Preventing and Managing Toxicities of High-Dose Methotrexate.

Oncologist. 2016 Dec;21(12):1471-1482

Authors: Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD

Abstract
: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m(2), is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.
IMPLICATIONS FOR PRACTICE: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m(2), is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.

PMID: 27496039 [PubMed - indexed for MEDLINE]

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

J Viral Hepat. 2016 Oct;23(10):789-97

Authors: Gane E, Ben Ari Z, Mollison L, Zuckerman E, Bruck R, Baruch Y, Howe AY, Wahl J, Bhanja S, Hwang P, Zhao Y, Robertson MN

Abstract
Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

PMID: 27291249 [PubMed - indexed for MEDLINE]

Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors.

Invest New Drugs. 2017 Nov 02;:

Authors: Bahleda R, Le Deley MC, Bernard A, Chaturvedi S, Hanley M, Poterie A, Gazzah A, Varga A, Touat M, Deutsch E, Massard C, Van De Velde H, Hollebecque A, Sallansonnet-Froment M, Ricard D, Taillia H, Angevin E, Ribrag V, Soria JC

Abstract
Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (-36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.

PMID: 29094232 [PubMed - as supplied by publisher]

[Side effects of psychotropic medication: Suggestions for clinical practice].

Dtsch Med Wochenschr. 2017 Nov;142(22):1690-1700

Authors: Grunze A, Mago R, Grunze H

Abstract
Psychotropics are highly effective medications that, however, have adverse drug reactions attached to them. They are indispensable for many patients. How to cope with side effects - watchful waiting, dose reduction, change of medication, addition of an "antidote" and behavioural modifications - depends on their nature, severity and finally the patients wish. This review is meant to aid clinician's and patient's decisions in case of the occurrence of compromising, frequent adverse drug reactions.

PMID: 29078215 [PubMed - indexed for MEDLINE]

Pigmentary changes in patients treated with targeted anticancer agents: A systematic review and meta-analysis.

J Am Acad Dermatol. 2017 Nov;77(5):902-910.e2

Authors: Dai J, Belum VR, Wu S, Sibaud V, Lacouture ME

Abstract
BACKGROUND: The discovery of signaling networks that drive oncogenic processes has led to the development of targeted anticancer agents. The burden of pigmentary adverse events from these drugs is unknown.
OBJECTIVE: To conduct a systematic review and meta-analysis of published clinical trials and determine the incidence and risk of development of targeted therapy-induced pigmentary changes.
METHODS: A comprehensive search was conducted to identify studies reporting targeted therapy-induced pigmentary changes. The incidence and relative risk were calculated. Case reports and series were reviewed to understand clinical characteristics.
RESULTS: A total of 8052 patients from 36 clinical trials were included. The calculated overall incidences of targeted cancer therapy-induced all-grade pigmentary changes in the skin and hair were 17.7% (95% confidence interval [CI], 11.9-25.4) and 21.5% (95% CI, 14.9-30.1), respectively. The relative risk of all-grade pigmentary changes of skin and hair were 93.7 (95% CI, 5.86-1497.164) and 20.1 (95% CI, 8.35-48.248). Across 53 case reports/series (N = 75 patients), epidermal growth factor receptor and breakpoint cluster region-abelson inhibitors were the most common offending agents.
LIMITATIONS: Potential under-reporting and variability in oncologists reporting these events.
CONCLUSION: There is a significant risk of development of pigmentary changes during treatment with targeted anticancer therapies. Appropriate counseling and management are critical to minimize psychosocial impairment and deterioration in quality of life.

PMID: 28918974 [PubMed - indexed for MEDLINE]

Serious infections among a large cohort of subjects with systemically treated psoriasis.

