Pharmacokinetics and Safety of Enzalutamide in Healthy Chinese Male Volunteers.

Clin Ther. 2019 Jan 11;:

Authors: Liu YM, Wu P, Fukushi R, Yamada S, Chen Q

Abstract
PURPOSE: This open-label, single-dose study evaluated the pharmacokinetic profiles of enzalutamide and its major metabolites and the safety of enzalutamide in healthy, Chinese male volunteers.
METHODS: Fourteen volunteers (median age, 28.5 years) received a single oral dose of enzalutamide (160 mg) under fasting conditions on day 1 and were followed for 50 days. Pharmacokinetic profiles were obtained for enzalutamide and its major metabolites, carboxylic acid metabolite (M1; inactive metabolite) and N-desmethyl enzalutamide (M2; active metabolite), on day 1 up to 1176 hours (49 days). Safety data were also collected.
FINDINGS: Enzalutamide plasma concentration rapidly increased (median Tmax, 1.5 hours) followed by a slow decrease (mean t½, 90.7 hours). M1 and M2 plasma concentrations increased gradually with a median Tmax of 72.0 and 121 hours, respectively. M1 and M2 mean metabolite-to-parent ratios were 0.2 and 1.3, respectively. Mean AUC0-∞ of enzalutamide plus M2 was 828 μg h/mL versus 368 μg h/mL for enzalutamide alone. Mean t½, maximum concentration, and Tmax of enzalutamide plus M2 were comparable with those of enzalutamide. Drug-related treatment-emergent adverse events were reported in 4 men (28.6%): 1 each of upper respiratory tract infection, chest discomfort, increased blood bilirubin, and decreased white blood cell count. No deaths or serious treatment-emergent adverse events were observed.
IMPLICATIONS: The pharmacokinetic profiles of enzalutamide, M1, M2, and enzalutamide plus M2 in healthy Chinese men were generally consistent with those in white men. No new safety concerns were found. Chinese Clinical Trial Registration identifier: CTR20150635.

PMID: 30642613 [PubMed - as supplied by publisher]

Adverse drug reactions of anticancer drugs derived from natural sources.

Food Chem Toxicol. 2019 Jan;123:522-535

Authors: Tewari D, Rawat P, Singh PK

Abstract
Cancer, a life threatening disease adversely affects huge population worldwide. Naturally derived drug discovery has emerged as a potential pathway in search of anticancers. Natural products-based drugs are generally considered safe, compared to their synthetic counterparts. A systematic review on adverse drugs reactions (ADRs) of the anticancer natural products has not been performed till date. We reviewed anticancer drugs, derived from plants, microbes and marine sources with their mechanistic action and reported ADRs. PubMed, ScienceDirect and Scopus were searched through Boolean information retrieval method using keywords "natural products", "cancer", "herbal", "marine drugs" and "adverse drug reaction". We documented ADRs of natural products based anticancer agents, mechanisms of action and chemical structures. It was observed that majority of the natural products based anticancer drugs possess ample adverse effects, dominantly hematological toxicities, alopecia, neurotoxicity and cardiotoxicity. These findings deviate from the preconceived notion about safer nature of herbal drugs. We also came across some anti-cancer natural products with less/no reported adverse events like Cabazitaxel and Arglabin. Comprehensive pharmacovigilance studies are needed to report ADRs and thereby predicting safety of anti-cancer drugs, either originated from natural sources or chemically synthesized.

PMID: 30471312 [PubMed - indexed for MEDLINE]

Evaluating exposure using confidence intervals: implication in tiered quantitation of metabolites for safety risks.

Bioanalysis. 2018 Oct;10(19):1553-1556

Authors: Niwa M, Ishii T, Ono K, Kuriyama S, Nakai N, Hosaka S, Mayumi T, Yasuda Y, Yamakawa T

PMID: 30295549 [PubMed - indexed for MEDLINE]

[The analysis of the association of the polymorphic variants of the TPMT, COMT, and ABCC3 genes with the development of hearing disorders induced by the cisplatin treatment].

