Population Pharmacokinetics of Ivosidenib (AG-120) in Patients with IDH1-Mutant Advanced Hematologic Malignancies

Abstract BACKGROUND: Ivosidenib, a potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is being assessed in a phase 1 study of mIDH1 advanced hematologic malignancies (NCT02074839). We characterized the pharmacokinetics (PK) of ivosidenib in this population, and the effects of patient/disease characteristics and concomitant medications. METHODS: Ivosidenib was given in continuous 28-day cycles at 100 mg twice daily and 300 mg, 500 mg, 800 mg, and 1200 mg once daily (QD). Enrollment is complete; 258 patients received ≥1 ivosidenib dose (78 in escalation, 180 in expansion); samples were available from 253 patients (223 received ivosidenib 500 mg QD). Ivosidenib concentrations were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based methods. Population PK modeling was conducted using NONMEM software. The impact of demographics, renal and hepatic function, disease type, Eastern Cooperative Oncology Group (ECOG) performance status, and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors/inducers and gastric acid reducers on ivosidenib PK was explored. RESULTS: Ivosidenib PK were best described using a 2-compartment model with first-order absorption, dose-dependent bioavailability, and a time-dependent change in relative bioavailability and clearance between Day 1 and steady state. Mean steady-state apparent clearance (CL/F) was 5.39 L/h (between-patient variability ~35%) and mean central volume of distribution (Vc/F) was 234 L (~47%). Less than dose-proportional bioavailability was observed, with a dose doubling translating to a ~40% increase in exposure. The moderate/strong CYP3A4 inhibitors voriconazole, fluconazole, and posaconazole were associated with 36%, 41%, and 35% reductions in CL/F, and hence 57%, 69%, and 53% increases in area under the plasma ivosidenib concentration-time curve (AUC), respectively (Figure 1). Baseline body weight had a significant impact on Vc/F. Low albumin at baseline and during treatment correlated with decreased CL/F and Vc/F. However, the effects of body weight and albumin did not appear to be clinically relevant. No effects of creatinine clearance or measures of liver function (alanine aminotransferase, aspartate aminotransferase, bilirubin, within the range studied) on ivosidenib CL/F were detected. Concomitant use of pantoprazole or famotidine did not affect ivosidenib CL/F. CONCLUSION: This population PK model of ivosidenib suggests that no dose adjustments are needed based on the range of patient and disease characteristics analyzed. Disclosures Le: Millennium: Patents & Royalties; Agios: Employment, Equity Ownership. Wada:Certara: Employment; Agios: Consultancy. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Yang:Agios: Employment, Equity Ownership.

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Population Pharmacokinetic (PK)/Pharmacodynamic (PD) Modeling of Myelosuppression in Patients with Hematologic Malignancies for CPX-351 and Standard-of-Care 7+3 Therapy

Blood ◽

10.1182/blood-2018-99-111918 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4037-4037

Author(s):

Qi Wang ◽

Sarah F. Cook ◽

Scott A. Van Wart ◽

Donald E. Mager ◽

Stefan Faderl

Keyword(s):