J Am Acad Dermatol. 2017 Nov;77(5):838-844

Authors: Dobry AS, Quesenberry CP, Ray GT, Geier JL, Asgari MM

Abstract
BACKGROUND: Biologic therapy is effective for treatment of moderate-to-severe psoriasis but may be associated with an increased risk for serious infection.
OBJECTIVE: To estimate the serious infection rate among patients with psoriasis treated with biologic as compared with nonbiologic systemic agents within a community-based health care delivery setting.
METHODS: We identified 5889 adult Kaiser Permanente Northern California health plan members with psoriasis who had ever been treated with systemic therapies and calculated the incidence rates and 95% confidence intervals (CIs) for serious infections over 29,717 person-years of follow-up. Adjusted hazard ratios (aHRs) were calculated using Cox regression.
RESULTS: Adjusting for age, sex, race or ethnicity, and comorbidities revealed a significantly increased risk for overall serious infection among patients treated with biologics as compared with those treated with nonbiologics (aHR, 1.31; 95% CI, 1.02-1.68). More specifically, there was a significantly elevated risk for skin and soft tissue infection (aHR, 1.75; 95% CI, 1.19-2.56) and meningitis (aHR, 9.22; 95% CI, 1.77-48.10) during periods of active biologic use.
LIMITATIONS: Risk associated with individual drugs was not examined.
CONCLUSION: We found an increased rate of skin and soft tissue infections among patients with psoriasis treated with biologic agents. There also was a signal suggesting increased risk for meningitis. Clinicians should be aware of these potential adverse events when prescribing biologic agents.

PMID: 28917384 [PubMed - indexed for MEDLINE]

Beyond anxiety and agitation: A clinical approach to akathisia.

Aust Fam Physician. 2017;46(5):296-298

Authors: Tachere RO, Modirrousta M

Abstract
BACKGROUND: When patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered.
OBJECTIVE: The aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward.
DISCUSSION: Akathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.

PMID: 28472575 [PubMed - indexed for MEDLINE]

Current Evidence on Safety and Practical Considerations for Administration of Sublingual Allergen Immunotherapy (SLIT) in the United States.

J Allergy Clin Immunol Pract. 2017 Jan - Feb;5(1):34-40.e2

Authors: Epstein TG, Calabria C, Cox LS, Dreborg S

Abstract
Liquid sublingual allergen immunotherapy (SLIT) has been used off-label for decades, and Food and Drug Administration (FDA)-approved grass and ragweed SLIT tablets have been available in the United States since 2014. Potentially life-threatening events from SLIT do occur, although they appear to be very rare, especially for FDA-approved products. Practice guidelines that incorporate safety precautions regarding the use of SLIT in the United States are needed. This clinical commentary attempts to address unresolved issues including controversy regarding the FDA mandate for the prescription of epinephrine autoinjectors for patients on SLIT; how to approach polysensitized patients; optimal timing and duration of SLIT administration; how to address gaps in therapy; whether antihistamines can prevent local reactions, if certain patient populations (such as persistent asthmatics) should not receive SLIT; and when to instruct patients to self-administer epinephrine. Key points are that physicians should focus on educating patients regarding: (1) when not to administer SLIT; (2) how to recognize a potentially serious allergic reaction to SLIT; and (3) when to administer epinephrine and seek emergency care.

PMID: 27815065 [PubMed - indexed for MEDLINE]

Local Side Effects of Sublingual and Oral Immunotherapy.

J Allergy Clin Immunol Pract. 2017 Jan - Feb;5(1):13-21

Authors: Passalacqua G, Nowak-Węgrzyn A, Canonica GW

Abstract
Sublingual immunotherapy (SLIT) is increasingly used worldwide, and several products have been recently registered as drugs for respiratory allergy by the European Medicine Agency and the Food and Drug Administration. Concerning inhalant allergens, the safety of SLIT is overall superior to that of subcutaneous immunotherapy in terms of systemic adverse events. No fatality has been ever reported, and episodes of anaphylaxis were described only exceptionally. Looking at the historical and recent trials, most (>90%) adverse events are "local" and confined to the site of administration. For this reason, a specific grading system has been developed by the World Allergy Organization to classify and describe local adverse events. There is an increasing amount of literature concerning oral desensitization for food allergens, referred to as oral immunotherapy. Also, in this case, local side effects are predominant, although systemic adverse events are more frequent than with inhalant allergens. We review herein the description of local side effects due to SLIT, with a special focus on large trials having a declared sample size calculation. The use of the Medical Dictionary for Regulatory Activities nomenclature for adverse events is mentioned in this context, as recommended by regulatory agencies. It is expected that a uniform classification/grading of local adverse events will improve and harmonize the surveillance and reporting on the safety of SLIT.

