Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis.

Oncologist. 2017 Apr;22(4):470-479

Authors: Nishijima TF, Shachar SS, Nyrop KA, Muss HB

Abstract
BACKGROUND: Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy.
METHODS: PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated.
RESULTS: A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors.
CONCLUSION: PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.

PMID: 28275115 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy of telbivudine in infants born to mothers treated during the second or third trimesters of pregnancy.

J Viral Hepat. 2017 Jun;24(6):514-521

Authors: Han GR, Jiang HX, Wang CM, Ding Y, Wang GJ, Yue X, Zhou L, Zhao W

Abstract
Telbivudine, an FDA pregnancy category B drug, has been found to reduce hepatitis B virus (HBV) perinatal transmission with no safety concerns in infants aged up to 1 year. This study evaluated the long-term efficacy and safety of telbivudine in 214 infants born to 210 pregnant women with chronic hepatitis B infection who were treated with telbivudine during pregnancy (weeks 20-32 of gestation). The infants were followed for up to 5 years after birth. The efficacy endpoint was the rate of perinatal transmission, which was established by HBsAg and HBV DNA levels at 7 and 12 months. Safety endpoints included head circumference, weight, height, congenital abnormality and hospitalization rates. In addition, the Denver Developmental Screening Test was performed in 92 randomly selected infants. None of the 214 infants born to these women were infected with HBV, and all had effective serum hepatitis B surface antibody (HBsAb) levels. Compared with Chinese standard values, there were few differences in the infants' mean head circumference, weight, and height values. No birth defects were diagnosed, and the congenital abnormality rate was 0.934%. Serious adverse events requiring hospitalization occurred in 20 infants (9.35%). The qualified Denver Developmental Screening Test rate in 92 infants was 97.82%, which was comparable to a rate of 92% in normal Chinese children. Thus, treatment with telbivudine during the second or third trimesters of pregnancy safely blocked perinatal transmission of HBV. Infants born to telbivudine-treated mothers showed normal growth and development during long-term follow-up of up to 5 years.

PMID: 28039902 [PubMed - indexed for MEDLINE]

Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience.

J Viral Hepat. 2017 Jun;24(6):464-471

Authors: Muñoz-Gómez R, Rincón D, Ahumada A, Hernández E, Devesa MJ, Izquierdo S, Ortiz M, Hernández-Albujar A, Fernández-Rodríguez C, Calvo M, González R, Lozano M, Castellano G, Fernández-Vázquez I

Abstract
Limited data are available on direct-acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15-29 mL/min/1.73m2 ) or 5 (eGFR<15 mL/min/1.73m2 or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty-six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.

PMID: 27976490 [PubMed - indexed for MEDLINE]

Herb-Drug Interactions: An Insight into Cardiovascular Diseases Based on Case Reports.

Cardiovasc Hematol Agents Med Chem. 2017;14(3):142-149

Authors: Batista C, Jesus NR, Silva CM, Silva TP, Campos MG

Abstract
Cardiovascular patients frequently use herbal medicinal products, in order to contribute to the improvement of their chronic condition without medical intervention. However, they are likely to suffer from adverse effects from natural products and herb-drug interactions. In this work we present the results collected from a public campaign "Learning Health, among Plants and Medicines", carried out by the Observatory of Herb-Drug Interactions (www.oipm.uc.pt), to alert cardiovascular patients and healthcare providers for the potential occurrence of herb-drug interactions with cardiovascular therapy. From the data received, it was highlighted the prevalence of certain natural products used by many cardiovascular patients in Portugal, particularly goji berries, green tea, mangosteen and rooibos that have significant cardiovascular effects. For this reason their intake should be carefully monitored in these patients. This prevalence of consumption suggests a pattern in their use in Portugal and a prevention of herb-drug interactions should be carried out by the health professionals. The ending results also indicate that there is still a lack of knowledge about the possible risks of herbal products intake, which may adversely affect the health of any patient. Thus becomes clear the value of the role of health professionals in the screening of such interactions.

PMID: 27748172 [PubMed - indexed for MEDLINE]

A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy.

Melanoma Res. 2016 Oct;26(5):469-80

Authors: Kottschade L, Brys A, Peikert T, Ryder M, Raffals L, Brewer J, Mosca P, Markovic S, Midwest Melanoma Partnership

Abstract
Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host's immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach.

PMID: 27306502 [PubMed - indexed for MEDLINE]

α1-Antitrypsin Infusion for treatment of Steroid Resistant Acute Graft-versus-Host Disease.

