Standard Safety Evaluations Research Articles

61O - Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours

61O - Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours

453PD - Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours

453PD - Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study

In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. NCT01689519.

Overcoming Soluble Target Interference in An Anti-Therapeutic Antibody Screening Assay For An Antibody–Drug Conjugate Therapeutic

The standard safety evaluation of biotherapeutics includes assessment of immunogenicity. Anti-therapeutic antibodies (ATA) can be detected in serum using immunoassays with a bridging format. However, these assays can be subject to interference. In the bridging ATA assay for 3A5 TDC, an antibody-drug conjugate that binds to the multimeric extracellular domain of MUC16 (CA125), soluble CA125 in the serum caused false-positive results by binding to the ATA assay reagents. This interaction was blocked by wheat germ agglutinin lectin as it binds to the glycans in CA125; thus, the specificity of the assay improved. The assay development and validation results showed that the addition of wheat germ agglutinin eliminates the interference from circulating CA125 without impacting the ability to detect ATA.

Development of NanoSafety Forecasting System from the Viewpoint of Nanomaterial-protein Interaction

With recent developments in nanotechnology, nanomaterials have been successfully employed in various industrial applications such as medicine and cosmetics. Nanomaterials demonstrate useful properties such as electronic reactivity and tissue permeability that are absent in micromaterials. Thus, it is anticipated that nanomaterials will be developed as innovative materials in medicine and the cosmetics industry. However, these innovative properties may be accompanied by unknown biological responses that could not have been detected by conventional toxicity assays. To promote industrial development and to establish an affluent society that enjoys only the benefits of nanomaterials, we urgently need to gather information on the properties and biological effects of nanomaterials, and to establish appropriate standard safety evaluation methods. We are therefore analyzing the association of nanomaterial interactions with macromolecules (proteins, DNA etc.) and biodistribution using nanosilicas (nSP) as a standard nanomaterial. The results of this study are useful for extrapolation to other nanomaterials and to establish practicable strategies for the development of prediction methods for nanomaterials.

ChemInform Abstract: Safety Assessment of Nanomaterials Using Toxicokinetics and Toxicoproteome Analysis

AbstractReview: 17 refs.

Safety Assessment of Nanomaterials Using Toxicokinetics and Toxicoproteome Analysis

With recent development of the nanotechnology, nanomaterials have been successfully employed in various industrial applications such as medicine and cosmetics. Nanomaterials show the useful properties such as electronic reactivity and the tissue permeability that were not provided by micromaterials. Thus, nanomaterials are expected as innovative materials for the development of medicine and cosmetics. However, these innovative properties may show unknown biological responses that could not been detected by the conventional toxicity assay. For industrial development and affluent society establishment that enjoyed only a benefit of nanomaterials, it is urgent to gather information of the properties and the biological effects, and to establish the standard safety evaluation method of nanomaterials. So, we are analyzing association among property, biodistribution and biological effects of nanomaterials to search for the safety biomarker (functional-, molecular- and biochemical-biomarker) using nanosilicas (nSP) as a standard nanomaterial. Because nSP shows high uniform dispersibility and is already used in medicine, cosmetics and food additive, the results of this study are useful to extrapolate it to other nanomaterials and to make practicable as safety biomarker. In this report, we show the latest knowledge about the linkage information among property, biodistribution and biological effects of nSP by toxicokinetics and toxicoproteomics, and the search study of safety biomarker based on these basic information.

Long-Term Safety of Divalproex Sodium Extended-Release in Children and Adolescents with Bipolar I Disorder

The objective of this open-label study was to assess the safety of divalproex sodium extended-release in the treatment of children and adolescents with acute mania associated with bipolar I disorder. This was a 6-month, Phase 3, open-label study in healthy subjects aged 9-17 years with a current Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition, Text Revision (DSM-IV-TR) diagnosis of bipolar I disorder manic or mixed episode. Divalproex sodium extended-release (DVPX-ER) was initiated at 15 mg/kg per day on day 1 (not to exceed 750 mg/day) with increases allowed to a maximum of 35 mg/kg per day. Study visits were conducted on day 1 and at months 1, 2, 3, and 6. Assessments included standard safety evaluations and appropriate rating scales for clinical effect. A total of 226 subjects were enrolled; 109 subjects completed the study. The most common adverse events were weight gain (16%), nausea (9%), and increased appetite (8%). Nonsymptomatic elevations of mean ammonia levels in plasma were observed. The mean Young Mania Rating Scale (YMRS) decreased 12.4 from baseline to final visit; small improvements were seen in behavior and caregiver stress ratings. DVPX-ER was generally well tolerated in children and adolescents with acute mania, with a side-effect profile similar to that observed in adults.

