The Pharmacokinetics and Safety Of Idelalisib In Subjects With Moderate Or Severe Hepatic Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5571-5571 ◽  
Author(s):  
Feng Jin ◽  
Michelle Robeson ◽  
Huafeng Zhou ◽  
Grace Hisoire ◽  
Srini Ramanathan
Keyword(s):  
Oral Dose ◽  
Hepatic Impairment ◽  
Healthy Subjects ◽  
Severe Hepatic Impairment ◽  
Employment Equity ◽  
Control Subjects ◽  
Matched Healthy Control ◽  
Healthy Control ◽  
Equity Ownership ◽  
Oral Doses

Abstract Background Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110s catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. Based on mass balance study of IDELA, the majority of the radioactive dose administered in healthy subjects was recovered in feces (∼78%).  The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in subjects with moderate or severe hepatic impairment following administration of a single oral dose of IDELA. Methods Eligible subjects were enrolled into 2 cohorts that included subjects with moderate or severe hepatic dysfunction as categorized by the ChildPugh-Turcotte (CPT) classification system and healthy controls matched for age, gender, and body mass index. Each subject received a single oral dose of IDELA at 150 mg under fed condition. Blood samples for IDELA and GS-563117 were collected over 6 days post-dose and were measured using a validated LC/MS/MS method. The ratio and 90% confidence interval of the least squares geometric means of PK exposure parameters in the hepatic impairment group(s) versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study. Results A total of 32 subjects were enrolled in the study. The majority of subjects were white (87.5%) males (71.9%) and median age was 52 years. Study treatments were generally well tolerated. The majority of the treatment-emergent AEs (TEAE) were assessed as Grade 1 in severity. The only TEAE reported in more than 1 subject was headache (5 subjects overall; 2 subjects with moderate hepatic impairment and 3 healthy subjects). Most treatmentemergent laboratory abnormalities were Grade 1 or 2 in severity. Single oral doses of IDELA 150 mg were well tolerated in subjects with hepatic impairment and in healthy matched controls. IDELA Cmax was generally comparable in the subjects with moderate (CPT Class B) or severe (CPT Class C) hepatic impairment relative to healthy matched control subjects, while mean AUC was higher (58% to 60%). GS-563117 exposures were lower in subjects with moderate and severe hepatic impairment relative to matched healthy control subjects, likely due to lower formation in the setting of liver impairment. Overall, the observed changes in mean exposures of IDELA and GS-563117 are not considered to be clinically relevant. Exploratory analyses indicated no relevant relationships between the IDELA or GS-563117 plasma exposures and CPT score for subjects with moderate or severe hepatic impairment. Conclusion No clinically relevant changes in IDELA and GS-563117 exposures were observed in subjects with moderate or severe hepatic impairment versus matched healthy control subjects. Single oral doses of IDELA 150 mg were well tolerated. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Hisoire:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

The Pharmacokinetics and Safety Of Idelalisib In Subjects With Severe Renal Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5572-5572 ◽  
Author(s):  
Feng Jin ◽  
Michelle Robeson ◽  
Huafeng Zhou ◽  
Grace Hisoire ◽  
Srini Ramanathan
Keyword(s):  
Renal Impairment ◽  
Oral Dose ◽  
Least Squares ◽  
Matched Control ◽  
Severe Renal Impairment ◽  
Employment Equity ◽  
Control Subjects ◽  
Healthy Control ◽  
Equity Ownership ◽  
Oral Doses

Abstract Abstract 5572 Background Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. Pharmacokinetics of IDELA and its major metabolite GS-563117 have been assessed in a number of clinical studies in healthy subjects and patients with hematologic malignancies. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. Based on a human mass balance study, renal elimination plays a minor role on elimination of IDELA (∼ 15% of dose excreted in urine). The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in subjects with severe renal impairment following administration of a single oral dose of IDELA. Methods Subjects with severe renal impairment (RI) (eGFR 15 – 29 ml/min) and healthy controls (eGFR ≥ 80 ml/min) matched for age, gender, and body mass index received IDELA 150 mg single dose. Blood and urine samples for IDELA and GS-563117 were collected over 6 days post-dose and were measured using a validated LC/MS/MS method. The ratio and 90% confidence interval of the least squares geometric means of PK exposure parameters in the renal impairment group versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study. Results A total of 12 subjects were enrolled in the study. The majority of subjects were female, white, and of nonHispanic/Latino ethnicity, and the median age was similar between the 2 groups (65 years of age for the severe group and 63 years for the healthy control group). Study treatments were generally well tolerated. Overall, 6 of 12 subjects (50.0%; 1 subject with severe renal impairment and 5 healthy matched control subjects) reported a total of 10 AEs; all were Grade 1 (mild) in severity. The most frequently reported AE was headache followed by nausea. No clinically significant abnormal changes were observed in vital signs (temperature, pulse, blood pressure, respiratory rate) and ECG results from baseline. Single oral doses of IDELA 150 mg were well tolerated. Following single oral administration of IDELA 150 mg, IDELA AUClast, AUCinf, and Cmax geometric least-squares mean ratio were 127%, 127%, and 105%, respectively, between subjects with severe renal impairment relative to matched control subjects (Table 1). Consistently, GS-563117 AUClast, AUCinf, and Cmax geometric least-squares mean ratio were 124%, 124%, and 96%, respectively, between subjects with severe renal impairment relative to matched control subjects. These minimal changes observed in IDELA and GS-563117 exposure in severe renal impairment vs matched control subjects are not considered to be clinically meaningful. There were no relevant relationships between IDELA or GS-563117 exposures and baseline estimated creatinine clearance. Conclusion There were no clinically relevant differences in the pharmacokinetics of IDELA or its primary metabolite GS563117 between subjects with severe renal impairment and matched healthy control subjects following a single oral dose of IDELA 150 mg. Dose adjustments for IDELA are not considered necessary in subjects with mild, moderate, or severe renal impairment following oral administration. Single oral doses of IDELA 150 mg were well tolerated. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Hisoire:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

