Systems Toxicology: Systematic Approach to Predict Toxicity.

Curr Pharm Des. 2016;22(46):6911-6917

Authors: Kiani NA, Shang MM, Tegner J

Abstract
Drug discovery is complex and expensive. Numerous drug candidates fail late in clinical trials or even after being released to the market. These failures are not only due to commercial considerations and less optimal drug efficacies but, adverse reactions originating from toxic effects also constitute a major challenge. During the last two decades, significant advances have been made enabling the early prediction of toxic effects using in silico techniques. However, by design, these essentially statistical techniques have not taken the disease driving pathophysiological mechanisms into account. The complexity of such mechanisms in combination with their interactions with drugspecific properties and environmental and life-style related factors renders the task of predicting toxicity on a purely statistical basis which is an insurmountable challenge. In response to this situation, an interdisciplinary field has developed, referred to as systems toxicology, where the notion of a network is used to integrate and model different types of information to better predict drug toxicity. In this study, we briefly review the merits and limitations of such recent promising predictive approaches integrating molecular networks, chemical compound networks, and protein drug association networks.

PMID: 27697024 [PubMed - indexed for MEDLINE]

A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.

Mov Disord. 2016 Sep;31(9):1373-80

Authors: Tison F, Keywood C, Wakefield M, Durif F, Corvol JC, Eggert K, Lew M, Isaacson S, Bezard E, Poli SM, Goetz CG, Trenkwalder C, Rascol O

Abstract
BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD).
METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose.
RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28.
CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.

PMID: 27214664 [PubMed - indexed for MEDLINE]

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

J Sex Med. 2017 Dec 27;:

Authors: Tuiten A, van Rooij K, Bloemers J, Eisenegger C, van Honk J, Kessels R, Kingsberg S, Derogatis LR, de Leede L, Gerritsen J, Koppeschaar HPF, Olivier B, Everaerd W, Frijlink HW, Höhle D, de Lange RPJ, Böcker KBE, Pfaus JG

Abstract
BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available.
AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups.
METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg).
OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure.
RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%).
CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD.
STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated.
CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2017;XX:XXX-XXX.

PMID: 29289554 [PubMed - as supplied by publisher]

Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study.

J Am Acad Dermatol. 2018 Jan;78(1):107-114.e1

Authors: Chasset F, Arnaud L, Jachiet M, Monfort JB, Bouaziz JD, Cordoliani F, Bagot M, Barbaud A, Francès C

Abstract
BACKGROUND: Changing from one antimalarial (AM) agent to another is often recommended in cutaneous lupus erythematosus (CLE) when the first AM agent is ineffective or poorly tolerated.
OBJECTIVE: To evaluate the effect on cutaneous response of a switch from hydroxychloroquine to chloroquine, or the reverse, after failure of the first AM agent.
METHODS: We conducted a retrospective observational study between 1997 and September 2015. The overall cutaneous response rate and reasons for failure of the switch were assessed for up to 48 months. Kaplan-Meier survival curves were used to assess the risk for failure of the second AM agent.
RESULTS: A total of 64 patients with CLE (78% were women) were included; for 48 patients, the switch was for inefficacy, and for 16, it was for adverse events. Median follow-up was 42 months (range, 3-171). Of the patients changed because of inefficacy, 56% were responders at month 3; however, the response decreased over time, with a median duration before failure of the second AM agent of 9 months (95% confidence interval, 6-24). For patients switched because of adverse events, the second AM agent was well tolerated in 69% of cases.
LIMITATIONS: Retrospective design and subjective evaluation of cutaneous response.
CONCLUSION: A change of AM agent should be considered in patients with CLE when the first AM agent is ineffective or poorly tolerated.

PMID: 29061479 [PubMed - indexed for MEDLINE]

Veterinary pharmacovigilance in India: A need of hour.

Indian J Pharmacol. 2017 Jan-Feb;49(1):2-3

Authors: Kumar R, Kalaiselvan V, Verma R, Kaur I, Kumar P, Singh GN

Abstract
Veterinary pharmacovigilance (PV) is important for the Medicine which are used for treating disease in animals. It becomes more important when these animals are further used for producing food. Adverse drug reactions (ADRs) have a direct impact on animals and indirect impact on human beings, for example, through milk products, other animal producing food products. Currently, PV program of India is playing a vital role in assessing the safety of medicines in Indian Population. The safety of medicine in animals can be assessed by veterinary PV. The research institutes involved in animal research and veterinary hospitals can be considered as ADR monitoring centers to assess the safety of medicines on animals.