PMID: 27527548 [PubMed - indexed for MEDLINE]

Serious Adverse Events Reports: Analysis and Outcome of Review by an Institutional Ethics Committee of a Tertiary Care Hospital in Mumbai, India.

J Empir Res Hum Res Ethics. 2016 Jul;11(3):267-73

Authors: Tripathi RK, Marathe PA, Kapse SV, Shetty YC, Kamat SK, Thatte UM

Abstract
The Indian regulations for clinical trials were amended in January 2013 regarding reporting time lines, relatedness, and compensation for Serious Adverse Events (SAEs). Our study assessed the extent of regulatory compliance in reporting SAEs to the Institutional Ethics Committee (IEC) over 4 years (January 2009-January 2013) before and 18 months after (February 2013-July 2014) the amended regulations. SAE reports were studied retrospectively for reporting time lines, relatedness, compensation, and IEC response before and after the law revision. Before 2013 had 89/160 (55.6%) SAEs reports submitted late while in the after period, only 2/11 reports were delayed (18%). In the before period, 26 SAE reports mentioned "relatedness" of which only 15 (57.6%) stated about compensation. After 2013, all the 9 non-death reports were complete. The IEC took median 17 days to respond before 2013, while after 2013 responded within 5 days. Thus, there was poor compliance in terms of SAE reporting time lines before the revision of the law.

PMID: 27353243 [PubMed - indexed for MEDLINE]

DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED TRIAL OF SELENIUM IN GRAVES' HYPERTHYROIDISM.

J Clin Endocrinol Metab. 2017 Sep 19;:

Authors: Kahaly GJ, Riedl M, König J, Diana T, Schomburg L

Abstract
Context: Supplemental Selenium (Se) may impact the clinical course of Graves' disease (GD).
Objective: Evaluate efficacy of add-on Se on medical treatment in GD.
Design: Double-blind, placebo-controlled, randomized, supplementation trial.
Setting: Academic endocrine outpatient clinic.
Patients: Seventy untreated hyperthyroid patients with GD.
Intervention: Additionally to methimazole (MMI), patients received during 24 weeks either sodium selenite 300 µg/day p.o. or placebo. MMI was discontinued at 24 weeks in euthyroid patients.
Main Outcome Measures: Response rate (week 24), recurrence rate (week 36), and safety.
Results: A response was registered in 25 of 31 patients (80%) and in 27 of 33 (82%) at week 24, odds ratio 0.93 (95% CI 0.26-3.25, p=0.904) in the Se (+MMI) and placebo (+MMI) groups, respectively. During a 12-week follow-up, 11 of 23 (48%) and 12 of 27 (44%) relapsed (OR 1.13, 0.29-2.66, p=0.81) in the Se and placebo groups, respectively. Serum concentrations of Se and selenoprotein P were unrelated to response and/or recurrence rates. At week 36, 12 of 29 (41%) and 15 of 33 (45%) were responders and still in remission in the Se and placebo groups, respectively (OR 0.85, 0.31-2.32, p=0.80). Serum levels of fT3/fT4, TSH-R-Ab, prevalence of moderate-to-severe Graves' orbitopathy, thyroid volume and MMI starting dose were significantly lower in responders versus non-responders. 56 and 63 adverse events occurred in the Se and placebo groups, respectively (p=0.164), while only one drug related side-effect (2.9%) was noted in 35 patients on placebo +MMI.
Conclusions: Supplemental Se did not impact response or recurrence rate in GD.

PMID: 29092078 [PubMed - as supplied by publisher]

Movement Disorders in Children and Adolescents Receiving Antipsychotic Pharmacotherapy: A Population-Based Study.

