An assay of drug-induced emesis in the squirrel monkey (Saimiri sciureus).

J Med Primatol. 2019 Apr 10;:

Authors: Wooldridge LM, Kangas BD

Abstract
BACKGROUND: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a shortage of animal models.
METHODS: The present studies characterized the responses of the squirrel monkey to pharmacologically diverse emetic drugs. Subjects were administered nicotine (0.032-0.56 mg/kg), lithium chloride (150-250 mg/kg), arecoline (0.01-0.32 mg/kg), or apomorphine (0.032-0.32 mg/kg) and observed for emesis and prodromal hypersalivation.
RESULTS: Nicotine rapidly produced emesis and hypersalivation. Lithium chloride produced emesis with a longer time course without dose-dependent hypersalivation. Arecoline produced hypersalivation but not emesis. Apomorphine failed to produce emesis or hypersalivation.
CONCLUSIONS: The squirrel monkey is sensitive to drug-induced emesis by a variety of pharmacological mechanisms and is well-positioned to examine antiemetic efficacy and clinically important side effects of candidate antiemetic pharmacotherapies.

PMID: 30968960 [PubMed - as supplied by publisher]

MMP-9/Gelatinase B Degrades Immune Complexes in Systemic Lupus Erythematosus.

Front Immunol. 2019;10:538

Authors: Ugarte-Berzal E, Boon L, Martens E, Rybakin V, Blockmans D, Vandooren J, Proost P, Opdenakker G

Abstract
Systemic Lupus Erythematosus (SLE) is a common and devastating autoimmune disease, characterized by a dysregulated adaptive immune response against intracellular antigens, which involves both autoreactive T and B cells. In SLE, mainly intracellular autoantigens generate autoantibodies and these assemble into immune complexes and activate the classical pathway of the complement system enhancing inflammation. Matrix metalloproteinase-9 (MMP-9) levels have been investigated in the serum of SLE patients and in control subjects. On the basis of specific studies, it has been suggested to treat SLE patients with MMP inhibitors. However, some of these inhibitors induce SLE. Analysis of LPR-/-MMP-9-/- double knockout mice suggested that MMP-9 plays a protective role in autoantigen clearance in SLE, but the effects of MMP-9 on immune complexes remained elusive. Therefore, we studied the role of MMP-9 in the clearance of autoantigens, autoantibodies and immune complexes and demonstrated that the lack of MMP-9 increased the levels of immune complexes in plasma and local complement activation in spleen and kidney in the LPR-/- mouse model of SLE. In addition, we showed that MMP-9 dissolved immune complexes from plasma of lupus-prone LPR-/-/MMP-9-/- mice and from blood samples of SLE patients. Surprisingly, autoantigens incorporated into immune complexes, but not immunoglobulin heavy or light chains, were cleaved by MMP-9. We discovered Apolipoprotein-B 100 as a new substrate of MMP-9 by analyzing the degradation of immune complexes from human plasma samples. These data are relevant to understand lupus immunopathology and side-effects observed with the use of known drugs. Moreover, we caution against the use of MMP inhibitors for the treatment of SLE.

PMID: 30967870 [PubMed - in process]

Current state of biologic pharmacovigilance in the European Union: improvements are needed.

Expert Opin Drug Saf. 2019 Mar;18(3):231-240

Authors: Felix T, Jordan JB, Akers C, Patel B, Drago D

Abstract
INTRODUCTION: Pharmacovigilance is essential to monitoring the safety profiles of authorized medicines. Compared with small-molecule drugs, biological drugs are more complex, more susceptible to structural variability due to manufacturing processes, and have the potential to induce immune-related reactions, underscoring the importance of safety monitoring for these products. Although highly similar to reference products, biosimilars are not expected to be structurally identical. For these reasons, proper reporting of potential adverse drug reactions (ADRs) using distinguishable names and batch numbers is essential for accurate tracing of all biological drugs. To address the need for robust pharmacovigilance, the European Parliament and Council of the European Union provided legislation regarding pharmacovigilance of biologics in 2010. Areas covered: This narrative review examines the current state of pharmacovigilance for biologics in the European Union (EU) and discusses relevant information on pharmacovigilance of biosimilars, the current EU pharmacovigilance system, and areas that could be improved. Expert opinion: Although steps have been taken to improve pharmacovigilance of biologics in the EU, several enhancements can still be made, including additional training for healthcare professionals on ADR reporting, the use of 2D barcodes that enhance traceability, and an open discussion of potentially missed opportunities in the pharmacovigilance of biosimilars.