PMID: 28458414 [PubMed - indexed for MEDLINE]

Tolerability of central nervous system symptoms among HIV-1 infected efavirenz users: analysis of patient electronic medical record data.

AIDS Care. 2017 08;29(8):1067-1073

Authors: Rosenblatt L, Broder MS, Bentley TGK, Chang E, Reddy SR, Papoyan E, Myers J

Abstract
Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor indicated for treatment of HIV-1 infection. Despite concern over EFV tolerability in clinical trials and practice, particularly related to central nervous system (CNS) adverse events, some observational studies have shown high rates of EFV continuation at one year and low rates of CNS-related EFV substitution. The objective of this study was to further examine the real-world rate of CNS-related EFV discontinuation in antiretroviral therapy naïve HIV-1 patients. This retrospective cohort study used a nationally representative electronic medical records database to identify HIV-1 patients ≥12 years old, treated with a 1st-line EFV-based regimen (single or combination antiretroviral tablet) from 1 January 2009 to 30 June 2013. Patients without prior record of EFV use during 6-month baseline (i.e., antiretroviral therapy naïve) were followed 12 months post-medication initiation. CNS-related EFV discontinuation was defined as evidence of a switch to a replacement antiretroviral coupled with record of a CNS symptom within 30 days prior, absent lab evidence of virologic failure. We identified 1742 1st-line EFV patients. Mean age was 48 years, 22.7% were female, and 8.1% had a prior report of CNS symptoms. The first year, overall discontinuation rate among new users of EFV was 16.2%. Ten percent of patients (n = 174) reported a CNS symptom and 1.1% (n = 19) discontinued EFV due to CNS symptoms: insomnia (n = 12), headache (n = 5), impaired concentration (n = 1), and somnolence (n = 1). The frequency of CNS symptoms was similar for patients who discontinued EFV compared to those who did not (10.3 vs. 9.9%; P = .86). Our study found that EFV discontinuation due to CNS symptoms was low, consistent with prior reports.

PMID: 28147708 [PubMed - indexed for MEDLINE]

Polypharmacy in older adults: Association Rule and Frequent-Set Analysis to evaluate concomitant medication use.

Pharmacol Res. 2017 Feb;116:39-44

Authors: Held F, Le Couteur DG, Blyth FM, Hirani V, Naganathan V, Waite LM, Seibel MJ, Handelsman DJ, Cumming RG, Allore HG, Gnjidic D

Abstract
The aim of this study was to apply Association Rule and Frequent-Set analysis, and novel means of data visualisation to ascertain patterns of medication use and medication combinations contributing to medication group clusters according to geriatric syndrome status in older adults. Participants were community-dwelling men (aged ≥70 years, n=1686), Sydney, Australia. Medication exposure was categorised at medication class level and data were analysed according to geriatric syndrome status (presence of at least one syndrome including frailty, falls, cognitive impairment and urinary incontinence). Association Rule and Frequent-Set analysis were performed to identify "interesting" patterns of medication combinations that occur together. This analysis involves advanced computer algorithms that investigated all possible combinations of medications in the dataset in order to identify those which are observed more or much less frequently than expected. Frequent-Set Analysis demonstrated one unexpected medication combination, antiulcer and antidiabetic medications (3.5% of participants) in the overall population (n=1687). Frequency of medication combinations was similar in participants with (n=666) and without (n=1020) geriatric syndromes. Among participants with geriatric syndromes, the most frequent combinations included antigout with lipid-lowering agents (5.7%) followed by angiotensin II and diuretics combination (22%). This novel methodology can be used to detect common medication combinations overall by data visualisation, and against specific adverse drug reactions such as geriatric syndromes. This methodology may be a valuable pharmacovigilance approach to monitor large databases for the safety of medications.

PMID: 27988385 [PubMed - indexed for MEDLINE]

Patient-provider communication and hormonal therapy side effects in breast cancer survivors.

