Therapeutic Doses In Patients Research Articles

Development of a Practical Nomogram for Personalized Anemia Management in Patients Treated with Ataxia Telangiectasia and Rad3-related Inhibitor Camonsertib.

Camonsertib is a highly selective and potent inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Dose-dependent anemia is a class-related on-target adverse event often requiring dose modifications. Individual patient risk factors for the development of significant anemia complicate the selection of a "one-size-fits-all" ATR inhibitor (ATRi) dose and schedule, possibly leading to suboptimal therapeutic doses in patients at low risk of anemia. We evaluated whether early predictors of anemia could be identified to ultimately inform a personalized dose-modification approach. On the basis of preclinical observations and a mechanistic understanding of ATRi-related anemia, we identified several potential factors to explore in a multivariable linear regression modeling tool for predicting hemoglobin level ahead of day 22 (cycle 2) of treatment. In patients treated with camonsertib monotherapy (NCT04497116), we observed that hemoglobin decline is consistently preceded by reticulocytopenia, and dose- and exposure-dependent decreases in monocytes. We developed a nomogram incorporating baseline and day 8 hemoglobin and reticulocyte values that predicted the day 22 hemoglobin values of patients with clinically valuable concordance (within 7.5% of observations) 80% of the time in a cross-validation performance test of data from 60 patients. The prediction of future hemoglobin decrease, after a week of treatment, may enable a personalized, early dose modification to prevent development of clinically significant anemia and resulting unscheduled dose holds or transfusions.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

The new S7B/E14 Q&A document provides additional opportunities to replace the thorough QT study.

Since 2015, concentration-QTc analysis can be used to exclude that a drug has a concerning effect on the QTc interval. This has enabled replacing the designated TQT study by implementation of serial ECGs into routine clinical pharmacology studies, such as the First-in-Human (FIH) study. This has led to an increased proportion of FIH studies with this added objective of QT evaluation with the intention of replacing the TQT study. With the more recent, February 2022 revision of the S7B/E14 Q&A document, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG and the non-rodent in vivo study are conducted according to described best practices, the previous requirement that a QTc effect > 10 ms must be excluded in healthy subjects at plasma concentrations 2-fold above what can be seen in patients can be reduced to covering concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect > 10 ms can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayed repolarization. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment. This article is protected by copyright. All rights reserved.

Acute-onset psychosis induced by a therapeutic dose of parenteral hyoscine butylbromide: A case report

Anticholinergic medications are frequently prescribed for gastrointestinal and genitourinary spasms. Psychosis, when present, results from anticholinergic overdose or toxicity. In the literature, anticholinergic-induced psychosis at therapeutic doses in patients with normal cognition is extremely uncommon. Here, we describe the case of a 28-year-old female who presented with auditory and visual hallucinations, stereotypy, and agitation after receiving a single intramuscular injection of 20 mg hyoscine butylbromide for dysmenorrhea. Even though it is rare for a therapeutic dose of hyoscine butylbromide to cause psychosis, clinicians should maintain a high index of suspicion and be cautious when administering or prescribing anticholinergics.

Спонтанные гематомы у госпитальных пациентов с новой коронавирусной инфекцией

Treatment of the new coronavirus infection (NCVI) is associated with high risks of hemorrhagic complications. This is due to the use of anticoagulants to prevent coagulopathy and thrombotic complications, which are the most frequent and severe complications of NCVI. The article presents the results of a retrospective analysis of 80 cases of spontaneous hematomas in patients with NCVI who were treated in a temporary infectious diseases hospital of the Republic of Clinical Hospital. Verification of the diagnosis was carried out using clinical data, ultrasound diagnostics, and computed tomography. The mean age of the patients was 62.4 ± 14.47 years. The most common localizations of spontaneous hematoma were: abdominal wall — 31.3%, retroperitoneal hematoma — 26.3%, chest hematoma — 16.3%, lower or upper limb — 8.8%, neck — 3.8%, combined hematomas — 5%. The number of small hematomas was 87.5%, large – 12.5%. The highest incidence of spontaneous hematomas (74%) and mortality (22%) was recorded in the group of patients receiving therapeutic doses of anticoagulants. X-ray endovascular diagnosis of the source of bleeding and its embolization was performed in 15 patients. The use of therapeutic doses in patients with NCVI is accompanied by a high risk of developing spontaneous hematomas and, as a result, increases the risk of death. X-ray endovascular embolization of spontaneous hematomas is an effective and safe method of treatment in patients with NCVI.