Novel severe traumatic brain injury blood outcome biomarkers identified with proximity extension assay

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Douglas D. Fraser ◽  
Michelle Chen ◽  
Annie Ren ◽  
Michael R. Miller ◽  
Claudio Martin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Severe Traumatic Brain Injury ◽  
Roc Curve ◽  
Vascular Pathology ◽  
Targeted Proteomics ◽  
Control Subjects ◽  
Matched Healthy Control ◽  
Healthy Control ◽  
Age And Sex

Abstract Objectives Severe traumatic brain injury (sTBI) patients suffer high mortality. Accurate prognostic biomarkers have not been identified. In this exploratory study, we performed targeted proteomics on plasma obtained from sTBI patients to identify potential outcome biomarkers. Methods Blood sample was collected from patients admitted to the ICU suffering a sTBI, using standardized clinical and computerized tomography (CT) imaging criteria. Age- and sex-matched healthy control subjects and sTBI patients were enrolled. Targeted proteomics was performed on plasma with proximity extension assays (1,161 proteins). Results Cohorts were well-balanced for age and sex. The majority of sTBI patients were injured in motor vehicle collisions and the most frequent head CT finding was subarachnoid hemorrhage. Mortality rate for sTBI patients was 40%. Feature selection identified the top performing 15 proteins for identifying sTBI patients from healthy control subjects with a classification accuracy of 100%. The sTBI proteome was dominated by markers of vascular pathology, immunity/inflammation, cell survival and macrophage/microglia activation. Receiver operating characteristic (ROC) curve analyses demonstrated areas-under-the-curves (AUC) for identifying sTBI that ranged from 0.870-1.000 (p≤0.005). When mortality was used as outcome, ROC curve analyses identified the top 3 proteins as vWF, WIF-1, and CSF-1. Combining vWF with either WIF-1 or CSF-1 resulted in excellent mortality prediction with AUC of 1.000 for both combinations (p=0.011). Conclusions Targeted proteomics with feature classification and selection distinguished sTBI patients from matched healthy control subjects. Two protein combinations were identified that accurately predicted sTBI patient mortality. Our exploratory findings require confirmation in larger sTBI patient populations.

scholarly journals Muscle α-adrenergic responsiveness during exercise and ATP-induced vasodilation in chronic obstructive pulmonary disease patients

2018 ◽  
Vol 314 (2) ◽  
pp. H180-H187 ◽  
Author(s):  
U. W. Iepsen ◽  
G. W. Munch ◽  
C. K. Ryrsø ◽  
N. H. Secher ◽  
P. Lange ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Control Subjects ◽  
Matched Healthy Control ◽  
Copd Patients ◽  
Sympathetic Vasoconstriction ◽  
Functional Sympatholysis ◽  
Healthy Control

Sympathetic vasoconstriction is blunted in exercising muscle (functional sympatholysis) but becomes attenuated with age. We tested the hypothesis that functional sympatholysis is further impaired in chronic obstructive pulmonary disease (COPD) patients. We determined leg blood flow and calculated leg vascular conductance (LVC) during 1) femoral-arterial Tyramine infusion (evokes endogenous norepinephrine release, 1 µmol·min−1·kg leg mass−1), 2) one-legged knee extensor exercise with and without Tyramine infusion [10 W and 20% of maximal workload (WLmax)], 3) ATP (0.05 µmol·min−1·kg leg mass−1) and Tyramine infusion, and 4) incremental ATP infusions (0.05, 0.3, and 3.0 µmol·min−1·kg leg mass−1). We included 10 patients with moderate to severe COPD and 8 age-matched healthy control subjects. Overall, leg blood flow and LVC were lower in COPD patients during exercise ( P < 0.05). Tyramine reduced LVC in both groups at 10-W exercise (COPD: −3 ± 1 ml·min−1·mmHg−1and controls: −3 ± 1 ml·min−1·mmHg−1, P < 0.05) and 20% WLmax(COPD: −4 ± 1 ml·min−1·mmHg−1and controls: −3 ± 1 ml·min−1·mmHg−1, P < 0.05) with no difference between groups. Incremental ATP infusions induced dose-dependent vasodilation with no difference between groups, and, in addition, the vasoconstrictor response to Tyramine infused together with ATP was not different between groups (COPD: −0.03 ± 0.01 l·min−1·kg leg mass−1vs. controls: −0.04 ± 0.01 l·min−1·kg leg mass−1, P > 0.05). Compared with age-matched healthy control subjects, the vasodilatory response to ATP is intact in COPD patients and their ability to blunt sympathetic vasoconstriction (functional sympatholysis) as evaluated by intra-arterial Tyramine during exercise or ATP infusion is maintained.NEW & NOTEWORTHY The ability to blunt sympathetic vasoconstriction in exercising muscle and ATP-induced dilation in chronic obstructive pulmonary disease patients remains unexplored. Chronic obstructive pulmonary disease patients demonstrated similar sympathetic vasoconstriction in response to intra-arterial Tyramine during exercise and ATP-induced vasodilation compared with age-matched healthy control subjects.