Women Health. 2017 Sep;57(8):976-989

Authors: Lin JJ, Chao J, Bickell NA, Wisnivesky JP

Abstract
Side effects from hormonal therapy (HT) for breast cancer treatment occur frequently and are associated with worse quality of life and HT non-adherence. Whether improved patient-physician communication is associated with patients' reporting of side effects is unknown. We undertook this study to assess factors associated with women's reports of HT side effects. Between December 2012 and April 2013, we conducted a cross-sectional survey of breast cancer patients undergoing HT in an urban medical center. Descriptive statistics, univariate analyses, and multivariate analyses were used to evaluate associations. Of the 100 participants, 67% reported having HT side effects. However, when prompted, an additional 9% reported experiencing specific HT-related symptoms. Despite very high communication scores, one-third of participants reported they had not discussed side effects with providers. Multivariate analysis showed that after controlling for age, education, race, and medication beliefs, women who had difficulty asking providers for more information were more likely to report side effects (odds ratio 8.27, 95% confidence interval 1.01-69.88). Although HT side effects often occur and are bothersome, patient-provider discussions about side effects remain suboptimal. Providers should actively ask patients about medication side effects so that they can be addressed to improve quality of life and potentially, medication adherence.

PMID: 27618729 [PubMed - indexed for MEDLINE]

Mavoglurant in Parkinson's patients with l-Dopa-induced dyskinesias: Two randomized phase 2 studies.

Mov Disord. 2016 Jul;31(7):1054-8

Authors: Trenkwalder C, Stocchi F, Poewe W, Dronamraju N, Kenney C, Shah A, von Raison F, Graf A

Abstract
BACKGROUND: Two phase 2 randomized, double-blind studies were designed to evaluate efficacy and safety of immediate-release (study 1) and modified-release (study 2) mavoglurant formulations in PD l-dopa-induced dyskinesia.
METHODS: Patients were randomized to mavoglurant 100-mg or placebo (4:3) groups (study 1) and mavoglurant 200-mg, mavoglurant 150-mg, or placebo (2:1:1) groups (study 2). Primary outcome was antidyskinetic efficacy, as measured by change from baseline to week 12 in modified Abnormal Involuntary Movement Scale total score.
RESULTS: Differences in least-squares mean (standard error) change in modified Abnormal Involuntary Movement Scale total score in week 12 did not reach statistical significance in either study (study 1: mavoglurant 100 mg twice a day versus placebo, 1.7 [1.31]; study 2: mavoglurant 150 mg twice a day (-1.3 [1.16]) and 200 mg twice a day (-0.2 [1.03]) versus placebo). Adverse events incidence was higher with mavoglurant than with placebo.
CONCLUSIONS: Both studies failed to meet the primary objective of demonstrating improvement of dyskinesia with mavoglurant treatment. © 2016 International Parkinson and Movement Disorder Society.

PMID: 27214258 [PubMed - indexed for MEDLINE]

A Placebo-Controlled Trial of AQW051 in Patients With Moderate to Severe Levodopa-Induced Dyskinesia.

Mov Disord. 2016 Jul;31(7):1049-54

Authors: Trenkwalder C, Berg D, Rascol O, Eggert K, Ceballos-Baumann A, Corvol JC, Storch A, Zhang L, Azulay JP, Broussolle E, Defebvre L, Geny C, Gostkowski M, Stocchi F, Tranchant C, Derkinderen P, Durif F, Espay AJ, Feigin A, Houeto JL, Schwarz J, Di Paolo T, Feuerbach D, Hockey HU, Jaeger J, Jakab A, Johns D, Linazasoro G, Maruff P, Rozenberg I, Sovago J, Weiss M, Gomez-Mancilla B

Abstract
BACKGROUND: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia.
METHODS: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics.
RESULTS: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls.
CONCLUSIONS: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society.

PMID: 26990766 [PubMed - indexed for MEDLINE]

Older Adults' Awareness of Deprescribing: A Population-Based Survey.