A mobile high-resolution gamma camera for therapeutic dose control during radionuclide therapy

Objective. Molecular radiotherapy is the most used treatment modality against malign and benign diseases of thyroid. In that context, the large heterogeneity of therapeutic doses in patients and the range of effects observed show that individualized dosimetry is essential for optimizing treatments according to the targeted clinical outcome. Approach. We developed a high-resolution mobile gamma camera specifically designed to improve the quantitative assessment of the distribution and biokinetics of 131I at patients’s bedside after treatment of thyroid diseases. The first prototype has a field of view of 5 × 5 cm2 and consists of a high-energy parallel-hole collimator made of 3D-printed tungsten, coupled to a 6 mm thick CeBr3 scintillator readout by an array of silicon photomultiplier detectors. The intrinsic and overall imaging performance of the camera was evaluated with 133Ba and 131I sources. In order to test its quantification capability in realistic clinical conditions, two different 3D-printed thyroid phantoms homogeneously filled with 131I were used. Both single view and conjugate view approaches have been applied, with and without scatter correction technique. Main Results. The camera exhibits high imaging performance with an overall energy resolution of 7.68 ± 0.01%, a submillimetric intrinsic spatial resolution of 0.74 ± 0.28 mm and a very low spatial distortion 0.15 ± 0.10 mm. The complete calibration of the camera shows an overall spatial resolution of 3.14 ± 0.03 mm at a distance of 5 cm and a corresponding sensitivity of 1.23 ± 0.01 cps/MBq, which decreases with distance and slightly changes with source size due to the influence of scattering. Activity recovery factors better than 97% were found with the thyroid phantoms. Significance. These preliminary results are very encouraging for the use of our camera as a tool for accurate quantification of absorbed doses and currently motivates the development of a fully operational clinical camera with a 10 × 10 cm2 field of view and improved imaging capabilities.

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine.

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Additional liabilities of these medications include pharmacokinetic profiles that require extended dosing to achieve therapeutic tissue concentrations. To improve chloroquine therapy, researchers have turned toward nanomedicine reformulation of chloroquine and hydroxychloroquine to increase exposure of target tissues relative to off-target tissues, thereby improving the therapeutic index. This review highlights these reformulation efforts to date, identifying issues in experimental designs leading to ambiguity regarding the nanoformulation improvements and lack of thorough pharmacokinetics and safety evaluation. Gaps in our current understanding of these formulations, as well as recommendations for future formulation efforts, are presented.

S3532 Severe Transaminitis and Acute Renal Failure in a Teenage Patient

INTRODUCTION: Alcoholic hepatitis is one of the many different causes of acute onset of symptomatic severe transaminitis. Though the exact amount of alcohol consumption that places an individual at risk is unknown, the majority of patients endorse heavy alcohol use for several decades. We present a rare case of alcoholic hepatitis in a teenager with a marked 250-fold increase in ALT and 137-fold increase in AST. CASE DESCRIPTION/METHODS: A 19-year-old female presented with nausea and multiple episodes of nonbilious, nonbloody vomiting. She reported drinking a large amount of hard liquor at a party three days before going to the hospital and since then, she developed nausea, vomiting, worsening right upper quadrant abdominal pain, weakness, and fatigue. Patient worked as a bartender and endorsed drinking significant amounts of hard liquor on a daily basis. Labs showed ALT 11,780 (4–47), AST 5492 (15–40), INR 2 (0.9–1.2). Patient was given IV Acetadote for several days until AST and ALT were below 1000. She was placed on folic acid, multivitamin, and thiamine for alcohol use disorder. Patient’s creatinine (Cr) on admission was 1.41 but peaked at 9.09 (0.3–1.2), causing concern for the need to initiate dialysis. UA showed hematuria and proteinuria. Abdominal US demonstrated no hydronephrosis. Tylenol and salicylate level were normal, and the hepatitis panel was nonreactive. Ultrasound of the abdomen with Doppler to evaluate for Budd-Chiari showed normal flow and hepatic vessels. Ceruloplasmin, ANA, anti-smooth muscle antibody, and antimitochondrial antibody were all negative. EBV antibody IgG was elevated 490 ((0–17.9 U/mL), EBV nuclear antibody was IgG 477 (0–17.9 U/mL), and EBV Ab IgM was non-reactive signifying past EBV infection. Mitochondrial Ab, RPR, CRP, C-ANCA, MPO Ab, PR-3 Abs, and P-ANCA were all non-reactive. The patient was discharged once LFTs, INR, and Cr all decreased to normal levels. DISCUSSION: There are many causes of acute hepatitis, including viruses, ischemia, and drug toxicity. Patients usually have elevated transaminases, AST/ALT ratio greater than 2, and elevated INR due to the inflamed liver’s decreased production of coagulation factors. Higher transaminase levels, such as those in the patient, raise the suspicion of concurrent viral or ischemic hepatitis or Tylenol use (which can be toxic in therapeutic doses in patients who abuse alcohol). It is crucial to counsel the patient on treatment for alcohol use disorder once the acute episode of hepatitis has resolved.