PMID: 30714424 [PubMed - indexed for MEDLINE]

Using patient support programs for pregnancy surveillance: Current paradigm, emerging opportunity.

Reprod Toxicol. 2019 03;84:122-124

Authors: Kaplan S, Shalit Y

PMID: 30660514 [PubMed - indexed for MEDLINE]

Metformin-associated lactic acidosis precipitated by liraglutide use: adverse effects of aggressive antihyperglycaemic therapy.

BMJ Case Rep. 2018 Nov 28;11(1):

Authors: Hooda A, Mehta A, Hannallah F

Abstract
Older patients with type 2 diabetes are prone to developing adverse events with aggressive antihyperglycaemic therapy. Metformin-associated lactic acidosis (MALA) is one such rare, life-threatening adverse drug effect. We report the case of a 70-year-old man with a glycated haemoglobin of 7.9% who was on a stable, maximally tolerated dose of metformin for managing his type 2 diabetes. He was initiated on liraglutide injections with hopes to achieve better glycaemic control, but developed unrelenting nausea and vomiting during the third week of treatment. He presented to the hospital with these symptoms and was noted to have severe MALA. He sustained an in-hospital cardiac arrest requiring emergent resuscitation along with vasopressor and mechanical ventilator support. He underwent continuous venovenous haemodiafiltration to remove metformin and correct the acidosis, following which he stabilised and supportive therapy was weaned off. He was discharged from the hospital on insulin therapy with incomplete renal recovery.

PMID: 30567126 [PubMed - indexed for MEDLINE]

Graves' disease: Introduction, epidemiology, endogenous and environmental pathogenic factors.

Ann Endocrinol (Paris). 2018 Dec;79(6):599-607

Authors: Wémeau JL, Klein M, Sadoul JL, Briet C, Vélayoudom-Céphise FL

Abstract
Graves' disease is the most frequent cause of hyperthyroidism. Many questions remain about the choice of diagnostic evaluations and treatment strategy according to clinical context (age, gender, pregnancy, etc.) and about the best management of the main extrathyroidal complication that is Graves orbitopathy. The exact pathogenic mechanisms are not fully clear. They associate genetic factors, interactions between endogenous and environmental factors, and immune system dysregulation. Graves' orbitopathy is one of the consequences of this partial understanding. Iatrogenic Graves' disease induced by the new targeted therapies are described and could help to better understand the molecular pathways involved in the disease and to develop new therapeutic approaches.

PMID: 30342794 [PubMed - indexed for MEDLINE]

Mind Matters: Treatment Concerns Predict the Emergence of Antiretroviral Therapy Side Effects in People with HIV.

AIDS Behav. 2019 Feb;23(2):489-498

Authors: Horne R, Chapman S, Glendinning E, Date HL, Guitart J, Cooper V

Abstract
The aim of this analysis of historical data was to determine whether patients' pre-treatment beliefs about antiretroviral therapy (ART) predict the subsequent reporting of side effects. Data were collected as part of a prospective, 12-month follow-up study. Of 120 people starting ART, 76 completed follow-up assessments and were included in the analyses. Participants completed validated questionnaires assessing their beliefs about ART, beliefs about medicines in general, perceived sensitivity to adverse effects of medicines, depression and anxiety before initiating ART and after 1 and 6 months of treatment. Adherence was assessed at 1, 6 and 12 months. Pre-treatment concerns about ART were associated with significantly more side effects at 1 month (p < 0.05) and 6 months (p < 0.005). Side effects at 6 months predicted low adherence at 12 months (p < 0.005). These findings have implications for the development of interventions to support patients initiating ART by providing a mechanism to pre-empt and reduce side effects.