J Child Adolesc Psychopharmacol. 2017 Nov 01;:

Authors: Biscontri RG, Jha S, Collins DM, Bugden S, Katz LY, Alessi-Severini S

Abstract
OBJECTIVES: To describe a cohort of young users of risperidone and quetiapine in the province of Manitoba (Canada) and assess the risk for movement disorders in the two treatments.
METHODS: This was a population-based study conducted on all residents of the province of 19 years of age and younger who received prescriptions for risperidone or quetiapine between April 1, 1996, and March 31, 2011. Incident rates of antipsychotic use were reported. The risk for movement disorders in patients treated with quetiapine compared with those treated with risperidone was assessed by time-to-event analysis using Cox proportional hazards models.
RESULTS: Between April 1, 1996, and March 31, 2011, 23,888 youth (age ≤19 years) were prescribed an antipsychotic agent. Among them, 8756 were identified as new incident users. After applying exclusion criteria, 2594 individuals comprised the cohort of users of risperidone and quetiapine. The use of quetiapine was associated with a lower risk of extrapyramidal symptoms (EPSs) adverse events. The unadjusted and adjusted hazard ratios (95% confidence interval [CI]) for quetiapine versus risperidone were 0.83 (0.56-1.25) and 0.53 (0.34-0.83), respectively.
CONCLUSION: EPS diagnoses have been detected in children treated with quetiapine; however, the risk of movement disorders appears to be higher with treatment with risperidone. Clinicians should always take into consideration the risk-benefit before treating children with antipsychotic medications and should be vigilant of the onset of drug-induced adverse events.

PMID: 29091743 [PubMed - as supplied by publisher]

Preclinical data on the combination of cisplatin and anti-CD70 therapy in non-small cell lung cancer as an excellent match in the era of combination therapy.

Oncotarget. 2017 Sep 26;8(43):74058-74067

Authors: Jacobs J, Deschoolmeester V, Rolfo C, Zwaenepoel K, Van den Bossche J, Deben C, Silence K, de Haard H, Hermans C, Rottey S, Vangestel C, Lardon F, Smits E, Pauwels P

Abstract
In contrast to the negligible expression of the immunomodulating protein CD70 in normal tissue, we have demonstrated constitutive overexpression of CD70 on tumor cells in a subset of primary non-small cell lung cancer (NSCLC) biopsies. This can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Early clinical trials of these antibodies have already shown promising results in CD70-positive malignancies. In this study, we explored the potential of cisplatin to induce CD70 expression in NSCLC. Using real-time measurement tools, we also assessed the efficacy of a combination regimen with cisplatin and anti-CD70 therapy under normoxia and hypoxia. We identified an induction of CD70 expression on lung cancer cells upon low doses of cisplatin, independent of oxygen levels. More importantly, the use of cisplatin resulted in an enhanced ADCC-effect of anti-CD70 therapy. As such, this combination regimen led to a significant decrease in lung cancer cell survival cell survival, broadening the applicability the applicability of CD70-targeting therapy. This is the first study that proves the potential of a combination therapy with cisplatin and CD70-targeting drugs in NSCLC. Based on our data, we postulate that this combination strategy is an interesting approach to increase tumor-specific cytotoxicity and reduce drug-related side effects.

PMID: 29088768 [PubMed]

Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma.

Ann Pharmacother. 2017 Aug;51(8):675-681

Authors: Corrigan PA, Beaulieu C, Patel RB, Lowe DK

Abstract
OBJECTIVE: To review the efficacy and safety of talimogene laherparepvec (T-VEC) as well as its pharmacology, pharmacokinetics, drug-drug interactions, handling procedures, cost considerations, and place in therapy.
DATA SOURCES: Searches of PubMed (1966 to February 2017) and Cochrane Library (1999 to February 2017) were conducted using the terms talimogene laherparepvec, T-VEC, OncoVEX, immunotherapy, melanoma, and oncolytic virus. Additional information was determined from bibliographies, manufacturer product labeling and website, meeting abstracts, Food and Drug Administration website, and clinicaltrials.gov.
STUDY SELECTION AND DATA EXTRACTION: A total of 79 English-language publications were identified. Articles that assessed T-VEC's pharmacokinetics, pharmacodynamics, mechanism, dosing, safety, and efficacy were included as well as narrative reviews that provided practical information.
DATA SYNTHESIS: Clinical trials have confirmed the safety and efficacy of T-VEC as monotherapy for the treatment of advanced melanoma, with an overall response rate (ORR) of 26%. Relative to granulocyte-macrophage colony-stimulating factor, T-VEC significantly increased durable response rate (DRR; 16.3% vs 2.1%, P < 0.001); however, median overall survival was not improved (23.3 vs 18.9 months, P = 0.051). Phase 1b trials have combined T-VEC and immunotherapies with promising results. T-VEC's adverse effects are generally considered mild to moderate in severity.
CONCLUSION: T-VEC is the first approved oncolytic virus for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma recurrent after initial surgery. T-VEC improves ORR and DRR as a single agent, shows promise in combination therapy, and is well tolerated. Ongoing trials will determine if T-VEC has a role in early treatment or in combination therapy for melanoma or other malignancies.

