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]

A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors.

Clin Cancer Res. 2017 Mar 01;23(5):1177-1185

Authors: Calvo E, Soria JC, Ma WW, Wang T, Bahleda R, Tolcher AW, Gernhardt D, O'Connell J, Millham R, Giri N, Wick MJ, Adjei AA, Hidalgo M

Abstract
Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors.Experimental Design: A standard 3 + 3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma.Results: Of the 74 patients enrolled, the most common malignancies were non-small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across five dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug-drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed downregulation of genes in the insulin-like growth factor receptor 1 pathway.Conclusions: Dacomitinib-figitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor adenoid cystic carcinoma. Clin Cancer Res; 23(5); 1177-85. ©2016 AACRSee related commentary by Sundar et al., p. 1123.

PMID: 27733479 [PubMed - indexed for MEDLINE]

Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies.

Clin Cancer Res. 2017 Mar 01;23(5):1186-1192

Authors: Kelly K, Mejia A, Suhasini AN, Lin AP, Kuhn J, Karnad AB, Weitman S, Aguiar RC

Abstract
Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1-13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49-315) versus 91 days (28-139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28-315).Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186-92. ©2016 AACR.

PMID: 27542768 [PubMed - indexed for MEDLINE]

Divergent roles for antigenic drive in the aetiology of primary versus dasatinib-associated CD8+ TCR-Vβ+ expansions.

Sci Rep. 2018 Feb 07;8(1):2534

Authors: Lissina A, McLaren JE, Ilander M, Andersson EI, Lewis CS, Clement M, Herman A, Ladell K, Llewellyn-Lacey S, Miners KL, Gostick E, Melenhorst JJ, Barrett AJ, Price DA, Mustjoki S, Wooldridge L

Abstract
CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8+ T-cell receptor (TCR)-Vβ+ populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vβ+) and residual (TCR-Vβ-) CD8+ T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8+ TCR-Vβ+ expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8+ TCR-Vβ+ expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8+ TCR-Vβ+ expansions.

PMID: 29416058 [PubMed - in process]

Imaging spectrum of immunomodulating, chemotherapeutic and radiation therapy-related intracranial effects.

Br J Radiol. 2018 Feb;91(1082):20170553

Authors: Lincoln CM, Fata P, Sotardi S, Pohlen M, Uribe T, Bello JA

Abstract
OBJECTIVE: A wide range of treatment-related side effects result in specific neurologic symptoms and signs and neuroimaging features. Even to the most seasoned neuroradiologist, elucidating therapy-related side effects from other common mimics can be challenging. We provide a pictorial survey of some common and uncommon medication-induced and therapy-related neuroimaging manifestations, discuss pathophysiology and common pitfalls in imaging and diagnosis.
METHODS: A case-based review is utilized to depict scenarios on a routine basis in a general radiology or neuroradiology practice such as medication-induced posterior reversible encephalopathy syndrome to the more challenging cases of pseudoprogression and pseudoregression in temozolmide and bevacizumab therapy in gliobastoma treatment protocols.
CONCLUSION: Knowledge of the treatment-induced imaging abnormalities is essential in the accurate interpretation and diagnosis from the most routine to most challenging of clinical situations. We provide a pictorial review for the radiologist to employ in order to be an invaluable provider to our clinical colleagues and patients.

PMID: 29039692 [PubMed - indexed for MEDLINE]

Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer.

Clin Cancer Res. 2017 Mar 15;23(6):1397-1406

Authors: Lee JM, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, Houston N, Goey AK, Sissung TM, Parker B, Minasian L, Chiou VL, Murphy RF, Widemann BC, Figg WD, Kohn EC

Abstract
Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination.Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum-DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum-DNA adducts.Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%).Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. Clin Cancer Res; 23(6); 1397-406. ©2016 AACR.

PMID: 27663600 [PubMed - indexed for MEDLINE]

The need for educating patients with schizophrenia about the adverse effects of medications.

Australas Psychiatry. 2016 Aug;24(4):352-5

Authors: Hashimoto Y, Tensho M

Abstract
OBJECTIVE: Medication non-adherence is observed in many patients with schizophrenia. We investigated the effects of educational intervention on patient awareness of the adverse effects of their medication for patients with schizophrenia.
METHODS: Inpatients with schizophrenia (N=87) in two Japanese hospitals were allocated to two groups, one that was aware of the adverse effects of medications and one that was unaware, according to their responses to the question 'In the past month, have you experienced any adverse effects from your medications?' Then, they were questioned about adverse effects.
RESULTS: Only 27.6% of patients recognized the adverse effects of their medications. After pharmacists educated them and showed them a list of adverse effects, the prevalence of recognition increased dramatically (≤96.6%). Most patients with schizophrenia clearly did not recognize the adverse effects of their medications. When patients experienced discomfort they tended to stop taking their medications.
CONCLUSIONS: Adverse effects are a common risk factor for discontinuation of medication, so early detection and reporting of such effects may result in them being addressed sooner. Considering the risks of relapse caused by discontinuation of medication, healthcare professionals should actively educate patients with schizophrenia about dysphoria and manage adverse effects.