A Phase I Study of Midostaurin (PKC412) Investigating Cardiac Interval Effects In Healthy Subjects

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4362-4362
Author(s):  
Adam del Corral ◽  
Catherine Dutreix ◽  
Alice Huntsman Labed ◽  
Sumita Rai ◽  
Kai Grosch ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Trough Level ◽  
Phase 1 ◽  
Peak Level ◽  
Qtc Interval ◽  
Phase 2 ◽  
Employment Equity ◽  
Phase 3 ◽  
Equity Ownership ◽  
Time Point

Abstract Abstract 4362 Midostaurin (PKC412) is a multi-targeted tyrosine kinase inhibitor (TKI) of several receptors, including wild-type and mutant variants of KIT and the FMS-like tyrosine kinase 3 (FLT3) receptor, and has known roles in hematopoiesis and leukemia. Midostaurin has demonstrated activity in acute myeloid leukemia (AML) and myelodysplastic syndrome in phase 1 and 2 trials, and is currently under investigation in a randomized phase 3 AML study at 50mg twice daily (bid) in combination with chemotherapy and a phase 2 monotherapy study of aggressive systemic mastocytosis (ASM) at 100mg bid. Despite the absence of specific midostaurin-related cardiac toxicity issues, we conducted a dedicated phase 1 study to directly investigate the effect of midostaurin on QTc interval. Healthy subjects were randomized to 3 treatment arms: placebo; midostaurin administered orally at 75mg bid on days 1 and 2 and once daily (od) on day 3; or an active control arm of moxifloxacin administered orally at 400mg od on day 3. The primary variable was QTcF interval on day 3 corrected for baseline and placebo in the midostaurin and moxifloxacin treatment arms. Drug exposure levels at each time point were confirmed for moxifloxacin, midostaurin, and its two metabolites – CGP62221 and CGP52421. Of 192 subjects enrolled, 166 completed the study. 24 of 80 subjects discontinued in the midostaurin arm: 19 (23%) due to adverse events (AEs), 17 of which encompassed expected gastrointestinal events. No patients were discontinued for AEs in the other 2 treatment groups. Discontinued patients were not included in the ECG analysis. In time-matched analysis of QTcF interval change, the maximum mean change in the midostaurin arm corrected for baseline and placebo was 0.72ms with a 90% confidence interval (CI) upper bound of 4.71ms, which excluded 10ms. At each nominal time point, the mean change from baseline placebo-corrected for midostaurin was <0ms. The QTcF change point estimate corrected for time-averaged baseline and placebo also showed a lack of QTc prolongation for midostaurin. Moxifloxacin had a maximum mean change corrected for baseline and placebo of 10.7ms with a lower unadjusted 90% CI of 6.4ms 1 hour post-dose on day 3. Plasma concentration vs QTcF change from baseline analysis confirmed a negative or lack of QT effect by midostaurin but a positive correlation for moxifloxacin. No symptomatic, clinically significant new post-baseline morphological abnormalities were identified in the study. 3 patients in the midostaurin group at a single time point or evaluation experienced new post-baseline T-wave abnormalities, as did 1 and 4 patients in the placebo and moxifloxacin groups, respectively, some at multiple time points. No subject had a new >30ms or >480ms change from baseline for QTcF or QTcI. For QTcB the only occurrences of change were in the 30–60ms category: 1 (1.3%) of the subjects on midostaurin met this non-specific outlier criterion; 7 (15.9%) on moxifloxacin; and 1 (1.5%) on placebo. 1 new U-wave abnormality was noted in the moxifloxacin group. The peak plasma concentration of midostaurin achieved in the present study (mean 2273ng/mL) covered the peak and trough plasma exposure observed at 50mg bid (2220ng/mL and 1005ng/mL, respectively) in AML patients. The peak level achieved for midostaurin was also above the steady-state trough level of 1060ng/mL, but below the peak concentration of 3500ng/mL, for the 100mg bid dose. Midostaurin was safe and generally well tolerated: 97% of the AEs noted in subjects while on study drug (n=61; 40%) were reported as grade 1. No grade 3/4 AEs were reported. While some TKIs exert pharmacologic effects on QTc interval, this carefully conducted trial demonstrates that midostaurin at 75mg bid has no effect on heart rate, AV conduction, or cardiac depolarization. The midostaurin exposure achieved in this study exceeds the peak and trough levels for the 50mg bid dose regimen under investigation in the AML phase 3 trial. The midostaurin exposure achieved also exceeds the steady state trough level, but not the peak level, of the 100mg bid dose regimen under investigation in the phase 2 ASM trial. Further, the effects of the long-acting metabolite CGP52421 cannot be fully addressed by this short study. Due to the lack of QT prolongation observed in this trial, we recommend reduced but continued ECG monitoring and omission of QT-related exclusion criteria in future midostaurin clinical trials. Disclosures: del Corral: Novartis Pharmaceuticals Corporation: Employment. Dutreix:Novartis Pharmaceuticals Corporation: Employment. Huntsman Labed:Novartis Pharmaceuticals Corporation: Employment. Rai:Novartis Pharmaceuticals Corporation: Employment. Grosch:Novartis Pharmaceuticals Corporation: Employment. Morganroth:eResearchTechnology Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Wang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal Of Rivaroxaban-Induced Anticoagulation In Healthy Subjects By Andexanet Alfa (PRT064445), An Antidote For Fxa Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3636-3636 ◽  
Author(s):  
Crowther Mark ◽  
Mathur Vandana ◽  
Kitt Michael ◽  
Lu Genmin ◽  
Pamela B. Conley ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Controlled Study ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Employment Equity ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Equity Ownership ◽  
Andexanet Alfa

