Clinical Safety Assessment Research Articles

Toxicokinetics and toxicity of potassium 2-(1-hydroxypentyl)-benzoate in beagle dogs

Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a prodrug of 3-n-butylphthalide (dl-NBP) for treatment of cerebral ischemic stroke in China, which undergoes lactonization to form dl-NBP in plasma. And, the phase II–III clinical trial of dl-PHPB has been approved by China Food and Drug Administration (CFDA) in 2013. In this study, a toxicity and toxicokinetics evaluation of dl-PHPB was performed using beagle dogs at specially high-dose 108 mg/kg/day (65-fold higher than humans at MHRD) for 4 weeks by intravenous administration, with a 3-week recovery period. And the plasma concentrations of dl-PHPB along with its metabolite dl-NBP were determined by HPLC-UV method. The results showed that dl-PHPB was quickly metabolized into dl-NBP, and no significant accumulation was observed. A slight to moderate behavior-associated toxicity was revealed in the process of delivery; and recovered to normal at the end of administration. Changes in the blood hematological profiles included significantly increased NEUT levels and lower LYM% content. Meanwhile, a notable increase in TG content was also observed in the serum biochemical parameters at 4-week post-exposure. These findings were reversible during the recovery period. The information from these studies would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.

The Efficacy and Safety of Oral Ferrous Gluconate in Premenopausal Women with Severe Iron Deficiency Anaemia

Objective: To evaluate the efficacy and safety of ferrous gluconate, given orally thrice daily for three months, to pre-menopausal women with severe iron deficiency anaemia.
 Method: A phase IV non randomized single arm open label drug trial was conducted at Gynaecology and Obstetrics Unit II in Abbasi Shaheed Hospital from Feb 2013 to March 2014, which is a 950 bedded public sector tertiary care hospital.
 Total fifty premenopausal women with documented severe iron deficiency anaemia, haemoglobin (Hb) between 6-8 g/dl were enrolled after taking written informed consent. Clinical evaluation and lab in- vestigation for serum ferritin and haemoglobin levels were conducted at baseline and after comple- tion of treatment. A standardized proforma for data collection was developed. Ferrous gluconate soft gelatin capsules were given as one capsule during or after the meal 3 times daily, for three months. All patients were evaluated four times during study first at the time of enrolment and after 30, 60, and 90 days for clinical efficacy and safety assessment.
 Results: In our study all fifty premenopausal women completed iron treatment. Analysis of therapeutic efficacy parameters i.e. haemoglobin, and serum ferritin levels showed improvement that was sta- tistically significant. By the end of treatment with oral ferrous gluconate, significant improvement in Hb levels was observed (7.574 ± 0.559 g/dl vs 11.020 ± 0.718, p<0.0001). Significant changes were noted in serum ferritin level (10.058 ± 5.059 ng/ml vs 27.136 ± 13.803, p<0.0001) after 3 months therapy. Ferrous gluconate proved to be safe in women with severe iron deficiency anaemia. The treated women did not exhibit any major side effect, only one serious side effect was reported (erythema nodosum). Mild self-limiting side effects including black discolouration of stool in 54% cases, nausea in 6%, constipation in 2% and diarrhoea in 2% was observed.
 Conclusion: Oral ferrous gluconate treatment for severe iron deficiency anaemia is well tolerated and highly effective in premenopausal women.

Evaluation of clinical safety and beneficial effects of stachyose-enriched α-galacto-oligosaccharides on gut microbiota and bowel function in humans.

Deshipu stachyose granules (DSG) is a mixture of α-galacto-oligosaccharides derived from the dietary roots of Lycopus lucidus Turcz. Our previous study showed that DSG could improve the faecal microbial composition, and facilitate intestinal peristalsis and fecal excretion in mice. This study was designed to investigate the effect of DSG on gut microbiota and bowel function in humans. Two human intervention studies were conducted. In the first study, 100 healthy adults were treated without or with 5 g per day of DSG for 14 days. The microbiota composition in fecal samples was quantitatively analyzed before and after DSG supplementation. We found that DSG consumption significantly elevated the fecal bifidobacteria and lactobacilli levels, and also decreased the fecal Clostridium perfringens concentration. In the second study, 103 constipated patients were treated with 5 g per day of placebo or DSG for 30 days, and subsequently subjected to bowel function evaluation. As a result, dietary intake of DSG effectively improved the bowel function of constipated patients, as evidenced by the increased defecation frequency, softer stools and easier defecation. Moreover, clinical safety assessment showed that DSG at 5 g per day did not cause significant adverse effects in both healthy and constipated volunteers. In conclusion, DSG at 5 g d-1 beneficially modulated the gut microbiota in healthy adults and potently improved the bowel function of constipated patients without consequent adverse events. This study suggests that DSG holds promising potential for safe treatment of functional constipation.

Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721).

Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example

A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro–in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher’s human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded Cmax values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro–in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction.

Non-Clinical Safety Assessment of Single and Repeated Administration of Hepatitis B (rDNA) Vaccine

Hepatitis B infection is an important public health concern all over the world. As no specific treatment is available, greatest emphasis is placed on prevention through immunization. A recently developed Hepatitis B (rDNA) vaccine, containing purified surface antigen of virus like particles derived from culturing genetically engineered Hansenula polymorpha yeast cells having the Hepatitis B surface antigen gene of Hepatitis B virus was evaluated to establish potential safety and tolerability of the Hepatitis B (rDNA) vaccine formulation. Non clinical safety assessment was evaluated as single dose studies in mice and rats and a repeat dose study in rats. No signs of acute toxicity were noted in mice and rats through clinical signs and gross necropsy examination. The local reactions observed in both the species at the injection site were attributed to the property of an adjuvanted vaccine. Similarly, the absence of systemic toxicity was evaluated after repeated administrations in the rat. In repeated dose study, additionally histiocytosis and/or lymphoid hyperplasia at femoral lymph node were observed. The incidences of such local effects were considered as innate immune response generated against the vaccine antigens and enhanced by the adjuvants. The vaccine was shown to be well tolerated without any obvious signs of adverse systemic toxicity, with findings largely attributable to the adjuvant used. The immunogenicity profile showed measurable antibody titer. Therefore, in these non-clinical models, the single and repeated dose administrations of Hepatitis B (rDNA) vaccine were considered as well tolerated up to absolute human dose (1 ml).

Data Resource Profile: The Scottish National Prescribing Information System (PIS).

Data Resource Basics: The Prescribing Information System (PIS) covers the prescribed,dispensed and reimbursed prescriptions in community pharmacies from the 5.3 million residents in Scotland. Summary information is available from 1993 and at an individual level from 2009 to the present. Data Collected: The raw data are generated by three data sources: ePrescribed -generated by GPs messages, eDispensed –generated by messages from community pharmacies and Reimbursed messages from scanned paper prescriptions dispensed in the community pharmacies. The four main categories of data collected are: (1) Patient-specific, (2) Prescriber, (3) Dispenser and (4) Drug-specific. PIS data can be linked via a unique identifier to other national databases, including hospital records, maternal and neonatal, the Scottish Cancer Registry and mortality records. The catalogue of databases is available in www.ndc.scot.nhs.uk . Subject to approval of the data controllers other external datasets can also be linked. Data Resource Use: PIS has been used to describe the utilisation of several groups of drugs;factors influencing prescribing and evaluation of interventions to improve it; generation of polypharmacy guidelines; risk of side effects; monitoring of antibiotic use and generation of policy recommendations; associations between community prescription of antimicrobials and deprivation or infection; evaluation of prescription fee abolition; clinical effectiveness, safety and health technology assessment of drugs approved in the last decade. Reasons to be cautious: PIS does not capture information about diagnosis or indication for treatment, over the counter medicines, medicines administered during inpatient hospital stays, upon discharge for short term use, outpatient supplies or some specialist drugs for chronic use. Drug data is currently coded according to the British National Formulary. For longitudinal studies, patient level data is available from 2009 and the frequency of data collection from the three sources is different. Collaboration and data access: PIS data are available upon request to the electronic Data Research and Innovation Service (NSS.eDRIS@nhs.net) and project approval by the Public Benefit and Privacy Panel. Funding and competing interests: This dataset is funded from the public monies available to the NHS. Current work to develop an improved PIS research ready analysis platform and this study is supported by the Farr Institute @ Scotland and its 10-funder consortium. The authors declare no conflict of interest.

The FDA's Experience with Emerging Genomics Technologies-Past, Present, and Future.