Blood. 2018 Feb 02;:

Authors: Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, Riwes MM, Kennel M, Antin JH, Cutler CS, Ho VT, Alyea EP, Parkin BL, Yanik GA, Choi SW, Lewis EC, Dinarello CA, Koreth J, Reddy P

Abstract
Corticosteroid resistance following acute GVHD (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness due to poor response or excessive toxicity, primarily from infection. Alpha-1 antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by down-modulation of inflammation and increasing ratios of regulatory to effector T cells. In this prospective multicenter clinical study we sought to determine the safety and response rate of AAT administration in SR-aGVHD (NCT01700036). Forty patients at a median age of 59 years received intravenous AAT twice weekly for four weeks as first line treatment for SR-aGVHD. The primary endpoint was overall response rate (ORR), the proportion of SR-aGVHD in CR+PR by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rate by day 28 was 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious-mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with pre-clinical data, correlative samples showed an increase in ratio of activated Tregs to effector T cells after AAT treatment. These data suggest that AAT is safe, and may be potentially efficacious in treating SR-aGVHD.

PMID: 29437593 [PubMed - as supplied by publisher]

[Safety data of the new, reduced-dose influenza vaccine FluArt after its first season on the market].

Orv Hetil. 2017 Dec;158(49):1953-1959

Authors: Vajó P, Gyurján O, Szabó ÁM, Kalabay L, Vajó Z, Torzsa P

Abstract
INTRODUCTION: The currently licensed seasonal influenza vaccines contain split, subunit or whole virions, typically in amounts of 15 µg hemagglutinin per virus strain for adult and up to 60 µg in elderly patients.
AIM: The present study reports safety data of the newly licensed, reduced dose vaccine with 6 µg of hemagglutinin per strain produced by Fluart (Hungary) after its first season on the market. The main objective of enhanced safety surveillance was to detect a potential increase in reactogenicity and allergic events that is intrinsic to the product in near real-time in the earliest vaccinated cohorts.
METHOD: The study methods were based on the Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU by the European Medicines Agency.
STATISTICS: We used the Fisher exact test with 95% confidence intervals.
RESULTS: We studied 587 patients and detected a total 24 adverse events, all of which have already been known during the licensing studies of the present vaccine. The frequencies of the adverse events were not different from what had been seen with the previously licensed 15 µg vaccine.
CONCLUSIONS: Based on the results, the authors conclude that the new, reduced dose vaccine FluArt is safe and tolerable. Orv Hetil. 2017; 158(49): 1953-1959.

PMID: 29199437 [PubMed - indexed for MEDLINE]

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

BMC Pharmacol Toxicol. 2017 Apr 28;18(1):18

Authors: Chartier M, Morency LP, Zylber MI, Najmanovich RJ

Abstract
BACKGROUND: Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.
METHODS: We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.
RESULTS: We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.
CONCLUSIONS: The detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.

PMID: 28449705 [PubMed - indexed for MEDLINE]

Consumption of antihistamines in Serbia in the period 2011-2015 and the correlation with adverse drug reaction reports.

Vojnosanit Pregl. 2016 Nov;73(11):1076-7

Authors: Radonjić V, Jović I, Kalaba M, Godman B, Košutić J

PMID: 29341563 [PubMed - indexed for MEDLINE]

A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.

Clin Cancer Res. 2017 Feb 15;23(4):899-907

Authors: Pratz KW, Rudek MA, Gojo I, Litzow MR, McDevitt MA, Ji J, Karnitz LM, Herman JG, Kinders RJ, Smith BD, Gore SD, Carraway HE, Showel MM, Gladstone DE, Levis MJ, Tsai HL, Rosner G, Chen A, Kaufmann SH, Karp JE

Abstract
Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899-907. ©2016 AACR.

PMID: 27551000 [PubMed - indexed for MEDLINE]

Performance of toxicity probability interval based designs in contrast to the continual reassessment method.

Stat Med. 2017 Jan 30;36(2):291-300

Authors: Horton BJ, Wages NA, Conaway MR

Abstract
Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27435150 [PubMed - indexed for MEDLINE]

Implementation of adaptive methods in early-phase clinical trials.

Stat Med. 2017 Jan 30;36(2):215-224

Authors: Petroni GR, Wages NA, Paux G, Dubois F

Abstract
There has been constant development of novel statistical methods in the design of early-phase clinical trials since the introduction of model-based designs, yet the traditional or modified 3+3 algorithmic design remains the most widely used approach in dose-finding studies. Research has shown the limitations of this traditional design compared with more innovative approaches yet the use of these model-based designs remains infrequent. This can be attributed to several causes including a poor understanding from clinicians and reviewers into how the designs work, and how best to evaluate the appropriateness of a proposed design. These barriers are likely to be enhanced in the coming years as the recent paradigm of drug development involves a shift to more complex dose-finding problems. This article reviews relevant information that should be included in clinical trial protocols to aid in the acceptance and approval of novel methods. We provide practical guidance for implementing these efficient designs with the aim of augmenting a broader transition from algorithmic to adaptive model-guided designs. In addition we highlight issues to consider in the actual implementation of a trial once approval is obtained. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 26928191 [PubMed - indexed for MEDLINE]

Effects of gender on capecitabine toxicity in colorectal cancer.