Oral pantoprazole in the form of granules or tablets are pharmacodynamically equivalent in suppressing acid output in patients with gastro‐oesophageal reflux disease and a history of erosive oesophagitis

To demonstrate the pharmacodynamic comparability between oral 40 mg pantoprazole delayed-release granules and tablets. This was a multicentre, randomized, open-label, 2-period, 2-sequence, 9-week crossover study in patients aged 18-65 years with gastro-oesophageal reflux disease and documented erosive oesophagitis. The primary endpoint was a comparison of the inhibition of pentagastrin-stimulated maximum acid output (MAO) at steady state after once daily dosing for 1 week and 23 h after the last dose of pantoprazole granules and tablets. Basal acid output was measured prior to MAO. Standard safety evaluations were performed. The one-sided t-test was used to test the null hypothesis that granules - 1.2 x tablet >/= 0 against the alternative hypothesis that this difference was <0 for both MAO and basal acid output values. Sixty patients completed the study. The mean MAO values were 7.11 +/- 4.98 and 7.29 +/- 4.77 mmol/h, while the mean basal acid output values were 0.74 +/- 0.91 and 0.58 +/- 0.63 mmol/h for the granules and tablets, respectively. The two formulations were shown statistically to be pharmacodynamically equivalent in suppressing MAO (P = 0.006), safe and well tolerated. Patients with gastro-oesophageal reflux disease who are unable to swallow the tablet may safely be prescribed the pantoprazole sodium granules.

The Pharmacokinetics of Pantoprazole Delayed Release Granules Administered by Three Different Methods in Healthy Subjects

Purpose: A new oral delayed release granule formulation of pantoprazole was developed as an alternative for adult subjects who cannot swallow tablets. The primary objective of this study was to determine the bioequivalence of this new formulation administered by 3 different methods in healthy subjects. Methods: This was a randomized, open-label, 3-period, crossover, in-patient study in 25 healthy adult subjects aged 18 to 50 years. Each subject received a single 40 mg dose of pantoprazole after at least a 10 hour fast for each of the following administration methods separated by a washout period: 1) granules sprinkled over applesauce; 2) granules mixed with apple juice; 3) granules mixed with apple juice and administered through a nasogastric (NG) tube. Blood samples were collected up to 24 hours post dose and analyzed for pantoprazole levels by a validated LC/MS/MS method. Standard safety evaluations were performed. The PK parameters were estimated using non-compartmental methods. The 90% confidence limits for the test-to-reference geometric mean ratio were calculated for Cmax and AUC. Results: The mean Cmax, AUCT, and AUC values were similar for the 3 dosing methods. For Cmax, AUCT, and AUC, the 90% CI's for the ratio of the geometric means were within the bioequivalent limits of 80%–125%. Four subjects reported adverse events while on treatment including: headache, diarrhea, bronchitis, increased cough, epistaxis, and local reaction to the NG tube. There were no deaths, serious adverse events, or discontinuations. Conclusions: Pantoprazole granules administered with apple juice orally or through an NG tube, or with applesauce are bioequivalent. Pantoprazole granules were safe and well tolerated when administered by the above methods.

Pharmacological and Pharmacokinetic Aspects of Functional Gastrointestinal Disorders

Medications are commonly used for the treatment of patients with functional gastrointestinal disorders. The general goal of this report is to review the pharmacokinetics and pharmacology of medications used in functional gastrointestinal disorders. Methods included literature review, consensus evaluation of the evidence for each topic assigned originally to 1 or 2 authors, and broader review at a harmonization session as part of the Rome III process. This report reviews the animal models that have been validated for the study of effects of pharmacologic agents on sensation and motility; the preclinical pharmacology, pharmacokinetics, and toxicology usually required for introduction of novel therapeutic agents; the biomarkers validated for studies of sensation and motility end points with experimental medications in humans; the pharmacogenomics applied to these medications and disorders; and the pharmacology of agents that are applied or have potential for treatment of functional gastrointestinal disorders, including psychopharmacologic agents. Clinician and basic investigators involved in the treatment or investigation of functional gastrointestinal disorders or disease models need to have a comprehensive understanding of a vast range of medications. It is anticipated that the interaction between investigators of basic science, basic and applied pharmacology, and clinical trials will lead to better treatment of these disorders.