The rapid advancement of emerging genomics technologies and their application for assessing safety and efficacy of FDA-regulated products require a high standard of reliability and robustness supporting regulatory decision-making in the FDA. To facilitate the regulatory application, the FDA implemented a novel data submission program, Voluntary Genomics Data Submission (VGDS), and also to engage the stakeholders. As part of the endeavor, for the past 10 years, the FDA has led an international consortium of regulatory agencies, academia, pharmaceutical companies, and genomics platform providers, which was named MicroArray Quality Control Consortium (MAQC), to address issues such as reproducibility, precision, specificity/sensitivity, and data interpretation. Three projects have been completed so far assessing these genomics technologies: gene expression microarrays, whole genome genotyping arrays, and whole transcriptome sequencing (i.e., RNA-seq). The resultant studies provide the basic parameters for fit-for-purpose application of these new data streams in regulatory environments, and the solutions have been made available to the public through peer-reviewed publications. The latest MAQC project is also called the SEquencing Quality Control (SEQC) project focused on next-generation sequencing. Using reference samples with built-in controls, SEQC studies have demonstrated that relative gene expression can be measured accurately and reliably across laboratories and RNA-seq platforms. Besides prediction performance comparable to microarrays in clinical settings and safety assessments, RNA-seq is shown to have better sensitivity for low expression and reveal novel transcriptomic features. Future effort of MAQC will be focused on quality control of whole genome sequencing and targeted sequencing.

Comprehensive Assessments of RNA-seq by the SEQC Consortium: FDA-Led Efforts Advance Precision Medicine.

Studies on gene expression in response to therapy have led to the discovery of pharmacogenomics biomarkers and advances in precision medicine. Whole transcriptome sequencing (RNA-seq) is an emerging tool for profiling gene expression and has received wide adoption in the biomedical research community. However, its value in regulatory decision making requires rigorous assessment and consensus between various stakeholders, including the research community, regulatory agencies, and industry. The FDA-led SEquencing Quality Control (SEQC) consortium has made considerable progress in this direction, and is the subject of this review. Specifically, three RNA-seq platforms (Illumina HiSeq, Life Technologies SOLiD, and Roche 454) were extensively evaluated at multiple sites to assess cross-site and cross-platform reproducibility. The results demonstrated that relative gene expression measurements were consistently comparable across labs and platforms, but not so for the measurement of absolute expression levels. As part of the quality evaluation several studies were included to evaluate the utility of RNA-seq in clinical settings and safety assessment. The neuroblastoma study profiled tumor samples from 498 pediatric neuroblastoma patients by both microarray and RNA-seq. RNA-seq offers more utilities than microarray in determining the transcriptomic characteristics of cancer. However, RNA-seq and microarray-based models were comparable in clinical endpoint prediction, even when including additional features unique to RNA-seq beyond gene expression. The toxicogenomics study compared microarray and RNA-seq profiles of the liver samples from rats exposed to 27 different chemicals representing multiple toxicity modes of action. Cross-platform concordance was dependent on chemical treatment and transcript abundance. Though both RNA-seq and microarray are suitable for developing gene expression based predictive models with comparable prediction performance, RNA-seq offers advantages over microarray in profiling genes with low expression. The rat BodyMap study provided a comprehensive rat transcriptomic body map by performing RNA-Seq on 320 samples from 11 organs in either sex of juvenile, adolescent, adult and aged Fischer 344 rats. Lastly, the transferability study demonstrated that signature genes of predictive models are reciprocally transferable between microarray and RNA-seq data for model development using a comprehensive approach with two large clinical data sets. This result suggests continued usefulness of legacy microarray data in the coming RNA-seq era. In conclusion, the SEQC project enhances our understanding of RNA-seq and provides valuable guidelines for RNA-seq based clinical application and safety evaluation to advance precision medicine.

Adverse events following immunization in patients with primary immunodeficiencies

BackgroundAdverse events following immunization (AEFI) requires special consideration in patients with primary immunodeficiency diseases (PID) because they may represent a “red flag” for the initial diagnosis and may cause disease complications. Therefore, the definition of appropriate vaccination schemes is a major issue in PID. The aim of this study is to describe the AEFI in a cohort of PID patients. MethodsMedical records from 379 PID patients were included. AEFI severity was classified according to the WHO 1999 guidelines. Causality was assessed using the Clinical Immunization Safety Assessment (CISA) 2009 criteria. ResultsEvidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients. ConclusionsOur study included a large cohort of PID patients and confirmed an increased risk of serious AEFI in these populations. The design and implementation of neonatal screening strategies for the early detection of congenital lymphopenias and other PID are urgently needed to avoid serious complications of the BCG vaccine usually applied immediately after birth. Our findings also support the use of the acellular pertussis vaccine to minimize the appearance of seizures in PID patients vaccinated with diphtheria, pertussis and tetanus (DPT).