J Am Geriatr Soc. 2017 Dec;65(12):2691-2696

Authors: Turner JP, Tannenbaum C

Abstract
OBJECTIVES: To determine older adults' awareness of the concept of medication-induced harm and their familiarity with the term "deprescribing." Secondary objectives were to ascertain determinants of self-initiated deprescribing conversations and to identify how older adults seek information on medication harms.
DESIGN: Cross-sectional population-based household telephone survey using random-digit dialling.
SETTING: Canada.
PARTICIPANTS: Community-dwelling adults aged 65 and older (N = 2,665; n = 898 men, n = 1,767 women, mean age 74.9 ± 7.2, range 65-100).
MEASUREMENTS: Information was gathered on age; sex; awareness of the term "deprescribing"; knowledge and information-seeking behaviors related to medication harms; and previous initiation of a deprescribing conversation with a healthcare professional. Three targeted classes of potentially inappropriate prescriptions were asked about: sedative-hypnotics, glyburide, and proton pump inhibitors. Descriptive statistics and regression analyses were used to quantify associations.
RESULTS: Two-thirds (65.2%, 95% confidence interval (CI) = 63.4-67.0%) of participants were familiar with the concept of medication-induced harms. Only 6.9% (95% CI = 5.9-7.8%) recognized the term deprescribing; 48% (95% CI = 46-50%) had researched medication-related harms. Older adults most commonly sought information from the Internet (35.5%, 95% CI = 33.4-37.6%), and from health care professionals (32.2%, 95% CI = 30.1-34.3%). Patient-initiated deprescribing conversations were associated with awareness of medication harms (odds ratio (OR) = 1.74, 95% CI = 1.46-2.07), familiarity with the term deprescribing (OR = 1.55, 95% CI = 1.13-2.12), and information-seeking behaviors (OR = 4.57, 95% CI = 3.84-5.45), independent of age and sex.
CONCLUSION: Healthcare providers can facilitate patient-initiated deprescribing conversations by providing information on medication harms and using the term "deprescribing."

PMID: 28913911 [PubMed - indexed for MEDLINE]

Unexpected drug-induced Raynaud phenomenon: Analysis from the French national pharmacovigilance database.

Therapie. 2017 Oct;72(5):547-554

Authors: Bouquet É, Urbanski G, Lavigne C, Lainé-Cessac P

Abstract
OBJECTIVE: To estimate the association between exposure to medicinal products and Raynaud phenomenon.
METHODS: The study used the data of all adverse drug reactions notified to the French national pharmacovigilance database. All cases reported between 1st January 1995 and 10th December 2012 were selected. A case/non-case method was used to measure disproportionality of the association between drug exposure and Raynaud phenomenon. The cases concerned all observations involving Raynaud phenomenon. Non-cases comprised all other reports of adverse drug reactions over the same period.
RESULTS/DISCUSSION: Among the 307,128 adverse drug reaction reports selected from the French national pharmacovigilance database, 175 involved Raynaud phenomenon, most of them affecting women (61.1%). The mean age was 50.1 years, and 8% had a past medical history of Raynaud phenomenon. According to the summaries of product characteristics, 42.3% of these cases were exposed to drugs known to induce Raynaud phenomenon. Unexpected Raynaud phenomenons (unlisted in the summaries of product characteristics) were associated with exposure to drugs for which Raynaud phenomenons are published (interferons, ribavirin, gemcitabine) or for which Raynaud phenomenons are not published (hepatitis B vaccine, isotretinoin, leflunomide, hydroxycarbamide, rofecoxib, telmisartan, zolmitriptan).
CONCLUSION: The case/non-case method is usually used to generate signals. Further epidemiological studies are now necessary to confirm these findings.

PMID: 28336160 [PubMed - indexed for MEDLINE]

Personalized Medicine in the Paediatric Population: The Balance Between Pharmacogenetic Progress and Bioethics.