Long-Term Outcomes of Galantamine Treatment in Patients With Alzheimer Disease

Objective The authors evaluated the long-term safety, efficacy, and tolerability of galantamine 24 mg/day in the treatment of Alzheimer disease by means of a 12-month, open-label extension of an earlier 5-month, double-blind, placebo-controlled trial with a 6-week withdrawal phase. Methods Patients completing two double-blind, placebo-controlled trials (N=699) were escalated to a 24-mg dose (12 mg bid) of galantamine during a period of 2 weeks and treated for 12 months beyond the initial 6.5-month, double-blind period (total treatment duration: 18.5 months). The primary efficacy measure was the change from baseline in the Alzheimer's Disease Assessment Scale (ADAS-Cog/11) score at 18.5 months; secondary endpoints included total scores on the Alzheimer's Disease Cooperative Study of Activities of Daily Living and the Neuropsychiatric Inventory. Standard safety evaluations, including adverse-event monitoring, were performed. Results Patients taking galantamine continuously throughout the double-blind and open-label studies (N=288) showed sustained cognitive benefits on ADAS-Cog/11 scores at 18.5 months. Patients were maintained close to baseline cognitive ability for 12 months, and safety was as expected and documented in other large studies of galantamine. Analysis of the subgroup of patients (N=113) who completed the entire 18.5 months of galantamine treatment showed that cognitive function was maintained up to 14 months. Conclusions Results of this open-label extension support the findings from previous galantamine studies and demonstrate the safety and tolerability of galantamine for up to 18.5 months.

Management of Patients with Alzheimer’s Disease plus Cerebrovascular Disease: 12-Month Treatment with Galantamine

We evaluated the long-term cognitive effects and safety of galantamine 24 mg/day in patients with Alzheimer’s disease plus cerebrovascular disease (AD + CVD or mixed dementia). Subgroup analysis was performed of patients with AD + CVD who participated in a 6-month, multicenter, randomized, double-blind, parallel-group study and a 6-month, open-label, active-treatment extension. Method: Two hundred and eighty-five patients with AD + CVD were randomized to receive either placebo (n = 97) or galantamine 24 mg/day (n = 188) for 6 months. Two hundred and thirty-eight (84%) patients continued with the open-label phase of the study (86 from the placebo group, 152 from the galantamine group) and were treated with galantamine 24 mg/day. The primary efficacy measure was cognitive performance as assessed using the eleven-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog/11). Standard safety evaluations and adverse-event monitoring were performed throughout the 12-month study period. Patients with AD + CVD treated with galantamine experienced statistically and clinically significant improvement in cognition at month 6 (mean change in ADAS-cog/11 score –1.1; p ≤ 0.05 vs. baseline) and maintained their cognitive function for the entire 12-month study (mean change in ADAS-cog/11 score +0.1). In contrast, the cognitive function deteriorated among those in the placebo group (mean change in ADAS-cog/11 at month 6 +2.0; p ≤ 0.001 vs. baseline). Patients with AD + CVD who were switched from placebo to galantamine for the open-label phase of the trial did show improvement in cognitive function; however, they never attained the same cognitive level as patients who had been treated with galantamine for the entire 12 months [mean (± SE) ADAS-cog/11 scores in the placebo/galantamine group 25.7 ± 1.32 and 24.2 ± 1.57 at months 6 and 12, respectively, and in the galantamine/galantamine group 21.5 ± 0.87 and 22.2 ± 1.06 at months 6 and 12, respectively]. The results of this subgroup analysis indicate that galantamine is effective for long-term maintenance of the cognitive function in patients with AD + CVD and is safe and well tolerated in this patient population.

Application of the Hydra Assay for Rapid Detection of Developmental Hazards

Adult hydra and artificial “embryos” composed of randomly reaggregated cells of dissociated hydra were exposed to test chemicals. The lowest concentration killing adult hydra became the numerator, and the lowest concentration disrupting development of “embryos” became the denominator of a ratio. This adult toxic (A) to developmentally toxic (D) or A/D ratio from hydra was compared to the A/D ratio calculated from published reports employing standard laboratory animals. Data from rodents were considered if both adult and developmental toxicities were consistent for: species, route, and duration of treatment and had a direct dose-response relationship indicating that the toxic manifestations were near the low end of a dose-response curve. The minimal expression of adult toxicity was usually loss in body weight, but developmental toxicity varied from abnormal development or death to reduced fetal weight. The hydra assay proved as effective as standard safety evaluations in rodents at detecting developmental hazards, i.e., substances capable of disrupting the conceptus at a small fraction of the minimal dose toxic to adults. It also was as effective as rodents in establishing that the majority of substances are capable of disrupting development of the conceptus only at doses also toxic to adults.