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.

SummaryThe emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2–4, and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.

Sympathetic overdrive in patients with impaired carbohydrate metabolism

Clinical studies have shown that sympathetic hyperactivation (sympathetic overdrive) is one of the main features of arterial hypertension, type 2 diabetes, and obesity, which are often found simultaneously.The landmark British Prospective Diabetes Study (UKPDS), which lasted 20 years, showed that beta-blockers reduce any-cause mortality by 23 % in patients with young and middle-aged hypertension, overweight or obese with diabetes 2 type. The researchers concluded that the advantage of long-term use of BB in this study is due to the fact that in a population of patients with obesity, diabetes mellitus, hypertension and an extremely high level of activity of the sympathetic system of β1-blockade is especially effective.An analysis of subsequent large-scale clinical trials of the effectiveness of beta-blockers (in particular, bisoprolol in CIBIS II) showed that in patients with heart failure and diabetes, these drugs reduce overall mortality by 16 %.The safety study of the use of bisoprolol in effective therapeutic doses in patients with type 2 diabetes mellitus and hypertension did not reveal a statistically significant negative effect of this highly selective β1-blocker on carbohydrate and lipid metabolism.

Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients

Olaparib is a poly ADP-ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure-response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N=410) and safety (N=757) analyses. Exposure-progression-free survival (Cox proportional hazards model indicated that a 300mg b.i.d. tablet was statistically superior to the 200mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure-safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300mg b.i.d. tablet, 200mg b.i.d. tablet, and 400mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.

Errors in the absorbed and the administered 131I therapeutic dose in patients with Graves' disease. A suggested more precise technique.

The aim of this study was to evaluate the relative error (RE) in the thyroid absorbed dose (TD) of iodine-131 (131I) in patients with Graves' disease comparing the simplified Quimby-Marinelli-Hine formula method (sQMHF) and the Standard Operational Procedures for dosimetry (SOPD) recommended by the European Association of Nuclear Medicine. This study included 45 patients with Graves' disease 12 men and 33 women; age 44.1±12.8 years. Thyroid mass (TM) was measured using ultrasound. Uptake of 131I (RAIU) was tested at 2, 4-6, 24, 48-72, and 96-168h after its administration and the half-life (T1/2eff) and resident time (RT) of 131I were computed. According to the sQMHF, a prescribed TD of 75Gy required 3.7MBq/g of 131I, correction based on the RAIU24h and T1/2eff. Subsequently, the therapeutic TD was computed according to the SOPD and the RE was recorded. The data were analyzed using t-tests. The TM, RAIU24h, therapeutic TD, and RE were 36.5±23.9g, 0.54±0.14, 89.4±9.4Gy, and -0.01±0.02, respectively. There was a significant difference (t-value 9.84, P<0.01) between the prescribed and therapeutic TD because the sQMHF ignores the absorbed dose deposited in the thyroid during the first 24h, which is included in the SOPD. In addition, the RE was significantly smaller than the variable coefficient (VC) of the therapeutic TD (t=-39.6, P<0.01). When the activity of 131I was calculated using the simplified Q-M-H formula, the therapeutic absorbed thyroid dose was significantly higher than what was expected for the prescribed dose. Precision of the individualized therapeutic absorbed dose could be improved by computing the activity of 131I using the standard operational procedures for dosimetry of the EANM.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

IntroductionObeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug–drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters.MethodsFive phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin).ResultsOCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs.ConclusionIn these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin).FundingIntercept Pharmaceuticals, Inc.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-017-0601-0) contains supplementary material, which is available to authorized users.