Curr Pharm Biotechnol. 2017;18(3):253-262

Authors: Schiavone S, Neri M, Pomara C, Riezzo I, Trabace L, Turillazzi E

Abstract
Personalized medicine (PM) is becoming increasingly important in contemporary clinical and research scenarios. In the context of PM, pharmacogenomics and pharmacogenetics are aimed at the genetic personalization of drug response. Extrinsic and intrinsic factors may explain interindividual variability in drug response. Among such factors, age seems to specifically intervene to modulate drug response since normal developmental changes may influence the exposure-response relation. Consequently, the potential benefit of pharmacogenomics (PGx) in the paediatric population is considerable. However, many challenges still exist in incorporating PGx into clinical practice. In fact, drug prescribing in the paediatric population is often based on extrapolation from clinical trials conducted on adults as there is often a lack of paediatric data. Children are not just 'small adults', as they have their own pharmacological characteristics in terms of drug metabolism and efficacy, adverse drug reactions and toxicity. Although children might potentially benefit from such research, many ethical concerns arise at the intersection of the spheres of drug development and genetic testing. Children require particular attention because of their vulnerability both in research and the clinical applications of PGx; furthermore, children range from preterm newborns and neonates to infants and toddlers and to adolescents, thus forming a further heterogeneous target group. In this paper, we focus on some ethically relevant concerns (i.e., informed consent, stigmatization, ancillary information) that might arise as a result of the possible application of PGx tests in both paediatric practice and research.

PMID: 28176639 [PubMed - indexed for MEDLINE]

Personalized Medicine and Adverse Drug Reactions: The Experience of An Italian Teaching Hospital.

Curr Pharm Biotechnol. 2017;18(3):274-281

Authors: La Russa R, Finesch V, Di Sanzo M, Gatto V, Santurro A, Martini G, Scopetti M, Frati P

Abstract
BACKGROUND: The personalized medicine is a model of medicine based on inherent difference given by the genetic heritage that characterizes us, diversity that can affect also our response to administered therapy. Nowadays, the term "adverse drug reaction" is identified with any harmful effect involuntary resulting from the use of a medicinal product; pharmacogenomics, in this field, has the aim to improve the drug response and to reduce the adverse reaction.
METHODS: We analyzed all reports of adverse reaction collected in the Pharmacovigilance Centre database of an Italian University Hospital, at the Sant'Andrea Hospital Sapienza University of Rome, in a period of two years.
RESULTS: Comparing the data result from our analysis with several studies found in literature, it is evident that adverse drug reactions represent an important problem in the management of a health care system. However, the development of pharmacogenetics and pharmacogenomics, allowing a personalized treatment, can improve clinical practice.
CONCLUSION: This study highlights the great potential of pharmacogenomics in reducing adverse reactions and suggests the need for further pharmacogenomic clinical trials to better personalize drug treatment and to refine the current pharmacovigilance strategies.

PMID: 28176638 [PubMed - indexed for MEDLINE]

FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science.

Drug Discov Today. 2016 Oct;21(10):1566-1570

Authors: Fang H, Harris SC, Liu Z, Zhou G, Zhang G, Xu J, Rosario L, Howard PC, Tong W

Abstract
Here, we provide a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug-drug interactions, adverse drug reactions (ADRs), and more. Labeling data have been collected over several decades by the FDA and are an important resource for regulatory research and decision making. However, navigating through this data is challenging. To aid such navigation, the FDALabel database was developed, which contains a set of approximately 80000 labeling data. The full-text searching capability of FDALabel and querying based on any combination of specific sections, document types, market categories, market date, and other labeling information makes it a powerful and attractive tool for a variety of applications. Here, we illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies.

PMID: 27319291 [PubMed - indexed for MEDLINE]

A narrative review of the safety concerns of deprescribing in older adults and strategies to mitigate potential harms.

Expert Opin Drug Saf. 2018 Jan;17(1):39-49

Authors: Reeve E, Moriarty F, Nahas R, Turner JP, Kouladjian O'Donnell L, Hilmer SN

Abstract
INTRODUCTION: As with prescribing or continuing medications, deprescribing brings with it the potential for harm as well as benefit. Uncertainty and avoidance of harm has been reported as a barrier to deprescribing in practice and may contribute to continuation of inappropriate medications. Areas covered: This narrative review covers four main safety concerns/potential harms of deprescribing in older adults: adverse drug withdrawal events, return of medical condition(s), reversal of drug-drug interactions and damage to the doctor-patient relationship. These are discussed in relation to medications in general, with some examples of medication classes used to illustrate the potential safety concerns. The majority of these harms can be minimized or even prevented by using a patient-centered, structured deprescribing process with planning, tapering and close monitoring during, and after medication withdrawal. Expert opinion: More research is needed into the safety concerns of deprescribing, however, avenues exist during drug development and post-marketing surveillance to gain knowledge on this topic. Questions remain about when it is suitable to discontinue certain medications/medication classes and there is uncertainty about the harms and benefits of both medication continuation and discontinuation in complex older adults.