Vestn Otorinolaringol. 2018;83(4):60-66

Authors: Mironovich OL, Bliznetz EA, Garbaruk ES, Belogurova MB, Subora NV, Varfolomeeva SR, Kachanov DY, Shamanskaya TV, Markova TG, Polyakov AV

Abstract
Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblastoma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) are conferring increased risk of developing cisplatin-induced hearing loss. However, in other studies the results were not replicated. In the present study, we replicated the previous studies based on an independent cohort of Russian patients. SNP genotypes for rs 12201199, rs4646316 and rs 1051640 were determined in DNA samples obtained from 16 patients who developed hearing loss and a group of 34 patients whose hearing was retained. The association between TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) variants and the hearing loss was not observed in our cohort.

PMID: 30113582 [PubMed - indexed for MEDLINE]

Potential Drug-Drug Interactions Among Critically Ill Pediatric Patients in a Tertiary Pulmonary Center.

J Clin Pharmacol. 2018 02;58(2):221-227

Authors: Hassanzad M, Arenas-Lopez S, Baniasadi S

Abstract
Patients in the pediatric intensive care unit (PICU) are at increased risk of potential drug-drug interactions (pDDIs) because of the complexity of pharmacotherapy. The current study aimed to assess the rate, pattern, risk factors, and management of pDDIs in the PICU of an academic pulmonary hospital. A prospective observational study was conducted for 6 months. Pharmacotherapy data of PICU-admitted patients were evaluated by a clinical pharmacologist. Interacting drugs, reliability, mechanism, potential outcome, and clinical management of pDDIs were identified using the Lexi-Interact database. Logistic regression was applied to analyze the risk factors that could be associated with the interactions. One hundred and twenty-three medication profiles were evaluated during the study period. Diseases of the respiratory system were the main diagnoses among intensive care unit (ICU)-admitted patients (56.1%). A total of 38.6% of the patients exposed to at least 1 major and/or contraindicated interaction during ICU admission. Most pDDIs occurred through metabolic (35.4%) and additive (34.8%) mechanisms. The existence of pDDIs was significantly associated with the number of prescribed medications. Exposure to pDDIs is frequent in critically ill pediatric patients and related to the number of medications. Daily and close cooperation between clinicians and clinical pharmacologists is recommended to prevent harmful outcomes of DDIs.

PMID: 28834562 [PubMed - indexed for MEDLINE]

12 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 2019/01/15

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.

Medicinal cannabis for chemotherapy-induced nausea and vomiting: prescribing with limited evidence.

Med J Aust. 2019 Jan;210(1):11-12.e1

Authors: Mersiades AJ, Stockler MR, Olver IN, Grimison P

PMID: 30636299 [PubMed - in process]

Long-term safety and efficacy of adjunctive rasagiline in levodopa-treated Japanese patients with Parkinson's disease.

J Neural Transm (Vienna). 2019 Jan 11;:

Authors: Hattori N, Takeda A, Takeda S, Nishimura A, Nakaya R, Mochizuki H, Nagai M, Takahashi R

Abstract
Rasagiline is a monoamine oxidase type-B inhibitor in development in Japan for Parkinson's disease (PD). This open-label study evaluated the long-term safety and efficacy of rasagiline in Japanese patients with PD receiving levodopa. Patients were aged 30-79 years and had wearing-off or weakened effect. Patients received rasagiline 1 mg/day for 52 weeks. The primary objective was to evaluate safety. Secondary endpoints included MDS-UPDRS Part II and Part III total scores (ON-state) and change from baseline in mean daily OFF-time. An additional endpoint was the Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index (SI) score. In total, 222 patients were enrolled; 52.3% had wearing-off phenomena. Treatment-emergent adverse events (TEAEs) were mostly mild or moderate and occurred in 83.3% of patients; 63.1% had drug-related TEAEs; and 21.2% had TEAEs resulting in discontinuation. Fall (16.7%), nasopharyngitis (14.0%), and dyskinesia (10.8%) were the most frequent TEAEs. Serious TEAEs were reported in 17.6% of patients, and led to discontinuation in 9.5%. At week 52 (last-observation-carried forward), the mean change from baseline in MDS-UPDRS Part III total score (ON-state) was - 7.6; the mean change from baseline in daily OFF-time was - 0.89 h in patients with wearing-off phenomena at the start of the run-in period. The mean change from baseline in PDQ-39 SI was - 0.64. No major safety issues were observed during this 52-week trial of rasagiline as an adjunct to levodopa in Japanese patients. Mean changes in MDS-UPDRS scores and daily OFF-time suggested that adjunctive rasagiline treatment with levodopa was efficacious, with efficacy maintained for at least 52 weeks.