J Oncol Pharm Pract. 2016 Jun;22(3):454-60

Authors: Ilich AI, Danilak M, Kim CA, Mulder KE, Spratlin JL, Ghosh S, Chambers CR, Sawyer MB

Abstract
BACKGROUND: Capecitabine is a highly water soluble prodrug of 5-fluorouracil that is dosed by patient body surface area. Body surface area dosing makes no allowances for differences in body composition. There is mounting evidence that lean body mass is a better predictor of toxicity than body surface area for drugs which distribute into the lean compartment. Because women, on average, have lower lean body mass than men, we expect that women would experience a higher incidence of toxicity than men when body surface area dosing is used.
OBJECTIVE: To determine whether female colorectal cancer patients experienced a higher incidence of dose-limiting toxicity than men when treated with adjuvant capecitabine.
METHODS: We conducted a retrospective chart review of colorectal cancer patients treated with adjuvant capecitabine at our institute between 2008 and 2012. Patients receiving capecitabine were identified from the pharmacy dispensing database and then screened for inclusion. Dosing and toxicity information were gathered and dose-limiting toxicity incidence (defined as a composite endpoint of dose delay, dose reduction, or discontinuation of therapy) was compared between males and females using the chi-square test. Binary logistic regression analysis was then performed to account for differences between male and female populations.
RESULTS: A total of 299 patients (163 males, 136 females) met inclusion criteria. Females had a significantly higher dose-limiting toxicity incidence than males (67.7 vs. 52.2%, p = 0.007). Relationships between gender and dose-limiting toxicity incidence remained significant after logistic regression analysis (OR: 2.04; 95% CI: 1.23-3.36).
CONCLUSION: Female colorectal cancer patients experience a higher dose-limiting toxicity incidence than male patients when given adjuvant capecitabine dosed according to body surface area.

PMID: 26002954 [PubMed - indexed for MEDLINE]

The role of netupitant and palonosetron in chemotherapy-induced nausea and vomiting.

J Oncol Pharm Pract. 2016 Jun;22(3):477-84

Authors: Abramovitz RB, Gaertner KM

Abstract
The combination of netupitant and palonosetron was approved by the Food and Drug Administration in October 2014 for the prevention of acute and delayed chemotherapy-induced nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic chemotherapy. Netupitant and palonosetron is available as a single capsule to be administered prior to each cycle of chemotherapy. The approval was based on phase II and III data in patients undergoing treatment with moderately and highly emetogenic chemotherapy. Netupitant and palonosetron's benefits include a convenient dosage form, dual-targeted mechanism, and favorable side effect profile, while its main limitations are cost and potential logistical issues surrounding administration. More studies are needed to adequately determine its role in therapy as well as which patients will derive the most benefit from its use.

PMID: 25914408 [PubMed - indexed for MEDLINE]

Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice.

J Oncol Pharm Pract. 2016 Jun;22(3):511-6

Authors: Holle LM, Puri S, Clement JM

Abstract
BACKGROUND: Oral chemotherapy is being routinely used in metastatic castrate-resistant prostate and renal cell cancer. Although convenient, these drugs require monitoring for adherence, toxicity, and drug interactions to maximize outcomes. Oncology pharmacists have the training and expertise that place them in an optimal position to collaboratively provide medication therapy management.
METHODS: A board-certified oncology pharmacist, working in collaboration with a medical oncologist, initiated an oral chemotherapy-monitoring program. The pharmacist provided education, completed medication therapy management; monitored for adherence and toxicity; and recommended treatment of toxicity and supportive care issues. Patient encounters included one of the following: collaboration with medical oncologist visit, pharmacist visit, or telephone or email follow-up between visits.
RESULTS: From December 2012 to May 2014, the pharmacist had 123 encounters with 20 patients with either metastatic prostate (n = 17) or renal cell cancer (n = 3). All patients were males (median age 80 years). Most encounters were clinic visits, in collaboration with physician visit or alone (52%); 36% were telephone encounters, and 11.3% were email follow-ups. Medication-related problems were identified in 25% of the 315 assessments made. Problems included: adverse drug reactions, 40%; inappropriate therapy, 20%; and noncompliance, 18%. Recommendations included: modification of laboratory monitoring, 25%; cancer or non-cancer therapy modification, 12%; drug discontinuation, 6.9%. Non-cancer therapy-related drug information and coordination of care accounted for 30% of recommendations.
CONCLUSION: Our program led to identification of a number of potentially clinically significant issues for patients on oral chemotherapy and demonstrated the benefit of the pharmacist in the multidisciplinary team to assist in addressing them.