Bridging Therapy with Sodium Bemiparin at Therapeutic-Dose: Experience in Our Hospital

INTRODUCTIONBridging therapy consists of the administration of a fast-acting anticoagulant such as the low-molecular-weight heparin (LMWH) during the period of cessation of oral anticoagulant therapy.The decision to continue with anticoagulant therapy or to discontinue the treatment with the establishment of the Bridging therapy have been carried out carefully and on an individual basis. While taking this decision, we have taken into account three factors: the urgency of surgery or invasive process, the risk of bleeding and thrombotic risk for the patient.In recent decades, there have been multiple studies supporting the LMWH treatment, at least as safe and effective and more cost-effective than unfractionated heparin (UFH) in the prophylaxis and treatment of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, the LMWH is considered as the drugs of choice in the prevention of venous thromboembolism.There are several types of commercialized LMWH, with different pharmacological properties, such as molecular weight, anti-Xa/IIa ratio and average life. The sodium bemiparin is the LMWH with greater anti-Xa/IIa ratio, which implies a lower risk of bleeding. In addition, it has shown a low incidence of VTE and bleeding in actual clinical practice.OBJECTIVEThere are few published data from bridging therapy at therapeutic doses in patients treated with oral anticoagulants (AVK) and perioperative management.It is intended to assess the efficacy (recurrence of thrombosis) and safe use of sodium bemiparin at anticoagulant doses on the bridging therapy and possible thrombotic and / or hemorrhagic complications (major and minor bleeding) resulting from this use.MATERIAL AND METHODSWe have analyzed 550 bridging therapies at full dose in our clinic in the last year. They were made to a total of 345 patients (174 men and 171 women) with CHADSVASC > 2, aged between 15 and 90, with an average age of 64 years old. The reasons of anticoagulation in our patients were atrial fibrillation, mechanical prostheses, DVT, pulmonary embolism and recurrent thrombosis in patients with thrombophilia. In 70% of the cases, there were comorbidities, such as heart failure, chronic obstructive pulmonary disease, anemia, kidney failure, liver disease and long-term aftereffects of stroke.The bridging therapy has consisted on suspending AVK 4 (acenocumarol) to 6 days (warfarin) before the procedure, and replacing it by sodium bemiparin at full doses <50 kgr: 5,000 IU/24h, 50 to 70 kgr: 7,500 IU/24 h, 70-100 kgr: 10,000 IU/24 h and >100 kgr: 12.500 IU/24 h, and administration of a prophylactic dose of 3,500 IU, 12 hours before the procedure, and another dose 6-12 hours after the procedure, depending on the risk of bleeding of the intervention and the thrombotic risk of the patient’s disease.The bridging therapy has been performed in 120 cases of major surgery (orthopedic surgery, ophthalmological procedures, valvular replacements etc), 210 cases of minor surgery (removal of nevus, complex dental extractions, dental implants), 140 cases of invasive procedures (colonoscopies, endoscopies ..), 30 cases of bleeding caused by AVK (epistaxis, petechiae and bruises, hemoptysis, menorrhagia and gastrointestinal bleeding), 15 cases of hospitalization with INR decompensation with various causes (infectious endocarditis, pneumonia, uncompensated heart failure...) and 35 cases for thrombophilia study. RESULTSAs complications of using bemiparin sodium, there have been: 1 case of heparin-induced thrombocytopenia, 20 cases of hematomas at the needle puncture sites and 2 cases of persistent uterine bleeding with progressive anemia with transfusional requirement. There was neither cases of major bleeding nor cases of thrombosis.CONCLUSIONSSodium bemiparin administered at therapeutic doses (115 IU/kg/24h) in the perioperative period, according to the scheme described above, it is associated with a low incidence of recurrence of VTE and bleeding. The complications presented in our sample have been very few, in patients with associated co-morbidities.In our study, sodium bemiparin has shown to be safe and effective with minimal bleeding complications.Treatment should be administered on an individual basis according to each patient and factors related to surgery. Further studies will confirm our results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Multi-Country Evaluation of Safety of Dihydroartemisinin/Piperaquine Post-Licensure in African Public Hospitals with Electrocardiograms.