PMID: 30187235 [PubMed - indexed for MEDLINE]

Temporal dynamics of whole body residues of the neonicotinoid insecticide imidacloprid in live or dead honeybees.

Sci Rep. 2017 07 24;7(1):6288

Authors: Schott M, Bischoff G, Eichner G, Vilcinskas A, Büchler R, Meixner MD, Brandt A

Abstract
In cases of acute intoxication, honeybees often lay in front of their hives for several days, exposed to sunlight and weather, before a beekeeper can take a sample. Beekeepers send samples to analytical laboratories, but sometimes no residues can be detected. Temperature and sun light could influence the decrease of pesticides in bee samples and thereby residues left for analysis. Moreover, samples are usually sent via normal postal services without cooling. We investigated the temporal dynamics of whole-body residues of imidacloprid in live or dead honeybees following a single-meal dietary exposure of 41 ng/bee under various environmental conditions, such as freezing, exposure to UV light or transfer of individuals through the mail system. Immobile, "dead" looking honeybees recovered from paralysis after 48 hours. The decrease of residues in living but paralysed bees was stopped by freezing (= killing). UV light significantly reduced residues, but the mode of transport did not affect residue levels. Group feeding increased the variance of residues, which is relevant for acute oral toxicity tests. In conclusion, elapsed time after poisoning is key for detection of neonicotinoids. Freezing before mailing significantly reduced the decrease of imidacloprid residues and may increase the accuracy of laboratory analysis for pesticides.

PMID: 28740208 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.

Lancet Gastroenterol Hepatol. 2019 Apr 03;:

Authors: Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Molé A, Attali P, Le Boulicaut J, Vasseur B, RELIVE Investigators

Abstract
BACKGROUND: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed.
METHODS: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693.
FINDINGS: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group.
INTERPRETATION: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed.
FUNDING: Onxeo.

PMID: 30954567 [PubMed - as supplied by publisher]

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Phase III, Non-Inferiority Study Comparing PrabotulinumtoxinA and OnabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Subjects.

Aesthet Surg J. 2019 Apr 05;:

Authors: Rzany BJ, Ascher B, Avelar RL, Bergdahl J, Bertucci V, Bodokh I, Carruthers JA, Cartier H, Delmar H, Denfeld R, Gross JE, Heckmann M, Hedén P, Hilton S, Inglefield C, Ogilvie P, Sattler G, Sebastian M, Solish N, Swift A, Trévidic P

Abstract
BACKGROUND: PrabotulinumtoxinA is a 900 kDa botulinum toxin type A produced by Clostridium botulinum.
OBJECTIVE: To investigate the efficacy and safety of prabotulinumtoxinA compared to onabotulinumtoxinA and placebo for the treatment of glabellar lines.
METHODS: This was a 150-day, multicenter, double-blind, controlled, single-dose Phase III study. Adult subjects (n=540) with moderate to severe glabellar lines at maximum frown as assessed by the investigator on the validated 4-point Glabellar Line Scale (GLS, 0=no lines, 1=mild, 2=moderate, 3=severe), who also felt that their glabellar lines had an important psychological impact, were enrolled. Subjects were randomized 5:5:1 to receive a single treatment (0.1 mL injected into each of 5 glabellar sites) of 20 U prabotulinumtoxinA (n=245), 20 U onabotulinumtoxinA (n=246) or placebo (n=49). The primary efficacy endpoint was the proportion of responders (subjects with a GLS score of 0 or 1 at maximum frown by investigator assessment) on Day 30.
RESULTS: Responder rates for the primary efficacy endpoint were 87.2%, 82.8%, and 4.2% in the prabotulinumtoxinA, onabotulinumtoxinA, and placebo groups, respectively. The absolute difference between prabotulinumtoxinA and onabotulinumtoxinA groups was 4.4%; 95% CI (-1.9, 10.8). Given that the lower bound of the 95% CI for the difference was > -10.0%, non-inferiority of prabotulinumtoxinA versus onabotulinumtoxinA was concluded. Five subjects (3 prabotulinumtoxinA, 1.2%; 1 onabotulinumtoxinA, 0.4%; 1 placebo, 2.0%) experienced serious adverse events; none were study-drug related.
CONCLUSION: A single treatment of 20 U prabotulinumtoxinA was safe and effective and non-inferior to 20 U onabotulinumtoxinA for the treatment of moderate to severe glabellar lines.