Abstract Background Direct factor Xa inhibitors have demonstrated compelling anticoagulant efficacy and/or safety profiles across multiple diverse patient populations. A specific antidote to reverse anticoagulation during episodes of serious uncontrolled bleeding or before urgent/emergent surgery is lacking. Andexanet alfa (proposed INN)(AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct fXa inhibitors. It thus acts as a decoy to reverse fXa inhibitor-mediated anticoagulation in preclinical and early clinical studies. Methods This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of rivaroxaban (riva), as well as the pharmacokinetics and safety in healthy subjects. Reversal of riva anticoagulation will be studied with up to 6 different dose cohorts/ regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Riva is administered at an oral dose of 20 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last riva dose – the approximate time of maximum riva concentration (mean ± SD: 0.64 ± 0.22 mM, n=18). Pharmacodynamic and safety data are collected through Day 48 with pharmacokinetic data through Day 10. Results We report here available data from the first 2 AnXa dose cohorts (210 mg and 420 mg, n =18). Immediately after completion of the 210 mg and 420 mg doses, anti-fXa activity decreased dose-dependently by 20% and 53%, respectively, from the pre-AnXa level and returned to placebo levels by approximately 2 hours after treatment (Figure). In parallel, the plasma concentrations of unbound riva were decreased by 32% and 51%, respectively, relative to pre-AnXa values. In addition, riva-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time were also rapidly partially reversed by AnXa in a dose-dependent manner. At 2 minutes after AnXa administration, the molar ratio of AnXa to total plasma riva was 0.8 for the 210 mg dose (1.2 µM/1.6 µM, respectively) and 1.2 for the 420 mg dose (2.6 µM/2.1 µM, respectively). AnXa infusion was not associated with increases in prothrombin fragments F1+2, thrombin-antithrombin, or D-dimer (all values were within normal ranges). As expected, tissue factor pathway inhibitor activity decreased due to its binding to AnXa. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. Adverse events occurring in 1 or more AnXa or placebo recipients included infusion-related reactions (n = 3, all mild in severity) and post-procedural hematoma, headache, or postural dizziness (n = 2 each). Summary/Conclusions Results from this ongoing clinical trial demonstrate that AnXa is able to dose-dependently partially reverse the anticoagulant effects of rivaroxaban, as assessed by pharmacodynamic markers, in healthy subjects. These data are consistent with previously reported results with apixaban in that AnXa sequesters rivaroxaban and apixaban in a similar stoichiometric manner. Additional data with higher doses of AnXa will also be presented. AnXa is well-tolerated and a potentially promising, universal antidote for fXa inhibitors. Disclosures: Mark: Portola Pharmaceuticals: Consultancy. Off Label Use: The use of PRT064445 as an antidote for reversal of anticoagulation from direct and indirect fXa inhibitors is investigational. Vandana:Portola Pharmaceuticals: Consultancy. Michael:Portola Pharmaceuticals: Employment, Equity Ownership. Genmin:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Stanley:Portola Pharmaceuticals: Employment, Equity Ownership. Castillo:Portola Pharmaceuticals: Employment, Equity Ownership. Hutchaleelaha:Portola Pharmaceuticals: Consultancy. Karbarz:Portola Pharmaceuticals: Employment. Lin:Portola Pharmaceuticals: Employment. Barron:Portola Pharmaceuticals: Employment. Russell:Portola Pharmaceuticals: Employment. Levy:Portola Pharmaceuticals: Employment. Connolly:Portola Pharmaceuticals: Consultancy. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

A Phase 1 Study Evaluating Pharmacokinetics (PK) and Safety of Carfilzomib in Patients with Advanced Malignancies and Varying Degrees of Hepatic Impairment (HI)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4496-4496
Author(s):  
Jennifer Brown ◽  
Ruth Plummer ◽  
Stephen Anthony ◽  
John Sarantopoulos ◽  
Filip De Vos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hepatic Impairment ◽  
Phase 1 ◽  
Hepatic Function ◽  
Employment Equity ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Advanced Malignancies ◽  
Patient Groups ◽  
Equity Ownership