A phase Ib dose escalation, safety, and tolerability study of sonidegib in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

371 Background: Sonidegib (LDE225) is a potent, selective, and orally bioavailable inhibitor of smoothened receptor that demonstrated preclinical activity in combination with gemcitabine (GEM). Here, we present data from a phase 1b trial of sonidegib in combination with GEM in patients (pts) with pancreatic adenocarcinoma (PA). Methods: Pts with histologically or cytologically confirmed, locally advanced, or metastatic PA who had not been treated previously or had progressed despite prior chemotherapy (other than GEM) were included in the study. Dose escalation started with sonidegib 400 mg, once a day, in combination with GEM 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle. Results: A total of 18 pts were enrolled (9 pts each the in dose escalation and dose expansion phases). Pts discontinued the study because of disease progression (n = 11, 61.1%), consent withdrawal (n = 3, 16.7%), administrative problems (n = 3, 16.7%), and grade 3 or 4 blood creatine kinase (CK) elevation (n = 1, 5.6%). Three of 9 pts in dose escalation phase experienced dose-limiting toxicities during the first 8 weeks including grade 3 mucositis (n = 1), grade 3 CK elevation (n = 1), and grade 3 aspartate aminotransferase elevation (n = 1). Drug-related adverse events (AEs) of all grades were reported in 14 pts (77.8%) and grade 3 or 4 AEs were reported in 10 pts (55.6%). The most commonly reported AEs were anemia and nausea. No pharmacokinetic (PK) interaction was observed. Based on considerations of the statistical model, clinical assessment of safety, tolerability, PK, and pharmacodynamic results, maximum-tolerated dose and recommended dose were established as 400 mg of sonidegib in combination with the fixed standard dose of GEM (1000 mg/m2).The objective response rate was 11.1% and the median progression-free survival (PFS) was 4.9 months. Conclusions: The combination of sonidegib and GEM was generally well tolerated with moderate activity. Although no formal comparison can be made due to small sample size of this study, this combination provided a median PFS comparable to the current standard of care without conferring any additional clinical benefit. Clinical trial information: NCT01487785.

Post-marketing clinical safety assessment of Shenmai injection based on active monitoring and passive monitoring in large data background

This paper adopted a series of related analysis methods to comprehensively analyze post-marketing clinical safety data of Shenmai injection from 4,220 cases of SRS and 32,358 cases of multicenter, prospective, registered hospital centralized monitoring in large data background, calculated ADR incidence rate was 0.93 per 1,000, main symptoms of ADR includes chest pain, chills, skin itching, palpitations, fever, nausea, dizziness, vomiting, flushing, numbness, allergic reaction, cyanosis, rash, low back pain, and "breath", "anaphylactoid reaction" and "flush" were the safety warning signals of Shenmai injection. Primary disease for chronic pulmonary heart disease, thyroid disease, and combined with cerebral vascular disease, prior to the injection and continuous use of alprostadil, cyclic adenosine monophosphate, combined with quinolones, penicillins were suspicious influence factors of ADR of Shenmai injection, these promot the clinical safety.

Clinical experience of using «Haemoblock» hemostatic solution in surgical practice

Aim. The clinical assessment of safety and hemostatic effect of «Haemoblock» hemostatic solution for arresting active bleeding from abdominal cavity tissues at open and laparoscopic surgeries.Methods. A total of 26 patients underwent surgeries. In 11 cases of acute calculous cholecystitis the drug was delivered to the bleeding surface during laparoscopic surgery by gauze soaked in «haemoblock» solution, which was introduced through 5 mm laparoscopic port (the first group). In 15 cases of acute adhesive intestinal obstruction, the drug was applied to the wound surface by moistened gauze during the open surgery (the second group).Results. In 23 (88.5%) cases of 26, stable hemostatic effect was obtained. Mean hemostasis time was 2.09±0.2 minutes in the first group and 2.53±0,15 minutes in the second group. The first group of patients, hemostasis occurred within 1-3 minutes in 10 (90.9%) of 11 patients, no secondary bleeding and suppuration was noticed. One patient (9.1%) of the first group developed recurrent bleeding from the gallbladder bed, requiring repeated surgery. Two (13.3%) patients of the second group had recurrent bleeding, requiring additional re-use of the drug with an exposure of 4 min. After using «Haemoblock», no postoperative complications such as fistula formation of adhesions, as well as reactive abdominal cavity effusions, were observed. No toxic of allergic reactions, irritating effect on the surrounding tissues no influence on systemic hemostasis were reported.Conclusion. «Haemoblock» is an effective local hemostatic that could be used as additional treatment to control parenchymal bleeding at abdominal and laparoscopic surgery.

Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis.

Objectives:To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity.Methods:In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety.Results:Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time.Conclusions:MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found.Classification of evidence:This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS.