The antimalarial drug piperaquine is associated with delayed ventricular depolarization, causing prolonged QT interval (time taken for ventricular de-polarisation and re-polarisation). There is a lack of safety data regarding dihydroartemisinin/piperaquine (DHA/PPQ) for the treatment of uncomplicated malaria, which has limited its use. We created a platform where electrocardiograms (ECG) were performed in public hospitals for the safety assessment of DHA/PPQ, at baseline before the use of dihydroartemisinin/piperaquine (Eurartesim®), and on day 3 (before and after administration of the final dose) and day 7 post-administration. Laboratory analyses included haematology and clinical chemistry. The main objective of the ECG assessment in this study was to evaluate the effect of administration of DHA/PPQ on QTc intervals and the association of QTc intervals with changes in blood biochemistry, full and differential blood count over time after the DHA/PPQ administration. A total of 1315 patients gave consent and were enrolled of which 1147 (87%) had complete information for analyses. Of the enrolled patients 488 (42%), 323 (28%), 213 (19%) and 123 (11%) were from Ghana, Burkina Faso, Tanzania and Mozambique, respectively. Median (lower—upper quartile) age was 8 (5–14) years and a quarter of the patients were children under five years of age (n = 287). Changes in blood biochemistry, full and differential blood count were temporal which remained within clinical thresholds and did not require any intervention. The mean QTcF values were significantly higher than on day 1 when measured on day 3 before and after administration of the treatment as well as on day 7, four days after completion of treatment (12, 22 and 4 higher, p < 0.001). In all age groups the values of QT, QTcF and QTcB were highest on day 3 after drug intake. The mean extreme QTcF prolongation from baseline was lowest on day 3 before drug intake (33 ms, SD = 19) and highest on day 3 after the last dose (60 ms, SD = 31). There were 79 (7%) events of extreme mean QTcF prolongation which were not clinically significant. Nearly a half of them (n = 37) were grade 3 and mainly among males (33/37). Patients in Burkina Faso, Mozambique and Tanzania had significantly lower mean QTcF than patients in Ghana by an average of 3, 4 and 11 ms, respectively. We found no evidence that Eurartesim® administered in therapeutic doses in patients with uncomplicated malaria and no predisposing cardiac conditions in Africa was associated with adverse clinically significant QTc prolongation.

The Effect of Antiemetics and Antihistamines on the QTc Interval in Emergent Dialysis Patients With Baseline QTc Prolongation

BackgroundUnfunded patients with end-stage renal disease (ESRD) who do not have routinely scheduled hemodialysis often receive medications known to prolong the QTc interval for their uremic symptoms even though they may have pre-existing QTc prolongation. ObjectivesThe purpose of this study was to determine the effects of these medications on the QTc interval in these patients. MethodsUnfunded patients with ESRD presenting to the emergency department (ED) for emergent hemodialysis (HD) with QTc prolongation on their initial electrocardiogram (ECG) were recruited. Approximately 2 hours after receiving an antihistamine or antiemetic, a second ECG was ordered and the QTc was measured. The patients were followed-up 1 week later. ResultsTwenty-nine percent (44/152) of the unfunded patients with ESRD presenting for HD at a county hospital had QT prolongation and were included with 107 total ED visits during the 4-week study period. The mean QTc was 483.7 msec on presentation to the ED, and the mean QTc measured 2 hours after receiving an antihistamine or antiemetic was 483.8 msec. None of the patients were admitted for life-threatening dysrhythmias. Thirty-six percent (16/44) of the recruited patients had QTc intervals >500 msec with a combined total of 31 patient visits, of which only 25.8% (8/31) had an increase in the QTc interval after an antihistamine or antiemetic medication was given. None of these patients had adverse outcomes, such a dysrhythmia or death, at 1-week follow-up. ConclusionThis study shows that medications known to cause QTc prolongation are safe to use in therapeutic doses in patients with ESRD who have pre-existing QT prolongation. Few patients in this cohort had significantly prolonged QTc intervals at baseline.