PMID: 30635744 [PubMed - as supplied by publisher]

Evaluating the analgesic effect and advantage of transcutaneous electrical acupoint stimulation combined with opioid drugs for moderate to severe cancer-related pain: a study protocol for a randomized controlled trial.

Trials. 2019 Jan 11;20(1):40

Authors: Liang Y, Bao G, Gong L, Zhou J, Kong X, Ran R, Shao X, Jiang Y, Zhang W, Liu B, Du J, Fang J, Nie N, Ji C, Fang J

Abstract
BACKGROUND: Transcutaneous electrical acupoint stimulation (TEAS), which is also known as acupuncture-like transcutaneous electrical nerve stimulation (TENS), has been widely used in acute or chronic pain. However, previous research has not demonstrated that TEAS is effective for cancer-related pain. Opioid drugs are strongly recommended for treating cancer-related pain, but opioid-induced immunosuppression is still the most intractable drug-induced medical problem. Evaluating the efficacy and potential advantage of TEAS combined with opioid drugs in moderate and severe cancer-related pain in China is important because such studies are lacking.
METHODS/DESIGN: This trial is a multicenter, prospective randomized controlled clinical trial. In total, 160 patients who were enrolled from two hospitals in the Zhejiang Province (China) will be randomly allocated into two groups: a TEAS group and sham TEAS group without acupoint electrical stimulation. Both groups will receive a 21-day interval of chemotherapy and conventional cancer pain therapy. Fifteen treatment sessions will be performed over a three-week period. The primary outcomes will be measured by changes in the Numerical Rating Scale (NRS) scores and equivalent dosage of morphine at baseline, three weeks of treatment and one two-week follow-up. The secondary outcome measures include cellular immunity function, life quality assessment, opioids side effects assessment, and safety and compliance evaluation.
DISCUSSION: This trial is expected to clarify whether TEAS is effective for cancer-related pain. These results demonstrate the advantage of TEAS combined with opioid drugs on improving immune function and decreasing opioid induced side effects.
TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-13003803 . Registered on 27 August 2013.

PMID: 30635007 [PubMed - in process]

21 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 2019/01/12

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.

Prevention of rocuronium induced mast cell activation with prophylactic oleuropein rich diet in anesthetized rabbits1.

Acta Cir Bras. 2018 Nov;33(11):954-963

Authors: Simsek T, Erbas M, Buyuk B, Pala C, Sahin H, Altinisik B

Abstract
PURPOSE: The effect of a prophylactic oleuropein-rich diet before anesthesia accompanied by the widely-used steroid-based neuromuscular drug rocuronium on mast cell activation was investigated in the study.
METHODS: 14 rabbits used in the study. The rabbits in the oleuropein group were given oleuropein-rich extract added to the animals' water at doses of 20 mg/kg oleuropein for 15 days orally. After 15 days, all rabbits in the two groups were given general anesthesia with rocuronium of 1 mg/kg. After 1 day, animals were sacrificed and the liver tissue sections stained with H&E, toluidine blue and tryptase for immunohistochemical study.
RESULTS: There was no statistically significant difference between ALT, AST and albumin averages of the oleuropein and control groups (p> 0.05). The tryptase average of the control group was higher than the tryptase average of the oleuropein group and this difference was statistically significant (p=0.003). The T. blue average in the oleuropein group was higher than the control group. However, there was no statistically significant difference between groups (p=0.482).
CONCLUSIONS: Rocuronium adverse effects, like hypersensitivity and anaphylaxis, may limit routine use of this substance. The use of oleuropein reduced the number of inflammatory cells and prevented degranulation.

PMID: 30517322 [PubMed - indexed for MEDLINE]

Adverse effects of amiodarone therapy in adults with congenital heart disease.