PMID: 28351167 [PubMed - indexed for MEDLINE]

Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease.

J Viral Hepat. 2017 Apr;24(4):287-294

Authors: Lawitz E, Poordad F, Gutierrez JA, Kakuda TN, Picchio G, Beets G, Vandevoorde A, Van Remoortere P, Jacquemyn B, Luo D, Ouwerkerk-Mahadevan S, Vijgen L, Van Eygen V, Beumont M

Abstract
Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

PMID: 27878906 [PubMed - indexed for MEDLINE]

Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study.

J Viral Hepat. 2016 Nov;23(11):850-856

Authors: Kawakami Y, Imamura M, Ikeda H, Suzuki M, Arataki K, Moriishi M, Mori N, Kokoroishi K, Katamura Y, Ezaki T, Ueno T, Ide K, Masaki T, Ohdan H, Chayama K

Abstract
The aim of this study was to evaluate the pharmacokinetic profile of daclatasvir (DCV) and asunaprevir (ASV) dual therapy in haemodialysis patients infected with hepatitis C virus (HCV). Eighteen haemodialysis patients and 54 patients with normal renal function were treated with DCV and ASV dual therapy for 24 weeks. We evaluated the pharmacokinetic profiles of DCV and ASV and examined the rate of sustained virological response 12 weeks after the end of treatment (SVR12 ) and incidence of adverse events during treatment of haemodialysis patients infected with chronic HCV genotype 1 infection. To adjust for potential differences in baseline characteristics between haemodialysis patients and patients with normal renal function, we used propensity scores case-control matching methods. Area under the plasma concentration time curve from 0 to 6 h (AUC0-6 h ) of DCV was slightly lower in haemodialysis patients than in patients with normal renal function (P > 0.6). AUC0-6 h of ASV was significantly lower in haemodialysis patients (P = 0.012). SVR12 rates were 100% (18/18) for haemodialysis and 96.2% (52/54) for patients with normal renal function. Changes in mean log10 HCV RNA levels and viral response were higher in haemodialysis patients compared to patients with normal renal function. No discontinuations due to adverse events occurred. In conclusion, DCV and ASV dual therapy for HCV infection is effective and safe with similar results in haemodialysis patients compared to patients with normal renal function.

PMID: 27346670 [PubMed - indexed for MEDLINE]

New developments for antibody-drug conjugate-based therapeutic approaches.

Curr Opin Immunol. 2016 Jun;40:14-23

Authors: de Goeij BE, Lambert JM

Abstract
The clinical success of Adcetris(®) (brentuximab vedotin) and Kadcyla(®) (ado-trastuzumab emtansine) has sparked clinical development of novel ADCs. These powerful anti-cancer agents are designed to allow specific targeting of highly potent cytotoxic agents to tumor cells while sparing healthy tissues. Despite the use of tumor-specific antibodies, the emerging clinical data with ADCs indicates that adverse effects frequently occur before ADCs have reached their optimal therapeutic dose, resulting in a relatively narrow therapeutic window. This review summarizes the therapeutic window of ADCs currently in clinical development, along with some strategies that may help to widen the window.

PMID: 26963132 [PubMed - indexed for MEDLINE]

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

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

These pubmed results were generated on 2017/11/01

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

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

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

These pubmed results were generated on 2017/11/01

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.

19 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 2017/10/31

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.