Abstract Introduction: The PK profile of carfilzomib is well characterized in patients with multiple myeloma. However, during clinical development of carfilzomib, patients with moderate to severe hepatic impairment (HI) were excluded from initial clinical studies. To support carfilzomib dose recommendations for patients with baseline HI, this study evaluated PK and safety of carfilzomib in patients with varying degrees of HI and relapsed or progressive advanced malignancies. Methods: This open-label, single-arm, phase 1 study evaluated adult patients with normal (Norm) hepatic function or, mild, moderate (Mod), severe HI receiving carfilzomib infusion on days (D) 1-2, 8-9, 15 and 16 in 28-D cycles (C). Dose was escalated from 20 mg/m2 on C1 D1-D2 to 27 mg/m2 on D8 of C1 and if tolerated, further to 56 mg/m2 on D1 of C2. Norm hepatic function defined as bilirubin and aspartate aminotransferase (AST) levels </=upper limit of normal (ULN). HI defined as mild: bilirubin >1-1.5 x ULN, or AST >ULN but with bilirubin </=ULN; Mod: bilirubin >1.5-3 x ULN with any AST; or severe: bilirubin >3 x ULN and any AST. The primary objective was to assess the effect of HI on area under the curve (AUC) from time 0 to the last concentration measured (AUC0-last) and from time 0 extrapolated to infinity (AUC0-inf) of carfilzomib. Secondary objectives included evaluation of carfilzomib maximum plasma concentration (Cmax), time to maximum concentration (Tmax), clearance (CL), terminal half-life (T1/2), volume of distribution at steady state (Vss), mean residence time (MRT), and safety and tolerability, as well as PK parameters for carfilzomib's major metabolites. Plasma for analysis of PK parameters were collected on C1D16 for carfilzomib 27 mg/m2 and on C2D1 for the 56 mg/m2 dose. PK parameters were evaluated using a non-compartmental approach. The carfilzomib PK in HI patients was compared with Norm patients using summary statistics and analysis of variance. Due to enrollment challenges and lack of demonstrable efficacy with carfilzomib monotherapy, enrollment of severe HI patient (mostly advanced solid tumors) was discontinued. Results: 11 Norm, 17 Mild, 14 Mod, and 4 severe patients were enrolled; 61% male, mean age 62 years. Of these patients, 10 Norm, 14 Mild, 9 Mod, and 0 severe HI patients were PK evaluable. Following carfilzomib 27 and 56 mg/m2, considerable PK variability was seen within each of the treatment groups, with an overlapping exposure observed between groups (Table 1). Median Tmax ranged from 0.29 to 0.48 hour with peak concentrations of carfilzomib most often observed at 15 minutes after start or immediately before the end of infusion. Thereafter, concentrations of carfilzomib declined rapidly with a mean T1/2 of approximately 0.5 to 0.7 hour in all patient groups. A dose-dependent increase in mean AUC and Cmax of carfilzomib was observed between 27 mg/m2 and 56 mg/m2 in all 3 patient groups (Table 1); however, there was no consistent trend of increasing exposure (AUC0-last, AUC0-inf, and Cmax) with increasing severity of HI (Table 1 and 2). The mean AUC of the most abundant metabolite, PR-389/M14 was similar across all groups. A mean increase of approximately 60%-80% was observed for M15 and M16 AUC0-last, AUC0-inf and Cmax in patients with Mod HI vs Norm patients. These metabolites have no known biological activity. Median duration of exposure was 6 (Norm), 4.3 (Mild), 2.3 (Mod), and 0.8 (severe) wks. Thirty-five (76%) patients had grade >/=3 adverse events (AEs) including 15 patients with treatment-related grade >/=3 AEs. Grade >/=3 increased blood bilirubin (22%; Mod HI patients only), anemia (15%), fatigue (15%), and increased alanine aminotransferase (9%; Mod HI patients only) occurred in >3 patients. Conclusions: No marked differences in exposures (AUC and Cmax) were observed between Norm patients and mild/Mod HI patients following carfilzomib doses of 27 and 56 mg/m2.No consistent trend in carfilzomib exposure related to HI severity was seen. With the exception of the increased frequency of AEs consistent with hepatic function abnormalities, the observed AE profile in this study was consistent with the known safety profile of carfilzomib. HI did not appear to substantially increase severity of AEs; however, the number of patients was limited. Based on the results in this study, no carfilzomib dose adjustment appears to be warranted in patients with relapsed or progressive advanced malignancies and mild or Mod HI. Disclosures Anthony: Spectrum Pharmaceuticals: Speakers Bureau; Paradigm Diagnostics: Consultancy. De Vos:European Organization for Research and Treatment of Cancer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dutch Working Group Neuro-Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; University Medical Center Utrecht: Employment. White:Amgen: Employment. Schupp:Amgen Inc.: Employment, Equity Ownership. Ou:Amgen: Employment, Equity Ownership.

scholarly journals Pharmacokinetic and Pharmacodynamic Properties of Romiplostim

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1463-1463
Author(s):  
Karen Arkam ◽  
Sameer Doshi ◽  
Bing-Bing Yang
Keyword(s):  
Healthy Volunteers ◽  
Healthy Subjects ◽  
Immune Thrombocytopenia ◽  
Receptor Complex ◽  
Platelet Response ◽  
Employment Equity ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership ◽  
Chronic Immune Thrombocytopenia