Congenit Heart Dis. 2018 Nov;13(6):944-951

Authors: Moore BM, Cordina RL, McGuire MA, Celermajer DS

Abstract
OBJECTIVE: Amiodarone is a highly effective antiarrhythmic therapy, however its toxicity profile often limits treatment. This is particularly relevant in adults with congenital heart disease (CHD), who are often young and in whom other antiarrhythmic agents commonly fail or are contraindicated. We sought to determine incidence and predictors of adverse effects caused by amiodarone in adult CHD (ACHD).
DESIGN: A retrospective review of patients with moderate to complex ACHD treated with amiodarone at our center between 2000 and 2017 was performed. Incidence and predictors of adverse effects were described. Efficacy of amiodarone therapy in controlling the clinical arrhythmia was assessed as complete, partial, or failed.
RESULTS: Amiodarone was prescribed in 57 patients of 902 ACHD patients reviewed (6%), for a mean duration of 2.7 ± 4.3 years. Significant adverse effects occurred in 56%, most commonly thyroid dysfunction, with amiodarone-induced thyrotoxicosis (AIT) in 30% and amiodarone-induced hypothyroidism in 14%. AIT frequently led to arrhythmia exacerbation and occurred most in those with Fontan anatomy. Severe dermatological effects were seen in 7% and bradycardia requiring pacing in 5%. Interstitial lung disease, peripheral neuropathy and alopecia were observed in single cases. Amiodarone toxicity led to discontinuation of the drug in 42%. Amiodarone was highly effective when tolerated, however, achieving complete arrhythmia control in 63%, partial control in 35%, with failure to control in only one patient.
CONCLUSIONS: Amiodarone therapy is effective in moderate to complex ACHD patients, but is frequently limited by adverse effects. ACHD patients seem especially vulnerable to thyroid dysfunction, with Fontan patients in particular at increased risk of AIT.

PMID: 30239160 [PubMed - indexed for MEDLINE]

Triggers for active surveillance of adverse drug events in newborns.

Cad Saude Publica. 2018 09 06;34(9):e00069817

Authors: Fabretti SC, Brassica SC, Cianciarullo MA, Romano-Lieber NS

Abstract
The study aimed to verify the application and performance of triggers for adverse drug events in hospitalized newborns. This prospective cohort study was conducted in the neonatal care units of a university hospital from March to September 2015. A list of triggers was developed for the identification of adverse drug events in this population. The list included antidote, clinical, and laboratory triggers. A total of 125 newborns who had received drugs during the hospitalization were included. Neonatal patient charts were screened to detect triggers. When a trigger was found, the patient chart was reviewed to identify possible adverse drug events. Each trigger's yield in the identification of adverse drug events was calculated and then classified according to its performance. Nine hundred and twenty-five triggers identified 208 suspected adverse drug events. The triggers' overall yield was 22.5%. The most frequently identified triggers were: drop in oxygen saturation, increased frequency of bowel movements, medications stop, and vomiting. The triggers with the best performance in the identification of adverse drug events were: increased creatinine, increased urea, necrotizing enterocolitis, prescription of flumazenil, hypercalcemia, hyperkalemia, hypernatremia, and oversedation. The triggers identified in this study can be used to track adverse drug events in similar neonatal care services, focusing on the triggers with the best performance and the lowest workload in the identification.

PMID: 30208171 [PubMed - indexed for MEDLINE]

An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region.

PLoS Negl Trop Dis. 2018 10;12(10):e0006850

Authors: Gadelha EPN, Ramasawmy R, da Costa Oliveira B, Morais Rocha N, de Oliveira Guerra JA, Allan Villa Rouco da Silva G, Gabrielle Ramos de Mesquita T, Chrusciak Talhari Cortez C, Chrusciak Talhari A

Abstract
BACKGROUND: American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil.
OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose.
MATERIALS AND METHODS: This study was conducted as a controlled, randomized, open-label clinical trial for a total number of 159 patients with CL. Individuals aged 16-64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment.
RESULTS: From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred.
CONCLUSION: The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02919605.

PMID: 30379814 [PubMed - indexed for MEDLINE]

Safety, efficacy and acceptability of praziquantel in the treatment of Schistosoma haematobium in pre-school children of Kwale County, Kenya.

