxicity and required interruption and/ormodification of thiopurine chemotherapy were recruited over a year period. Thirty-two patients were on maintenance and another 32 completed their chemotherapy. Seventy healthy age-matched and sex-matched children served as controls. They were subjected to clinical assessment, haematological panel investigations and TPMT gene polymorphism for G238C, G460A and A719G alleles assessment using PCRfollowed byRFLP analysis.Although none of the studied patients had themutantTPMTvariant alleles,myelosuppression toxicity in the form of different degree of neutropenia was detected in all patients. As a result of myelosuppression toxicity, most of the patients needed 6-MP dose modification either once (53.1%), twice (15.6%), or ≥ thrice (25.1%) during their maintenance course and 96.9% of the patients required to stop 6-MP for less than a week (62.5%), up to 2 weeks (28.1%), or > 2 weeks (6.3%). Patients also developed infection who mostly (71%) needed hospitalization. None of the studied G238C, G460A and A719G TPMT variant alleles were detected. Infections and febrile neutropenia were common causes of 6-PM dose modification and interruption.

PMID: 29321348 [PubMed - indexed for MEDLINE]

We have had a gutful: The need for deprescribing proton pump inhibitors.

J Clin Pharm Ther. 2018 Feb;43(1):65-72

Authors: Naunton M, Peterson GM, Deeks LS, Young H, Kosari S

Abstract
WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitor (PPI) prescribing may often be inappropriate and expose patients to a risk of adverse effects, while incurring unnecessary healthcare expenditure. Our objective was to determine PPI usage in Australia since 2002 and review international studies investigating inappropriate PPI prescribing, including those that discussed interventions to address this issue.
METHODS: Australian Pharmaceutical Benefits Scheme (PBS) and Repatriation Pharmaceutical Benefits Scheme (RPBS) data were analysed. A narrative literature review relevant to the objective was conducted. Time series analysis was also used to examine the trend of reported PPI appropriate use across the international studies included in this review.
RESULTS AND DISCUSSION: Proton pump inhibitor use in Australia increased between 2002 and 2010 and then gradually decreased. Estimates of the extent of inappropriate use in the international literature had a wide variation (11-84%). There appeared to be little change in the extent of appropriate PPI use reported through 34 international studies from 2000 to 2016. Interventions to address inappropriate use included patient-centred deprescribing, academic detailing, educational programmes and drug safety notifications.
WHAT IS NEW AND CONCLUSION: Proton pump inhibitors continue to be overused worldwide and should be a focus for deprescribing programmes. Ongoing education and awareness campaigns for health professionals and patients, including electronic reminders at the point of prescribing, are strategies that have potential to reduce PPI use in individuals who do not have an evidence-based clinical indication for their long-term use.

PMID: 28895169 [PubMed - indexed for MEDLINE]

Using Human Genetics to Predict the Effects and Side Effects of Lipoprotein(a) Lowering Drugs.

J Am Coll Cardiol. 2016 12 27;68(25):2773-2775

Authors: Tybjærg-Hansen A

PMID: 28007140 [PubMed - indexed for MEDLINE]

FDA Encourages Reporting of Tobacco Product Adverse Experiences.

Chest. 2016 12;150(6):1169-1170

Authors: Retzky SS

PMID: 27938736 [PubMed - indexed for MEDLINE]

Safety Meta-Analysis: A Call for Appropriate Use of Disproportionality Measures From Spontaneous Reporting Systems.

J Am Coll Cardiol. 2016 05 10;67(18):2193

Authors: Raschi E, Salvo F, Poluzzi E, De Ponti F

PMID: 27151356 [PubMed - indexed for MEDLINE]

Clinicopathological features of He Shou Wu-Induced Liver Injury: This Ancient Anti-Aging Therapy Is Not Liver-Friendly.