Abstract Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts, resulting from increased platelet destruction and inadequate platelet production. Romiplostim is a 59 kDa peptibody which binds to and activates the thrombopoietin (TPO) receptor on platelet precursors in the bone marrow, and increases platelet counts. This analysis integrates the pharmacokinetic (PK) and pharmacodynamic (PD) properties of romiplostim in animals, healthy volunteers and patients with ITP, and describes its intricate PK-PD inter-relationship. Methods and Results: In healthy subjects, over a wide range of doses examined, the PK and PD (platelet response) of romiplostim were dependent on both the dose administered and the baseline platelet counts. Following SC administration, platelet counts increased in a dose-dependent fashion after 4 to 9 days, peaking at 12 to 16 days (Wang Clin Pharmacol Ther. 2004;76:628-38). When romiplostim binds to the TPO receptor on megakaryocytes and platelets, the peptibody-receptor complex is internalized and degraded inside the cells. Therefore, as platelet counts increase, a higher number of free receptors are available to clear romiplostim (Wang AAPS J. 2010;12:729-40). Results from rodent studies suggest that as the dose increases, the TPO receptors become saturated and the contribution of the kidney to clearance increases. Additionally, proteolysis plays a role in the clearance of romiplostim; however, the cytochrome P450 enzymes are not involved in protein catabolism (Wang Pharm Res. 2011;28:1931-8), hence there are no known drug-drug interactions or dietary restrictions (Nplate Prescribing Information 2014). Following SC administration, serum concentrations of romiplostim were markedly lower, however, platelet response was similar after the same dose of intravenous (IV) and SC administration (Wang Clin Pharmacol Ther. 2004;76:628-38). This suggests that the PD response is driven by the length of time that the romiplostim concentrations remained above a threshold rather than by the magnitude of concentrations achieved. This effect was verified in a mechanistic PK-PD modeling study in animals (Krzyzanski Pharm Res. 2013;30:655-69). In patients with ITP receiving SC romiplostim at a dose of 1 mcg/kg, the peak platelet response was achieved at 18 days (range 8 to 43; Bussel N Engl J Med. 2006;355:1672-81). Pharmacodynamic model analysis showed that compared with healthy subjects, patients with ITP had a shorter platelet life span and a decreased rate of production of progenitor cells, but no major difference in the time to maturation of megakaryocytes. The PD response in this modeling analysis was not notably affected by age, body weight, sex, and race (Perez-Ruixo J Clin Pharmacol. 2012;52:1540-51). The frequency of once-weekly dosing was selected because once every 2 weeks dosing was determined to be inadequate to achieve and maintain platelet counts in the therapeutic range (Bussel N Engl J Med. 2006;355:1672-81). A mechanistic PK-PD model based on data from the healthy subjects further suggested that weekly dosing resulted in a sustained platelet response while dosing less frequently resulted in high fluctuation of platelet counts (Wang AAPS J. 2010;12:729-40). Large inter- and intra-individual variability in the PD response was observed at a given dose; therefore, dose adjustments should be made based on a patient's platelet counts, using a titrated dosing scheme to prevent having platelet counts over 400 x 109/L (Perez-Ruixo J Clin Pharmacol. 2012;52:1540-51). Conclusion: Romiplostim is a peptibody that binds and activates the TPO receptor, and consequently increases platelet production in individuals with chronic ITP. The peptibody-receptor complex is internalized and degraded inside the cells, without involvement of the liver. Romiplostim's PD response is driven by the length of time that its concentrations remained above a threshold rather than by the magnitude of concentrations achieved. Moreover, weekly dosing has demonstrated a sustained platelet response while less frequent dosing resulted in fluctuating platelet counts. Disclosures Arkam: Amgen Inc.: Employment, Equity Ownership. Off Label Use: Romiplostim is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This abstract also describes PK data from healthy volunteers.. Doshi:Amgen Inc.: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership.

scholarly journals ASLAN003, a Novel and Potent Dihydroorotate Dehydrogenase (DHODH) Inhibitor, Induces Differentiation of Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4047-4047 ◽  
Author(s):  
Jianbiao Zhou ◽  
Jessie Yiying Quah ◽  
Jing Yuan Chooi ◽  
Sabrina Hui-Min Toh ◽  
Yvonne Ng ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Lines ◽  
Research Funding ◽  
Tissue Bank ◽  
Dihydroorotate Dehydrogenase ◽  
Employment Equity ◽  
Healthy Control ◽  
Equity Ownership ◽  
Nbt Reduction