PMID: 30951166 [PubMed - as supplied by publisher]

Misleading impaired liver function in a non-small-cell lung cancer patient treated with pembrolizumab: a case report.

Anticancer Drugs. 2019 Apr 03;:

Authors: Osman GA, Marra A, Iacono D, Giannelli V, Ricciardi S, Remotti D, Vecchione A, Ricci A, Palange P, Migliorino MR

Abstract
In the last few years, immunotherapy has become part of everyday clinical practice for the treatment of many solid tumors including metastatic non-small-cell lung cancer. These drugs, however, can yield a specific toxicity profile that consists of immune-related adverse events (irAEs). Hepatotoxicity is one of irAEs and occurs in about 1-3% of cases and may be manifested by the presence of increate levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase) and/or biliary stasis evidence; in these cases, a differential diagnosis with other hepatic diseases must be considered. We present the case of a 73-year-old man who presented with an alteration in liver function during treatment with pembrolizumab (anti-programmed death 1 monoclonal antibody) for a stage IV nonsquamous non-small-cell lung cancer, which was initially mistaken for drug-induced irAEs hepatic toxicity.

PMID: 30950836 [PubMed - as supplied by publisher]

First-in-Human Pharmacokinetics and Safety Study of GSK3008356, a Selective DGAT1 Inhibitor, in Healthy Volunteers.

Clin Pharmacol Drug Dev. 2019 Apr 05;:

Authors: Okour M, Gress A, Zhu X, Rieman D, Lickliter JD, Brigandi RA

Abstract
Diacylglycerol acyltransferase (DGAT) enzymes are involved in triglyceride (TG) biosynthesis. GSK3008356 is a potent and selective DGAT1 inhibitor that was administered orally in a 2-part study as double-blind, randomized, placebo-controlled single doses (SDs) and repeat doses (RDs) in healthy subjects to investigate its pharmacokinetics, pharmacodynamics, and safety/tolerability. Gastrointestinal adverse events were considered drug related and increased with dose and when given as multiple doses. In the SD part (n = 80), GSK3008356 was dosed from 5 to 200 mg as single or multiple doses per day. In the RD part (n = 24), GSK3008356 was dosed twice daily at 1, 3, and 10 mg for 14 days. GSK3008356 was generally well tolerated in the SD and RD parts. With single doses, absorption was rapid (median tmax , 0.5-1.5 hours), whereas single-day divided dosing resulted in higher tmax . Following 14-day RD oral administration, GSK3008356 was also rapidly absorbed, with median tmax ranging from 0.5 to 0.75 hours on days 1 and 14. Estimated mean half-life ranged from 1.5 to 4.6 hours with SDs and 1.3 to 2.1 hours with RDs. Exposure of GSK3008356 was largely dose proportional after RDs. At higher doses, there was a trend toward lower absolute postprandial TG level in some subjects.

PMID: 30950565 [PubMed - as supplied by publisher]

Effect of WSP, a Chinese Herbal Formula, on Th17/Treg Ratio and HBeAg Seroconversion in Telbivudine-Treated HBeAg-Positive Chronic Hepatitis B Patients with High Baseline ALT Levels (20-30 Times the ULN).