Liver Int. 2018 Aug 01;:

Authors: Wang Y, Wang L, Saxena R, Wee A, Yang R, Tian Q, Zhang J, Zhao X, Jia J

Abstract
BACKGROUND AND AIMS: Polygonum Multiflorum Thumb (PMT), an ancient anti-aging Chinese herb known traditionally as He Shou Wu, has side effects of liver toxicity. To determine the main clinical and pathological characteristics of liver toxicity induced by PMT and the clinical course after its cessation.
METHODS: Data of patients, diagnosed as drug-induced liver injury and hospitalized in Beijing Friendship Hospital from August 2005 to August 2017, were retrospectively reviewed. Clinical, pathological data and outcome after cessation of He Shou Wu were obtained and analyzed. Kruskal-Wallis and Chi-square (χ2 ) tests were performed.
RESULTS: Twenty-nine patients with He Shou Wu-induced liver injury were enrolled. The median age was 53 years (range 15-74) and 75.9% (22/29) were women. The most common symptom was jaundice (79.3%, 23/29). Of nine patients with liver biopsies, six showed acute cholestatic hepatitis, two acute and one chronic hepatocellular injury pattern. The latency, liver chemistries and outcomes were comparable between pure He Shou Wu (5 patients) and its compounds (24 patients). Twenty-five of 29 patients (86.2%) had normal serum alanine aminotransferase levels after 45 days (range: 10-138 days) and total bilirubin of 46 days (range: 0-551 days). One patient was rechallenged with He Shou Wu and two developed autoimmune features. One patient died of liver failure and three had chronic persistent liver injury.
CONCLUSIONS: The main clinicopathological injury pattern of He Shou Wu-induced liver injury is moderate to severe hepatitis with or without cholestasis. Most patients recover completely; however, chronic disease and death do occur. (249 words). This article is protected by copyright. All rights reserved.

PMID: 30066422 [PubMed - as supplied by publisher]

Dienogest Versus Leuprolide Acetate for Recurrent Pelvic Pain Following Laparoscopic Treatment of Endometriosis.

J Obstet Gynaecol India. 2018 Aug;68(4):306-313

Authors: Abdou AM, Ammar IMM, Alnemr AAA, Abdelrhman AA

Abstract
Objective: To compare the efficacy and safety of dienogest (DNG) with depot leuprolide acetate (LA) in patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
Design: Prospective randomized trial.
Setting: Zagazig University hospitals, Egypt.
Patients: Two hundred and forty-two patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
Intervention: Dienogest (2 mg/day, orally) or depot LA (3.75 mg/4 weeks, intramuscularly) for 12 weeks.
Main Outcome Measures: A visual analogue scale was used to test the intensity of pain before and after the end of treatment.
Results: There was highly significant reduction in pelvic pain, back pain and dyspareunia in both groups with mean of difference in dienogest group (28.7 ± 5.3, 19.0 ± 4.3 and 20.0 ± 3.08 mm, respectively) and in LA group (26.2 ± 3.01, 19.5 ± 3.01 and 17.9 ± 2.9 mm, respectively). The most frequent drug-related adverse effects in dienogest group were vaginal bleeding and weight gain (64.5 and 10.8%, respectively) which were significantly higher than LA group (21.5 and 3.3%, respectively). While the most frequent drug-related adverse effects in LA group were hot flushes and vaginal dryness (46.3 and 15.7%, respectively) which were significantly higher than dienogest group (15.7 and 3.3%, respectively).
Conclusion: Daily dienogest is as effective as depot LA for relieving endometriosis-associated pelvic pain, low back pain and dyspareunia. In addition, dienogest has acceptable safety, tolerability and lower incidence of hot flushes. Thus, it may offer an effective and well-tolerated treatment in endometriosis.

PMID: 30065547 [PubMed]

Predicting potential drug-drug interactions on topological and semantic similarity features using statistical learning.

PLoS One. 2018;13(5):e0196865

Authors: Kastrin A, Ferk P, Leskošek B

Abstract
Drug-drug interaction (DDI) is a change in the effect of a drug when patient takes another drug. Characterizing DDIs is extremely important to avoid potential adverse drug reactions. We represent DDIs as a complex network in which nodes refer to drugs and links refer to their potential interactions. Recently, the problem of link prediction has attracted much consideration in scientific community. We represent the process of link prediction as a binary classification task on networks of potential DDIs. We use link prediction techniques for predicting unknown interactions between drugs in five arbitrary chosen large-scale DDI databases, namely DrugBank, KEGG, NDF-RT, SemMedDB, and Twosides. We estimated the performance of link prediction using a series of experiments on DDI networks. We performed link prediction using unsupervised and supervised approach including classification tree, k-nearest neighbors, support vector machine, random forest, and gradient boosting machine classifiers based on topological and semantic similarity features. Supervised approach clearly outperforms unsupervised approach. The Twosides network gained the best prediction performance regarding the area under the precision-recall curve (0.93 for both random forests and gradient boosting machine). The applied methodology can be used as a tool to help researchers to identify potential DDIs. The supervised link prediction approach proved to be promising for potential DDIs prediction and may facilitate the identification of potential DDIs in clinical research.