Abstract CT149: Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study

Abstract Veliparib is a potent oral poly(ADP-ribose) polymerase inhibitor that impairs DNA damage repair and shows single-agent activity in tumors with homologous recombination repair defects as well as in combination with DNA-damaging chemotherapies. Nonclinical studies suggested a potential risk of QT prolongation at the peak plasma concentration (Cmax) achieved at the maximum tolerated dose for veliparib monotherapy (400 mg twice daily). This phase 1, single-dose, double-blind, placebo (PBO)-controlled, randomized crossover study (NCT02009631) evaluated the effect of veliparib on corrected QT (QTc) interval in patients (pts) with relapsed/refractory solid tumors. Methods: Eligible pts (?18 years) with metastatic or unresectable solid tumors and ECOG PS ?1 received single-dose oral veliparib (200 mg [V200], 400 mg [V400]) or PBO in a 6-sequence, 3-period crossover design, with ?3-day interperiod washout time. The primary objective was to assess the effect of veliparib on QT interval with Fridericia's correction (QTcF). Lack of clinically relevant effect on QTc interval was shown if the 95% upper confidence bound (UCB) for the maximum baseline-adjusted QTcF difference between veliparib and PBO (??QTcF) for the 400 mg dosing was &amp;lt;10 msec (ICH E14 guidelines). Pharmacokinetics and safety were also evaluated. Results: Forty-seven pts (85% female; median age 58 years) were enrolled and analyzed. After single-dose administration, maximum ??QTcF of V400 compared to PBO was 6.4 msec with a 95% UCB of 8.9 msec; for V200 the maximum ??QTcF was 3.6 msec, with a 95% UCB of 6.1 msec. Mean time to maximum plasma concentration (Tmax) was similar for V200 (2.4 ± 0.7 h) and V400 (2.5 ± 0.6 h). Mean Cmax was 1.32 ± 0.38 μg/mL and 2.61 ± 0.85 μg/mL, and total exposure (AUC?) was 12.0 ± 3.98 μg•h/mL and 25.5 ± 8.37 μg•h/mL, for V200 and V400, respectively. Treatment-emergent adverse events (TEAEs) were experienced by 36.2%, 48.9%, and 47.8% of pts while receiving V200, V400, and placebo, respectively. Most common TEAEs were nausea (12.8%) and myalgia (8.5%) while receiving V200; nausea (8.5%) and vomiting (8.5%) while receiving V400; and nausea (6.5%) while receiving PBO. TEAEs were mainly grade 1/2, with grade 3 vomiting and depression experienced by 1 pt each. The most common TEAE possibly related to study drug was nausea (19.1%), reported in 8.5%, 6.4%, and 4.3% of pts while receiving V200, V400, and PBO, respectively. One pt discontinued treatment after the V200-V400 sequence due to study drug-unrelated AEs. There were no deaths or serious AEs. Conclusions: Single-dose veliparib (200 or 400 mg) did not exhibit clinically relevant QT prolongation greater than the 10 msec threshold per ICH E14 guideline. Citation Format: Wijith Munasinghe, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane M. Medina, Dennis M. Bergau, Silpa Nuthalapati, David M. Hoffman, Stacie L. Shepherd, Hao Xiong. Assessment of the cardiac safety of veliparib in a thorough QT/QTc study at therapeutic doses in patients with relapsed/refractory solid tumors: a randomized, placebo-controlled crossover study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT149.