Risk and Protective Factors for Relapse in Outpatients with Schizophrenia.

We aim to determine risk and protective factors influencing relapse incidence in outpatient with schizophrenia. A longitudinal, observational study was done with outpatients with schizophrenia (F20) or schizoaffective disorder (F25)(DMS-IV and ICD-10), without hospitalization during the previous 6 months. The patients were consecutively included into the study to received oral (O-A) or long-acting injectable (depot-A) antipsychotics. Clinical stage evolution, compliance, efficacy and safety assessments (including PANSS, CGI-SSI, hospitalization rates, and adverse events) were recorded before and after 6 and 12 months of treatment. Results 60 outpatients (aged 34.5±8.9, male 73%), 75% schizophrenia and 25% schizoaffective disorder diagnosis, 68.3% fewer than 15 years of schizophrenia evolution, 76.7% fewer than 5 times previous hospitalizations were treated with O-A (41.7%) or depot-A (58.3%) antipsychotics for at least one year. Depot-A treated patients showed a significant higher compliance compared to O-A patients during the all following time, lower PANSS (total, positive and negative) scores and CGI-SSI score (p Conclusion There were protective factors which delayed relapse incidence in schizophrenia: Use of sustained-release preparations, family support. There were risk factors for occurrence of relapse in schizophrenia: cocaine, heroin and alcohol consumption, absence of family support, greater severity of patients assessed through CGI-SI, male sex, age older than 25 years and long-term evolution of the disorder. Cannabis use did not affect the incidence of relapse.

Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients.

SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days. Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection. SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity. SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.

Clinical safety assessment of oral higenamine supplementation in healthy, young men.

Higenamine, an herbal agent also known as norcoclaurine, is thought to stimulate β-androgenic receptors and possess lipolytic activity. It is currently making its way into the dietary supplement market. To our knowledge, no studies have been conducted to determine the safety profile of oral higenamine when used alone and in conjunction with other commonly used lipolytic agents. Forty-eight men were assigned to ingest either a placebo, higenamine, caffeine, or higenamine + caffeine + yohimbe bark extract daily for a period of 8 weeks. Before and after 4 and 8 weeks of supplementation, the following variables were measured: resting respiratory rate, heart rate, blood pressure, urinalysis, complete blood count, metabolic panel, liver enzyme activity, and lipid panel. No interaction effects were noted for any variable (p > 0.05), with no changes of statistical significance occurring across time for any of the four conditions (p > 0.05). This is the first study to determine the safety profile of oral higenamine intake in human subjects. Our data indicate that 8 weeks of daily higenamine supplementation, either alone or in conjunction with caffeine and yohimbe bark extract, does not result in a statistically significant change in any of the measured outcome variables. Additional studies, inclusive of a larger sample size, are needed to extend these initial findings.

Cardiovascular Safety Monitoring During Oncology Drug Development and Therapy

Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers.

The clinical liver safety assessment best practices workshop: rationale, goals, accomplishments and the future.

The workshop was successful in bringing international experts from industry, academia, and regulatory agencies together to address the need for industry-wide standardization of liver safety data collection, causality assessment, and liver safety data management. It should be noted that the consensus statements contained in the manuscripts are simply that. They are not regulatory policy, but hopefully will stimulate progress toward the lengthy process of updating and revising the 2009 guidance document. There was near unanimous agreement that future guidelines and policies should be based as much as possible on data that should be available through precompetitive collaboration. Importantly, the workshop established a core international group of concerned experts from academia, industry and regulatory bodies to improve and standardize the approaches to assessing liver safety in clinical trials. An important goal to consider in this effort would be the establishment of a Liver Safety Research Consortium.

The Relevance of Immunogenicity in Preclinical Development

This communication discusses the relevance of immunogenicity in preclinical trials and its importance in the development of biopharmaceuticals. The preclinical and non clinical development of Biopharmaceuticals is reviewed and discussed, with a focus on the specific regulatory requirements for the preclinical and clinical safety assessment of large molecules. Immunogenicity data obtained for Interferon and Rituximab during preclinical safety assessment studies are presented in this communication. Interferon and Rituximab are biopharmaceuticals that have been demonstrated to elicit immunogenic reactions in both preclinical animal models and clinical trials. The production of Anti-Drug Antibodies (ADAs) has several consequences on the systemic exposure and on the toxicity/ pharmacodynamic profile of a biopharmaceutical assessed in the preclinical stage. The impact must be carefully assessed especially when using the preclinical data to establish the Maximum Recommended Safe Starting Dose (MRSD) of the first clinical trials.