Abstract Background: Differentiation therapies achieve remarkable success in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, clinical benefits of differentiation therapies are negligible in non-APL AML, which accounts for the majority of AML cases. Dihydroorotate dehydrogenase (DHODH) regulates the fourth step of the de novo pyrimidine synthesis pathway. DHODH is a key therapeutic target for auto-immune diseases and cancer, particularly differentiation of AML. ASLAN003 is a novel, potent small molecule DHODH inhibitor being developed in AML by ASLAN Pharmaceuticals. Methods: We investigated activity of ASLAN003 in AML cell lines and primary bone marrow (BM) cells (NUS Leukemia Tissue Bank) from patients with AML (N = 14) or myelodysplastic syndromes (MDS) (N = 6) and healthy control (N = 1). We performed CTG assay, FACS analysis of cell viability and myeloid markers, wright-giemsa staining, NBT reduction assay, and qRT-PCR analysis of key lineage transcription factors to evaluate the effects of ASLAN003 on cell growth, differentiation, apoptosis, and gene expression changes in vitro. Two AML cell lines and 1 leukemic patient derived xenograft (PDX) line (NUS Leukemia Tissue Bank) were studied in NSG xenograft mice. Mice were administrated with vehicle control or ASLAN003 50 mg/kg by oral gavage once daily. Results: ASLAN003 inhibited leukemic cell growth of THP-1, MOLM-14 and KG-1 with IC50 of 152, 582 and 382 nM, respectively, at 48 h. Treatment of these leukemia cells with ASLAN003 for 96 h consistently resulted in remarkable increase of CD11b (p < 0.001) and displayed morphologic changes of terminal differentiation and positivity for NBT reduction. ASLAN003 was active in differentiation with an EC50 of 28, 85, and 56 nM, in these 3 lines, respectively. ASLAN003 induced approximately 2-fold higher CD11b+ cells than Brequinar (BRQ), another DHODH inhibitor. Addition of uridine rescued differentiation and improved cell viability in ASLAN003 treated-cells, implying on-target specificity of ASLAN003. Mechanistically, ASLAN003 induced differentiation through induction of myeloid lineage transcription factor Runx1, Pu.1, Gif1 and repression of HoxA9, Gata1. The response of primary BM cells to ASLAN003 was classified into 3 categories: sensitive if any of myeloid markers CD11b, CD14, CD13 or CD33 increased ≥ 15%; moderate: ≥ 5%, but < 15%; resistant: < 5%. Among AML samples, we observed 6 (43%) sensitive cases, 6 (43%) moderate cases and 2 (14%) resistant cases. Three (50%) MDS samples displayed sensitive response and 3 cases (50%) showed moderate response. The healthy control sample was resistant to ASLAN003. Importantly, ASLAN003 promoted differentiation and cell death of myeloid cells in one relapsed AML case. Morphologic analysis and NBT assay demonstrated the features of neutrophil differentiation in selected ASLAN003-treated primary AML blasts. For in vivo experiments, significantly prolonged survival was seen in ASLAN003-treated groups when compared to vehicle control group in both MOLM-14 (p = 0.031) and THP-1 (p < 0.001) xenograft models. ASLAN003 substantially reduced disseminated tumors and leukemic infiltration into liver in xenografted mice. The human CD45+ cells were significantly reduced in BM, peripheral blood, spleen and liver, with significantly increased differentiation of AML cells (CD11b and CD14 positive cells) in BM of treated mice in both models (p < 0.01). We also evaluated the therapeutic efficacy of ASLAN003 in one PDX line, AML-14. At the end of experiments (day 77 post treatment), all PDX mice were alive in both control and ASLAN003 group. The leukemic burden was significantly lower in ASLAN003-treated PDXs than in vehicle-treated PDXs (p = 0.04). Overall, these data demonstrate potent in vivo efficacy of ASLAN003 in inducing myeloid differentiation of blast cells and the drug appears highly tolerable even after prolonged administration. Conclusion: ASLAN003 is a novel, highly potent DHODH inhibitor that induces terminal differentiation, inhibits cell growth and promotes cell death of AML blasts, including relapsed AML blasts. ASLAN003 prolongs survival and shows therapeutic effects in mice bearing different AML cell lines and reduces leukemic burden in an AML PDX model. Currently, ASLAN003 efficacy is being evaluated in a Phase IIa clinical trial in patients with AML (NCT03451084; Ting, ASH abstract 2018). Disclosures Seet: ASLAN Pharmaceuticals: Employment, Equity Ownership. Ooi:ASLAN Pharmaceuticals: Employment, Equity Ownership. Lindmark:ASLAN Pharmaceuticals: Employment, Equity Ownership. McHale:ASLAN Pharmaceuticals: Employment, Equity Ownership. Chng:Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Aslan: Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.

Analysis of the IDH1G105 (SNPrs11554137) Polymorphism in 961 AML Patients and in a Large Cohort of 475 Healthy Controls

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2518-2518
Author(s):  
Susanne Schnittger ◽  
Christiane Eder ◽  
Tamara Alpermann ◽  
Thomas Illig ◽  
Norman Klopp ◽  
...  
Keyword(s):  
Minor Allele ◽  
Adverse Impact ◽  
Favourable Effect ◽  
Intermediate Risk ◽  
Control Cohort ◽  
Employment Equity ◽  
Male Ratio ◽  
Healthy Control ◽  
Major Allele ◽  
Equity Ownership

Abstract Abstract 2518 Introduction: Mutations in IDH1 and IHD2 at arginines 132 and 140 or 172, respectively, have recently been shown to play an important role in AML. Also the IDH1105GGT minor allele of the IDH1G105 (SNPrs11554137) polymorphism that is localized in the same exon as the IDH1R132 mutation has recently been reported to be an adverse prognostic factor in AML (JCO: 14, 2356–2364, 2010). Aim: We aimed at further delineating the frequency and impact of the IDH1105GGT minor allele in AML and also analyzed a healthy control cohort. Methods:IDH1G105 (SNPrs11554137) was analyzed in 961 AML patients by a LightCycler-based melting curve assay. Female/male ratio was 433/528 and age ranged from 13.1–100.4 years (median, 66.7 years). The results were compared to a healthy control cohort from the KORA (Cooperative Health Research in the Region of Augsburg) survey S4, which consists of 475 cases who where matched to the leukemia samples with respect to sex (193f/282m) and age (median: 67, range 32–81 years). Informed consent for participation in anonymized genetic studies was obtained from all individuals. IDH1G105 in the healthy cohort was analyzed by Sanger sequencing. Further mutation analyses were available in subsets of the AML patients, respectively, as follows: (IDH1R132 n=625, IDH2R140 n=587, IDH2R172 n=590, FLT3-ITD n=629, FLT3-TKD n=503, NPM1 n=628, CEBPA n=587, RUNX1 n=231, MLL-PTD n=629, NRAS n=273, KRAS n=133, ASXL1 n=470) and were analyzed as described previously. A subcohort of 634 AML with intermediate risk karyotype was analyzed for survival. Female/male ratio of this subcohort was 280/354 and age ranged from 15.7–86.6 years (median, 66.9 years). The adverse impact of IDH1R132, IDH2R140 and IDH2R172 on the NPM1+/FLT3-ITD- group has been shown previously for this group (Blood 2010 116: Abstract 102). Results: The IDH1105GGT minor allele was detected in 11.2% (108/961) in AML and in 8.8% (42/475) of the KORA control. This slight difference does not reach statistical significance (p=0.17) and thus there is no indication that this variance is a predisposing factor for leukemia. Also the frequency of a homozygous IDH1105GGT minor allele was not different between the AML cohort (3/108, 2.8%) and the KORA cohort (2/42, 4.8%, n.s.). In the AML cohort there was no association of the IDH1105GGT minor allele with age, WBC, platelet count or any of the above mentioned molecular mutations. In contrast, some differences in survival were observed: patients with the IDH1105GGT minor allele had a longer event free survival (EFS) than those with the IDH1105GGC major allele (median: 30.1 vs. 21.6 months, p=0.052) in the intermediate risk cohort. This prognostically favourable effect of the IDH1105GGT minor allele was most prominent in the NPM1+/FLT3- group with a median EFS of 45.1 vs 23.5 months as compared to those with the IDH1105GGC major allele (p=0.015). Conclusions: 1) The polymorphic IDH1105GGT minor allele was not found to be a marker predisposing for AML. 2) No association of the IDH1105GGT minor allele to any mutation or other biological parameters was detected. 3) We were not able to reproduce the previously published adverse impact of the IDH1105GGT minor allele on survival in AML. In contrast, in our cohort of 475 patients with intermediate risk AML the EFS was even better in patients carrying the IDH1105GGT minor allele, especially in the subcohort with NPM1+/FLT3−ITD−. Thus, we would suppose that the IDH1105GGT minor allele is a favorable molecular marker in intermediate risk AML. However, as these findings are in contrast to previously published data, further confirmation in additional studies is necessary to draw firm conclusions on the utility of the IDH1105 polymorphism as a marker for diagnostics and prognosis in AML. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Serum Mir-4254, Mir-19a and Mir-33b Are Potential Markers For Diagnosis and Prognostic Evaluation In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3222-3222 ◽  
Author(s):  
Mu Hao ◽  
Meirong Zang ◽  
Qin Yu ◽  
Li Fei ◽  
Wenjuan Yang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Roc Curve ◽  
Diagnostic Tool ◽  
Healthy Subjects ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Prognostic Evaluation ◽  
Control Subjects ◽  
Healthy Control ◽  
Powerful Diagnostic Tool