PMID: 25900102 [PubMed - indexed for MEDLINE]

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Predicting drug-induced arrhythmias by multiscale modeling.

Int J Numer Method Biomed Eng. 2018 Feb 09;:

Authors: Sahli Costabal F, Yao J, Kuhl E

Abstract
Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which often hinders the development of new drugs. Here we establish a high resolution, multiscale computational model to quickly assess the cardiac toxicity of new and existing drugs. The input of the model is the drug-specific current block from single cell electrophysiology; the output is the spatio-temporal activation profile and the associated electrocardiogram. We demonstrate the potential of our model for a low risk drug, ranolazine, and a high risk drug, quinidine: For ranolazine, our model predicts a prolonged QT interval of 19.4% compared to baseline and a regular sinus rhythm at 60.15 beats per minute. For quinidine, our model predicts a prolonged QT interval of 78.4% and a spontaneous development of torsades de pointes both in the activation profile and in the electrocardiogram. Our model reveals the mechanisms by which electrophysiological abnormalities propagate across the spatio-temporal scales, from specific channel blockage, via altered single cell action potentials and prolonged QT intervals, to the spontaneous emergence of ventricular tachycardia in the form of torsades de pointes. Our model could have important implications for researchers, regulatory agencies, and pharmaceutical companies on rationalizing safe drug development and reducing the time-to-market of new drugs. This article is protected by copyright. All rights reserved.

PMID: 29424967 [PubMed - as supplied by publisher]

Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

Curr Med Res Opin. 2018 Feb 09;:1-12

Authors: Middleton G, Gridelli C, De Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Visseren-Grul CM, San Antonio B, John WJ, Zimmermann AH, Chouaki N, Paz-Ares L

Abstract
OBJECTIVES: To assess the long-term pemetrexed maintenance therapy on patients' renal function.
METHODS: In the PARAMOUNT Phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays, and treatment discontinuations associated with impaired renal function.
RESULTS: Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (P < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years), and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had preexisting conditions and/or were receiving nephrotoxic drugs.
CONCLUSIONS: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.

PMID: 29424248 [PubMed - as supplied by publisher]

Management of QT prolongation induced by anti-cancer drugs: Target therapy and old agents. Different algorithms for different drugs.

Cancer Treat Rev. 2018 Feb;63:135-143

Authors: Coppola C, Rienzo A, Piscopo G, Barbieri A, Arra C, Maurea N

Abstract
The side effects of anticancer drugs still play a critical role in survival and quality of life. Although the recent progresses of cancer therapies have significantly improved the prognosis of oncologic patients, side effects of antineoplastic treatments are still responsible for the increased mortality of cancer survivors. Cardiovascular toxicity is the most dangerous adverse effect induced by anticancer therapies. A survey conducted by the National Health and Nutrition Examination, showed that 1807 cancer survivors followed up for seven years: 51% died of cancer and 33% of heart disease (Vejpongsa and Yeh, 2014). Moreover, the risk of cardiotoxicity persists even with the targeted therapy, the newer type of cancer treatment, due to the presence of on-target and off-target effects related to this new class of drugs. The potential cardiovascular toxicity of anticancer agents includes: QT prolongation, arrhythmias, myocardial ischemia, stroke, hypertension (HTN), thromboembolism, left ventricular dysfunction and heart failure (HF). Compared to other cardiovascular disorders, the interest in QT prolongation and its complications is fairly recent. However, oncologists have to deal with it and to evaluate the risk-benefit ratio before starting the treatment or during the same. Electrolyte abnormalities, low levels of serum potassium and several drugs may favour the acquired QT prolongation. Treatment of marked QT prolongation includes cardiac monitoring, caution in the use or suspension of cancer drugs and correction of electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia). Syndrome of QT prolongation can be associated with potentially fatal cardiac arrhythmias and its treatment consists of intravenous administration of magnesium sulphate and the use of electrical cardioversion.

PMID: 29304463 [PubMed - indexed for MEDLINE]

Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Clin Cancer Res. 2017 Mar 01;23(5):1149-1155

Authors: Coutré SE, Furman RR, Flinn IW, Burger JA, Blum K, Sharman J, Jones J, Wierda W, Zhao W, Heerema NA, Johnson AJ, Tran A, Zhou C, Bilotti E, James DF, Byrd JC, O'Brien S

Abstract
Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103.Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1-12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149-55. ©2017 AACR.

PMID: 28073846 [PubMed - indexed for MEDLINE]