PLoS Negl Trop Dis. 2018 10;12(10):e0006852

Authors: Kimani BW, Mbugua AK, Kihara JH, Ng'ang'a M, Njomo DW

Abstract
BACKGROUND: The recommended strategy for control of schistosomiasis is preventive chemotherapy with praziquantel (PZQ). Pre-school children (PSC) are excluded from population treatment programs. In high endemic areas, these children are also at risk, and require treatment with PZQ. The Government of Kenya initiated the National School-Based Deworming Programme (NSBDP) where PSC in Early Childhood Development Education (ECDE) Centers are only eligible for treatment with albendazole (ABZ) but not with PZQ.
METHODOLOGY/PRINCIPAL FINDINGS: 400 PSC were enrolled, from 10 randomly selected ECDE Centers in Kwale County, Kenya where children were treated with crushed PZQ tablets mixed with orange juice, at a single dose of 40 mg/kg. Adverse events were assessed 24 hours post-treatment through questionnaires administered to the parents or guardians. Acceptability was determined by observing if the child spat and/ or vomited all or part of the PZQ dose immediately after treatment. Efficacy was assessed by examining urine samples for Schistosoma haematobium eggs in the 5 weeks post-treatment follow-up. Children testing negative for S. haematobium during the follow-up were considered cured. Egg reduction rate (ERR) was calculated as the decrement in the infection intensity (group's geometric mean egg counts per 10 ml of urine) following treatment expressed as a proportion of the pre-treatment infection intensity. Before treatment, 80 out of the 400 children enrolled in the study tested positive for S. haematobium (20.0% (95% confidence interval (CI) 16.4-24.2%). Of these, 41 had infections of heavy intensity (51.3%) while the rest (48.7%) were of light intensity. Five weeks post-treatment, 10 children who had heavy intensity infection were diagnosed with S. haematobium (prevalence: 2.5% (95% CI 1.5-4.9%). Infection intensities decreased significantly from 45.9 (95% CI: 31.0-68.0) eggs/ 10 ml urine to1.4 (95% CI: 1.1-1.7) eggs/ 10 ml urine during pre-and post-treatment respectively. The ERR was 96.9%. There were no severe adverse events during follow up 24 hours post treatment. Treatment tolerability among the 400 children was high as none of the children spat and/ or vomited as observed in this study.
CONCLUSION/SIGNIFICANCE: The study revealed that crushed PZQ is safe and effective in the treatment of urogenital schistosomiasis in this age group. It is therefore recommended that PZQ should be administered to the PSC in Kwale County.

PMID: 30332403 [PubMed - indexed for MEDLINE]

A liver-immune coculture array for predicting systemic drug-induced skin sensitization.

Lab Chip. 2018 10 23;18(21):3239-3250

Authors: Chong LH, Li H, Wetzel I, Cho H, Toh YC

Abstract
Drug-induced skin sensitization is prevalent worldwide and can trigger life-threatening health conditions, such as Stevens Johnson Syndrome. However, existing in vitro skin models cannot adequately predict the skin sensitization effects of drugs administered into the systemic circulation because dermal inflammation and injury are preceded by conversion of parent drugs into antigenic reactive metabolites in the liver and subsequent activation of the immune system. Here, we demonstrate that recapitulation of these early tandem cellular processes in a compartmentalized liver-immune coculture array is sufficient to predict the skin sensitization potential of systemic drugs. Human progenitor cell (HepaRG)-derived hepatocyte spheroids and U937 myeloid cells, a representative antigen presenting cell (APC), can maintain their respective functions in 2 concentric micro-chambers, which are connected by a diffusion microchannel network. Paradigm drugs that are reported to cause severe cutaneous drug reactions (i.e. carbamazepine, phenytoin and allopurinol) can be metabolized into their reactive metabolites, which diffuse efficiently into the adjoining immune compartment within a 48 hour period. By measuring the extent of U937 activation as indicated by IL8, IL1β and CD86 upregulation upon drug administration, we show that the liver-immune coculture array more consistently and reliably distinguish all 3-paradigm skin sensitizing drugs from a non-skin sensitizer than conventional bulk Transwell coculture. Given its miniaturized format, design simplicity and prediction capability, this novel in vitro system can be readily scaled into a screenable platform to identify the skin sensitization potential of systemically-administered drugs.