PMID: 29738537 [PubMed - indexed for MEDLINE]

Pharmacogenetic Analysis of the UK MRC (Medical Research Council) MAGIC Trial: Association of Polymorphisms with Toxicity and Survival in Patients Treated with Perioperative Epirubicin, Cisplatin, and 5-fluorouracil (ECF) Chemotherapy.

Clin Cancer Res. 2017 Dec 15;23(24):7543-7549

Authors: Smyth E, Zhang S, Cunningham D, Wotherspoon A, Soong R, Peckitt C, Valeri N, Fassan M, Rugge M, Okines A, Allum W, Stenning S, Nankivell M, Langley R, Tan P

Abstract
Purpose: Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathologic response rates, survival, and toxicity for patients randomized to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial.Experimental Design: DNA was extracted from nontumor resection formalin-fixed paraffin-embedded (FFPE) blocks. ERCC1, ERCC2, XRCC1, DYPD, and OPRT SNPs were evaluated using Sequenom, GSTP1, GSTT1 deletion, and TYMS (TS) 5' 2R/3R using multiplex PCR. Post PCR amplification, TS 2R/3R and GSTT1 samples underwent gel electrophoresis.Results: Polymorphism data were available for 289 of 456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathologic response to chemotherapy. Median overall survival (OS) for patients treated with surgery alone with any TS genotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with a TS 2R/2R genotype treated with chemotherapy was not reached, whereas median OS for 2R/3R and 3R/3R patients were 1.44 and 1.60 years, respectively (log rank P value = 0.0053). The P value for the interaction between treatment arm and genotype (3R/3R and 3R/2R vs. 2R/2R) was 0.029. No polymorphism was statistically significantly associated with chemotherapy toxicity.Conclusions: In MAGIC, patients with a TS 2R/2R genotype appeared to derive a larger benefit from perioperative ECF chemotherapy than patients with 3R containing genotypes. Further exploration of this potential predictive biomarker in this patient population is warranted. Clin Cancer Res; 23(24); 7543-9. ©2017 AACR.

PMID: 28972045 [PubMed - indexed for MEDLINE]

A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors.

Clin Cancer Res. 2017 Dec 15;23(24):7490-7497

Authors: Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, Stagg R, Kapoun AM, Xu L, Uttamsingh S, Brachmann RK, Smith DC

Abstract
Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months.Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR.

PMID: 28954784 [PubMed - indexed for MEDLINE]

Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years.

Mol Genet Metab. 2017 Nov;122(3):46-53

Authors: Berry SA, Longo N, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Robinson B, Vockley J

Abstract
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients.
METHODS: Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100μmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development.
RESULTS: 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule.
CONCLUSION: GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.

PMID: 28916119 [PubMed - indexed for MEDLINE]

FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen.

Clin Cancer Res. 2017 Dec 15;23(24):7448-7453

Authors: Barone A, Chi DC, Theoret MR, Chen H, He K, Kufrin D, Helms WS, Subramaniam S, Zhao H, Patel A, Goldberg KB, Keegan P, Pazdur R

Abstract
On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44-0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448-53. ©2017 AACR.

PMID: 28774898 [PubMed - indexed for MEDLINE]

Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.

Clin Cancer Res. 2017 Dec 15;23(24):7440-7447

Authors: Yap C, Billingham LJ, Cheung YK, Craddock C, O'Quigley J

Abstract
The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR.

PMID: 28733440 [PubMed - indexed for MEDLINE]

Registries in European post-marketing surveillance: a retrospective analysis of centrally approved products, 2005-2013.

Pharmacoepidemiol Drug Saf. 2017 Dec;26(12):1442-1450

Authors: Bouvy JC, Blake K, Slattery J, De Bruin ML, Arlett P, Kurz X

Abstract
PURPOSE: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct.
METHODS: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems.
RESULTS: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates.
CONCLUSIONS: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.

PMID: 28345151 [PubMed - indexed for MEDLINE]