Abstract 4698: Combination of ceritinib (LDK378) with PI3K inhibitors (buparlisib [BKM120] and alpelisib [BYL719]) demonstrates synergistic preclinical antitumor activity in ALK-rearranged non-small cell lung cancer (NSCLC)

Abstract Introduction: NSCLCs harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene are highly sensitive to ALK inhibition. Ceritinib is a novel ALK inhibitor that demonstrates significant preclinical and clinical antitumor potency, including in tumors that have developed resistance to the approved ALK inhibitor crizotinib. Upregulation of the phosphatidylinositol 3-kinase (PI3K) pathway may be involved in ALK inhibitor resistance, suggesting that combining ceritinib with a PI3K inhibitor may provide synergistic antitumor activity in ALK-rearranged NSCLC. Here, we assess the synergy and antiproliferative activity of PI3K inhibitor/ceritinib combinations in crizotinib-naïve primary preclinical models of NSCLC. Methods: In vitro experiments used the EML4−ALK-translocated lung cancer cell line H2228 to screen for synergistic combinations of ceritinib with 18 other compounds (PI3K, MEK, and CDK4/6 inhibitors, among others). In vivo experiments used a human-mouse primary xenograft lung cancer model with similar EML4−ALK translocation (LUF1656). Tumor fragments (diameter 2−3 mm) from stock mice inoculated with LUF1656 lung cancer tissue were harvested and used for inoculation into nu/nu mice for tumor development. Once mean tumor size had reached ∼150 mm3, treatment was initiated with single-agent or combination regimens of buparlisib (pan-PI3K inhibitor; 35 mg/kg QD), alpelisib (PI3Kα inhibitor; 30 mg/kg QD), or ceritinib (25 mg/kg [low dose] or 50 mg/kg [full dose] QD). All doses used were equivalent to known therapeutic doses in patients. Results: In vitro experiments revealed the strongest antiproliferative activity when ceritinib was combined with either buparlisib or alpelisib versus the other compounds tested. In vivo, low-dose ceritinib in combination with buparlisib improved tumor growth delay over single-agent, full-dose ceritinib. Full-dose ceritinib plus alpelisib showed no significant difference in tumor growth delay versus full-dose ceritinib alone. Low-dose ceritinib plus alpelisib appeared to be better tolerated than full-dose ceritinib plus alpelisib, but with similar efficacy to low-dose ceritinib alone. A delayed tumor growth rate after treatment interruption was noted in all ceritinib combinations. Conclusion: Synergy was observed between ceritinib and PI3K inhibitors in a crizotinib-naïve ALK-translocated lung model in vitro. In the in vivo EML4−ALK lung preclinical cancer models, low-dose ceritinib (25 mg/kg) combined with buparlisib showed improved efficacy versus full-dose ceritinib (50 mg/kg) alone. Preclinical experiments exploring combinations of PI3K- and ALK-targeted therapies in crizotinib-resistant ALK-rearranged tumors are also ongoing. Citation Format: Emmanuelle Di Tomaso, Ronald Linnartz, Fang Li, Cristian Massacesi, Samit Hirawat. Combination of ceritinib (LDK378) with PI3K inhibitors (buparlisib [BKM120] and alpelisib [BYL719]) demonstrates synergistic preclinical antitumor activity in ALK-rearranged non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4698. doi:10.1158/1538-7445.AM2015-4698

P.2.f.012 Effects of escitalopram and duloxetine on electrocardiography at therapeutic doses in patients with major depression

P.2.f.012 Effects of escitalopram and duloxetine on electrocardiography at therapeutic doses in patients with major depression

SU-E-T-208: Incidence Cancer Risk From the Radiation Treatment for Acoustic Neuroma Patient

Purpose: The present study aimed to compare the incidence risk of a secondary cancer from therapeutic doses in patients receiving intensitymodulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic radiosurgery (SRS). Methods: Four acoustic neuroma patients were treated with IMRT, VMAT, or SRS. Their incidnece excess relative risk (ERR), excess absolute risk (EAR), and lifetime attributable risk (LAR) were estimated using the corresponding therapeutic doses measured at various organs by radio-photoluminescence glass dosimeters (RPLGD) placed inside a humanoid phantom. Results: When a prescription dose was delivered in the planning target volume of the 4 patients, the average organ equivalent doses (OED) at the thyroid, lung, normal liver, colon, bladder, prostate (or ovary), and rectum were measured. The OED decreased as the distance from the primary beam increased. The thyroid received the highest OED compared to other organs. A LAR were estimated that more than 0.03% of AN patients would get radiation-induced cancer. Conclusion: The tyroid was highest radiation-induced cancer risk after radiation treatment for AN. We found that LAR can be increased by the transmitted dose from the primary beam. No modality-specific difference in radiation-induced cancer risk was observed in our study.