PMID: 29072544 [PubMed - indexed for MEDLINE]

Non-Health Care Facility Cardiovascular Medication Errors in the United States.

Ann Pharmacother. 2017 Oct;51(10):825-833

Authors: Kamboj AK, Spiller HA, Casavant MJ, Hodges NL, Chounthirath T, Smith GA

Abstract
BACKGROUND: Prior studies have not examined national trends and characteristics of unintentional non-health care facility (HCF) medication errors associated with cardiovascular drugs.
OBJECTIVE: To investigate non-HCF medication errors associated with cardiovascular drugs reported to poison control centers in the United States.
METHODS: A retrospective analysis of non-HCF medication errors associated with cardiovascular drugs from 2000 to 2012 was conducted using the National Poison Data System database.
RESULTS: There were 278 444 medication errors associated with cardiovascular drugs reported to US poison control centers during the study period, averaging 21 419 exposures annually. The overall rate of cardiovascular medication errors per 100 000 population increased 104.6% from 2000 to 2012 ( P < 0.001) and the highest rates were among older adults. Most cases (83.6%) did not require treatment at a HCF. Serious medical outcomes were reported in 4.0% of exposures. The cardiovascular drugs most commonly implicated in medication errors were β-blockers (28.2%), calcium antagonists (17.7%), and angiotensin-converting enzyme inhibitors (15.9%). Most of the 114 deaths were associated with cardiac glycosides (47.4%) or calcium antagonists (29.8%). Most medication errors involved taking or being given a medication twice (52.6%).
CONCLUSIONS: This study describes characteristics and trends of non-HCF cardiovascular medication errors over a 13-year period in the United States. The number and rate of cardiovascular medication errors increased steadily from 2000 to 2012, with the highest error rates among older adults. Further research is needed to identify prevention strategies for these errors, with a particular focus on the older adult population.

PMID: 28608723 [PubMed - indexed for MEDLINE]

Dysregulation of cytokine mediated chemotherapy induced cognitive impairment.

Pharmacol Res. 2017 Mar;117:267-273

Authors: Ren X, St Clair DK, Butterfield DA

Abstract
One of the major complaints patients who survive cancer often make is chemotherapy induced cognitive impairment (CICI), which survivors often call "chemo brain." CICI is a side effect of chemotherapy due to the cytotoxicity and neurotoxicity of anti-cancer drugs causing structural and functional changes in brain, even when drugs that do not cross the blood brain barrier (BBB) are used. Diminished cognitive functions including diminution of learning and memory, concentration and attention, processing speed and executive functions that reduce quality of life and ability to work are common signs and symptoms of CICI. There still is not a clarified and complete mechanism for CICI, but researchers have pointed to several biochemical candidates. Chemotherapy-induced, cytokine-mediated involvement in CICI will be mainly discussed in this review paper with emphasis on different types of cytokines, correlated with BBB and epigenetic changes. Mechanisms of ROS-generating, anti-cancer drugs and their relation to cytokine-mediated CICI will be emphasized.

PMID: 28063894 [PubMed - indexed for MEDLINE]

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

Ann Oncol. 2016 Jul;27(7):1291-8

Authors: Chatterjee M, Turner DC, Felip E, Lena H, Cappuzzo F, Horn L, Garon EB, Hui R, Arkenau HT, Gubens MA, Hellmann MD, Dong D, Li C, Mayawala K, Freshwater T, Ahamadi M, Stone J, Lubiniecki GM, Zhang J, Im E, De Alwis DP, Kondic AG, Fløtten Ø

Abstract
BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients.
PATIENTS AND METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.
RESULTS: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses.
CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.
CLINICALTRIALSGOV REGISTRY: NCT01295827.

PMID: 27117531 [PubMed - indexed for MEDLINE]

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

Ann Oncol. 2016 Jul;27(7):1273-9

Authors: Folprecht G, Pericay C, Saunders MP, Thomas A, Lopez Lopez R, Roh JK, Chistyakov V, Höhler T, Kim JS, Hofheinz RD, Ackland SP, Swinson D, Kopp M, Udovitsa D, Hall M, Iveson T, Vogel A, Zalcberg JR

Abstract
BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC.
PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis.
RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%).
CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity.
CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

PMID: 27091810 [PubMed - indexed for MEDLINE]