PMID: 30252012 [PubMed - indexed for MEDLINE]

Does public perception bias lead to more frequent reporting of adverse events: branded vs generic drugs.

Expert Opin Drug Saf. 2018 Aug;17(8):753-756

Authors: Qian J, Mishuk AU, Hansen RA

PMID: 30052091 [PubMed - indexed for MEDLINE]

In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices.

J Pharmacol Toxicol Methods. 2018 Sep - Oct;93:7-14

Authors: Valentin JP, Guillon JM, Jenkinson S, Kadambi V, Ravikumar P, Roberts S, Rosenbrier-Ribeiro L, Schmidt F, Armstrong D

Abstract
INTRODUCTION: In 2015, IQ DruSafe conducted a survey of its membership to identify industry practices related to in vitro off target pharmacological profiling of small molecules.
METHODS: An anonymous survey of 20 questions was submitted to IQ-DruSafe representatives. Questions were designed to explore screening strategies, methods employed and experience of regulatory interactions related to in vitro secondary pharmacology profiling.
RESULTS: The pharmaceutical industry routinely utilizes panels of in vitro assays to detect undesirable off-target interactions of new chemical entities that are deployed at all stages of drug discovery and early development. The formats, approaches and size of panels vary between companies, in particular i) choice of assay technology; ii) test concentration (single vs. multiple concentrations) iii) rationale for targets and panels selection (taking into account organizational experience, primary target, therapeutic area, availability at service providers) iv) threshold level for significant interaction with a target and v) data interpretation. Data are generated during the early phases of drug discovery, principally before in vivo GLP studies (i.e., hit-to-lead, lead optimization, development candidate selection) and used to contextualize in vivo non-clinical and clinical findings. Data were included in regulatory documents, and around half of respondents experienced regulatory questions about the significance of the results.
CONCLUSION: While it seems that in vitro secondary pharmacological profiling is generally considered valuable across the industry, particularly as a tool in early phases of drug discovery for small molecules, there is only loose consensus on testing paradigm, the required interpretation and suitable follow up strategies to fully understand potential risk.

PMID: 30030184 [PubMed - indexed for MEDLINE]

The use of human tissue in safety assessment.

J Pharmacol Toxicol Methods. 2018 Sep - Oct;93:29-34

Authors: Jackson SJ, Prior H, Holmes A

Abstract
INTRODUCTION: The safety-related failure of drugs during clinical phases of development is a significant contributor to drug attrition, wasting resources and preventing treatments from reaching patients. A lack of concordance between results from animal models and adverse events in the clinic has been identified as one potential cause of attrition. In vitro models using human tissue or cells have the potential to replace some animal models and improve predictivity to humans.
METHODS: To gauge the current use of human tissue models in safety pharmacology and the barriers to greater uptake, an electronic survey of the international safety assessment community was carried out and a Safety Pharmacology Society European Regional Meeting was organised entitled 'The Use of Human Tissue in Safety Assessment'.
RESULTS: A greater range of human tissue models is in use in safety assessment now than four years ago, although data is still not routinely included in regulatory submissions. The barriers to increased uptake of the models have not changed over that time, with inadequate supply and characterisation of tissue being the most cited blocks.
DISCUSSION: Supporting biobanking, the development of new human tissue modelling technology, and raising awareness in the scientific and regulatory communities are key ways in which the barriers to greater uptake of human tissue models can be overcome. The development of infrastructure and legislation in the UK to support the use of post-mortem or surgical discard tissue will allow scientists to locally source tissue for research.

PMID: 29753134 [PubMed - indexed for MEDLINE]

An overview of the safety pharmacology society strategic plan.

J Pharmacol Toxicol Methods. 2018 Sep - Oct;93:35-45

Authors: Pugsley MK, Authier S, Koerner JE, Redfern WS, Markgraf CG, Brabham T, Correll K, Soloviev MV, Botchway A, Engwall M, Traebert M, Valentin JP, Mow TJ, Greiter-Wilke A, Leishman DJ, Vargas HM

Abstract
Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009.

PMID: 29330132 [PubMed - indexed for MEDLINE]