Evid Based Complement Alternat Med. 2019;2019:7260369

Authors: Zhang Y, Wang YT, Luo JX, Hu XY, Yang F, Lin W, Liang X, Zhao BJ, Zhang S, Chen YY

Abstract
Chronic hepatitis B (CHB) is a global health problem. Clinically, many patients have baseline alanine aminotransferase (ALT) levels above 20 times the upper limit of normal (ULN), but there are few reports about these patients. The prospective randomized placebo-controlled clinical study was designed to investigate the effect of WSP, a Chinese herbal formula, on telbivudine- (LDT-) treated HBeAg-positive CHB patients with high baseline ALT levels (20-30 times the ULN) and kidney-yang deficiency syndrome. Eligible patients were randomized to receive LDT 600 mg/day in combination with WSP (treatment group) or placebo granules (control group) 16.28 g/day for 52 weeks. The results showed that HBeAg seroconversion (SC) rate (44.1%) in the treatment group (n=34) was significantly superior to that (20.6%) in the control group (n=34) at 52 weeks (P < 0.05). Meanwhile, WSP could promote HBV DNA negative conversion (85.3% versus 61.8%, P < 0.05) and ALT normalization (94.1% versus 76.5%, P < 0.05) compared with the placebo. There were no drug-related serious adverse events. During the treatment, the peripheral blood Th17/Treg ratio first increased and then decreased in the treatment group and reached the peak at 12 weeks (P < 0.05). At 12, 24, 36, and 52 weeks, Th17/Treg ratio in the treatment group was better than those in the control group (all P < 0.05). In addition, the patients (n=22) with HBeAg SC had higher Th17/Treg ratio than the patients (n=46) without SC at 12 weeks (0.68±0.26 versus 0.43±0.18, P < 0.001). In conclusion, WSP could safely enhance HBeAg SC and promote HBV DNA negative conversion and ALT normalization in LDT-treated HBeAg-positive CHB patients with high baseline ALT levels (20-30 times the ULN) and kidney-yang deficiency syndrome. Th17/Treg ratio was not only related to the mechanisms of WSP but also a good predictor of 52-week HBeAg SC.

PMID: 30949222 [PubMed]

Successful clozapine rechallenge in a patient with suspected drug induced lupus.

BMJ Case Rep. 2019 Apr 03;12(4):

Authors: Pathak S, Cherry S, Samad S, Aftab A

Abstract
Clozapine is the most effective treatment for patients with refractory schizophrenia. Clozapine is also associated with serious and potentially lethal side effects including drug induced lupus (DIL). There have been four previous published case reports describing clozapine inducing a lupus-like syndrome including one previous case where a clozapine rechallenge was attempted without success. This case report describes a successful clozapine rechallenge in a patient with suspected DIL.

PMID: 30948402 [PubMed - in process]

Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.

Lancet Oncol. 2019 Apr 01;:

Authors: Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, Wahner Hendrickson AE, Azodi M, DiSilvestro P, Oza AM, Cristea M, Berek JS, Chan JK, Rimel BJ, Matei DE, Li Y, Sun K, Luptakova K, Matulonis UA, Monk BJ

Abstract
BACKGROUND: Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.
METHODS: QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.
FINDINGS: Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related.
INTERPRETATION: We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.
FUNDING: Tesaro.

PMID: 30948273 [PubMed - as supplied by publisher]

Physician Awareness of Immune Responses to Polyethylene Glycol-Drug Conjugates.

Clin Transl Sci. 2018 03;11(2):162-165

Authors: McSweeney MD, Versfeld ZC, Carpenter DM, Lai SK

Abstract
Antibodies against polyethylene glycol (PEG) can critically jeopardize the efficacy and safety of PEGylated therapeutics. For some PEG-drugs, a sizeable fraction of patients develop anti-PEG antibodies (APA), leading to reduced efficacy and potential adverse events. We surveyed physicians from several specialties to assess their awareness of APA. Overall, 83% of the physicians surveyed indicated that they have recently prescribed PEGylated drugs. Although 91% of respondents were aware of antidrug antibodies in general, only 22% were aware of APA responses. Further, there was limited awareness (35%) of PEG's inclusion in prescribed PEGylated therapeutics. These findings bring to light a need for improved awareness of APA, potentially via targeted education of physicians who prescribe specific PEGylated therapeutics that could induce or are otherwise affected by APA. Finally, it will be critical to quantitate the extent of knowledge transfer from the research community to clinicians, especially on topics of patient safety.

PMID: 29383836 [PubMed - indexed for MEDLINE]