Abstract Introduction A sensitive, noninvasive diagnosis and better disease classification would be very useful for improve the outcome of multiple myeloma. In this study, we proposed a microarray based biology approach to identify miRNAs as new biomarkers for the diagnosis and prognostic evaluation of multiple myeloma. Methods and Results Microarray-based miRNAs expression profiling data indicated that 95 mature miRNAs were differentially expressed between myeloma patients (n=7) and healthy subjects (n=5, fold change>3.0 with P<0.01). The decrease of miR-19a/miR-92a (P<0.0001) and the increase of miR-214, 135b, 4254, 3658 and 33b (P<0.05) in myeloma patients were further validation confirmed by Q-PCR. The expression pattern of these miRNAs (miR-19a, miR-92a, miR-214, miR-135b, miR-3658, miR-4254 and miR-33b) were further detected by Taqman probes Q-PCR in 84 newly diagnosed patients, 34 cases in remission, 40 relapsed patients and 34 healthy controls. The data showed the expression of miR-19a (1.39±0.33 vs 2.56±0.18) and miR-92a (0.35±0.20 vs 1.73±0.13) were significantly lower in newly diagnosed patients compared with healthy control subjects (all P<0.05).Whereas, miR-214 (1.68±0.12 vs 1.08±0.10), miR-135b (2.25±0.28 vs 0.01±0.05), miR-4254 (1.11±0.09 vs -0.21±0.16), miR-3658 (2.26±0.29 vs 0.47±0.09) and miR-33b (2.71±0.24 vs 2.03±0.39) were significantly higher in patients than the healthy subjects (all P<0.001). Among these miRNAs, the expression of miR-19a, miR-4254 and miR-33b were closely associated with disease progressions. The expression of miR-19a in healthy control subjects and patients in remission were significantly higher than that in newly diagnosed and relapsed patients. While miR-4254 and miR-33b were significantly lower in healthy subjects and CR patients compared to newly diagnosed and relapsed patients. ROC (receiver operating characteristic) analysis was conducted in this study and the results showed that serum miR-4254 yielded an AUC (area under the ROC curve) of 0.9261 (P<0.001) with 79.3% sensitivity and 98.5% specificity for discriminating myeloma patients from healthy controls at a cut-off value of 0.66 (RQ value). Therefore, use of miR-4254 alone provides an excellent discrimination between healthy subjects and myeloma patients. Similarly, serum miR-19a is also a potential marker with an AUC of 0.722 ( P<0.001). At a cut-off value of 2.08 (RQ value), the sensitivity for miR-19a was 77.30% and the specificity was 70.00%. However, the AUC of miR-33b was 0.63 (P<0.05). At a cutoff value of 1.015 (RQ value), the sensitivity for miR-33b was 84.10% and the specificity was 61.0%. miR-33b is not a reliable independent marker to discriminate myeloma patients from healthy controls. Then we preformed PLS-DA in various miRNA biomarkers and found that the combination of miR-4254 and miR-19a together was an even more powerful diagnostic tool for myeloma distinguishing. The ROC curve of the classifier had an AUC of 0.950 (P<0.05). miR-4254 combined with miR-33b provided the same powerful diagnostic tool for myeloma. Moreover, Kaplan-Meier survival analysis showed that patients with higher expression of miR-19a or miR-33b had significantly favorite PFS and OS than those with low expression. However, our data did not show the expression of miR-4254 correlated with favorite survival in myeloma patient. Conclusion Serum miR-4254, miR-19a and miR-33b are novel, non-invasive, sensitive and reliable biomarkers for multiple myeloma diagnosis and prognosis evaluation. Footnotes * Asterisk with author names denotes non-ASH members. Disclosures: No relevant conflicts of interest to declare.

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