PMID: 26912469 [PubMed - indexed for MEDLINE]

The Drug-Drug Interaction Profile of Presatovir.

J Clin Pharmacol. 2018 Feb 07;:

Authors: Xin Y, Weng W, Murray BP, Eisenberg EJ, Chien JW, Ling J, Silverman JA

Abstract
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUCinf ), and decreased by rifampin (40.3% in Cmax and 82.5% in AUCinf ) and efavirenz (55.7% in AUCinf ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.

PMID: 29412463 [PubMed - as supplied by publisher]

Fimasartan-induced liver injury in a patient with no adverse reactions on other types of angiotensin II receptor blockers: A case report.

Medicine (Baltimore). 2017 Nov;96(47):e8905

Authors: Park DH, Yun GY, Eun HS, Joo JS, Kim JS, Kang SH, Moon HS, Lee ES, Lee BS, Kim KH, Kim SH

Abstract
RATIONALE: Angiotensin II receptor blockers (ARBs) are widely used for patients with hypertension, and fimasartan is a recently approved ARBs. Fimasartan can cause headache, dizziness, itching, and coughing. There have been several reports of hepatotoxicity in ARBs. However, there have not yet been published reports of the hepatotoxicity of fimasartan.
PATIENT CONCERNS: A 73-year-old man with hypertension experienced liver injury after fimasartan administration. He had a previous history of taking 3 types of ARBs each for more than 2 years before taking fimasartan, and there were no side effects on ARBs except for fimasartan.
DIAGNOSES: Other factors that could cause liver injury were excluded in diagnostic tests, and fimasartan was suspected to be the causative agent.
INTERVENTION: Fimasartan was immediately discontinued and the patient was managed with supportive care via hepatotonics.
DIAGNOSES: Other factors that could cause liver injury were excluded in diagnostic tests, and fimasartan was suspected to be the causative agent.
OUTCOME: The liver injury due to fimasartan was confirmed by histology and accidental redosing.
LESSONS: We emphasize that liver function should be monitored during fimasartan administration because fimasartan may cause hepatotoxicity in patients who have no side effects with other types of ARBs. And fimasartan-induced liver injury may appear later than other ARBs.

PMID: 29382024 [PubMed - indexed for MEDLINE]

Magnitude of Antiretroviral Drug Toxicity in Adult HIV Patients in Ethiopia: A cohort study at seven teaching hospitals.

Ethiop J Health Sci. 2017 Feb;27(Suppl 1):39-52

Authors: Gudina EK, Teklu AM, Berhan A, Gebreegziabhier A, Seyoum T, Nega A, Medhin G, Kebede A, Assefa Y

Abstract
BACKGROUND: The introduction of antiretroviral therapy (ART) has resulted in significant mortality reduction and improvement in the quality of life. However, this has come at a cost of increased drug toxicity. The objective of this study was to assess the patterns and predictors of ART toxicity in adult HIV patients in Ethiopia.
METHODS: This is a prospective cohort study conducted at seven teaching hospitals between September 2009 and December 2013 involving 3921 HIV patients on ART. Adverse drug reactions (ADR) due to ART were identified based on clinical assessment and/or laboratory parameters. Multivariable random effects Poisson regression analysis was used to identify factors independently associated with toxicity.
RESULT: ADR due to ART drugs was reported in 867 (22.1 %) of the participants; 374 (9.5%) had severe forms. About 87% of reported toxicities were limited to three organ systems - the skin, nervous system and blood. The overall incidence of ADR was 9 per 100 person years. About a third of toxicities occurred during the first six months after ART initiation with the incidence rate of 22.4 per 100 person years. Concomitant anti-tuberculosis treatment was the strongest independent predictor of toxicity.
CONCLUSION: ADR was found to be highly prevalent in HIV patients on ART at tertiary hospitals in Ethiopia. Most of these conditions occurred early after ART initiation and in those with concomitant anti-tuberculosis treatment. Thus, routine monitoring of patients on ART should be strengthened with particular emphasis in the first 6 months. Strategies should also be devised to replace older and more toxic agents with newer and safer drugs available.

PMID: 28465652 [PubMed - indexed for MEDLINE]