Platelet Count ◽

Median Time ◽

Median Duration ◽

Model Development ◽

Hematologic Malignancies ◽

Employment Equity ◽

Compartment Models ◽

Platelet Counts ◽

Population Pk ◽

Equity Ownership

Abstract CPX-351 (Vyxeos®), a liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, has demonstrated a significant survival benefit vs standard 7+3 in patients (pts) with high-risk/secondary AML. A population PK/PD analysis assessed the correlation between cytarabine and daunorubicin plasma concentrations and myelosuppressive effects (neutropenia, thrombocytopenia) of CPX-351 and 7+3. The PK/PD population for model development included pts with advanced hematologic malignancies from 3 clinical studies. For CPX-351 and 7+3, respectively, 129 and 79 pts were included in the final neutropenia PK/PD analysis and 137 and 86 pts were included in the final thrombocytopenia PK/PD analysis. For the neutropenia model, median age and body weight were 67 y (range: 23-81) and 78.7 kg (39.5-156.5) for CPX-351 and 68 y (60-75) and 83.0 kg (53.9-136.0) for 7+3. PK/PD analyses were conducted using nonlinear mixed-effects modeling in NONMEM. Pt-specific PK profiles were simulated using previously developed population PK models for CPX-351 and 7+3. Blood cell dynamics were described by transit-compartment models with proliferating, maturating, and circulating neutrophils or platelets. The effects of CPX-351 or 7+3 were applied to the proliferation phases of the compartment models by a molar composite PK driver (plasma cytarabine + daunorubicin). Inhibition of proliferation of blood cells by CPX-351 and 7+3 is assumed to be similar, via a sigmoidal Imax function. Co-medication of granulocyte colony stimulating factor (GCSF) or platelet infusion was accounted for during model development. Covariates (eg, demographics, clinical laboratory measures, disease status) were evaluated. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and graphical representations of goodness-of-fit. In the final neutrophil PK/PD models, baseline circulating neutrophil counts were similar for CPX-351 (3.55 × 109/L) and 7+3 (3.76 × 109/L). Mean transit times (MTT) between maturation compartments were estimated at values of 113 h for CPX-351 and 88 h for 7+3. Effects of GCSF on neutrophil production were assumed to be similar for CPX-351 and 7+3. Both treatments had similar maximum inhibition on neutrophil proliferation, with Imax values around 1. However, estimated IC50 values were very different: 24.9 µM for CPX-351 and 0.0286 µM for 7+3. In the final platelet PK/PD models, baseline circulating platelet counts were the same (98.1 × 109/L) for both CPX-351 and 7+3. The MTTs between each compartment of the maturation processes were 91.2 h for CPX-351 and 120 h for 7+3. Drug-specific parameters for CPX-351 and 7+3, respectively, were as follows: Imax, 0.316 and 1; IC50, 0.324 and 0.0982 µM. To better understand the behavior of the models and parameter estimates, simulations were conducted to evaluate the temporal events of myelosuppression. Model simulations were conducted for 200 pts with characteristics similar to the PK/PD model population. During simulations, no platelet transfusion or GCSF was administered. Pts received CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) as a 90-min IV infusion on Days 1, 3 and 5 or 7+3 (cytarabine 100 mg/m2/day IV for 7 days continuously + daunorubicin 60 mg/m2 IV on Days 1-3). Median time to initially observe a blood neutrophil count <0.5 × 109/L was longer following CPX-351 (8.3 d) vs 7+3 (7.4 d) treatment. The median duration with neutrophil counts <0.5 × 109/L was longer with CPX-351 (23 d) vs 7+3 (14 d). The median lowest neutrophil counts were well below 0.2 × 109/L for both CPX-351 (0.007 × 109/L) and 7+3 (0.026 × 109/L). Median time to initially observe a platelet count <50 × 109/L was 6.4 d after CPX-351 and 5.8 d after 7+3, while the median time to an observed platelet count <20 × 109/L was 10.8 d and 8.9 d, respectively. The median duration with platelet counts <20 × 109/L was longer with CPX-351 (18 d) vs 7+3 (8 d), and the median duration of platelet counts <50 × 109/L was 22 d and 15 d, respectively. The median lowest platelet counts were 11.3 × 109/L with CPX-351 and 4.7 × 109/L with 7+3. In summary, the median duration of myelosuppressive effects was longer with CPX-351 than 7+3, and the median time for initial detection of myelosuppression with CPX-351 was 1 to 2 days later than with 7+3, which might affect the clinical monitoring scheme. Disclosures Wang: Jazz Pharmaceuticals: Employment, Equity Ownership. Cook:Jazz Pharmaceuticals: Consultancy. Van Wart:Jazz Pharmaceuticals: Consultancy. Mager:Jazz Pharmaceuticals: Consultancy. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership.

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Novel Population Pharmacokinetic Modeling of Arabinosyl Cytosine Triphosphate: Insights On Potential Preferential Formation of Ara-CTP Directly From Elacytarabine As Well As From Ara-C

Blood ◽

10.1182/blood.v120.21.3547.3547 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3547-3547

Author(s):

Corinne Seng Yue ◽

Varsha V. Gandhi ◽

Susan O'Brien ◽

Farhad Ravandi ◽

Tove Flem Jacobsen ◽

...

Keyword(s):

Cancer Cells ◽

Research Funding ◽

Hematologic Malignancies ◽

Employment Equity ◽

Cholesterol Levels ◽

Population Pk ◽

Equity Ownership ◽

Quality Of Fit ◽

Arabinosyl Cytosine

Abstract Abstract 3547 Objectives: Elacytarabine (CP-4055) is an elaidic acid ester of arabinosyl cytosine (Ara-C), administered as a liposomal formulation, that is being developed to treat hematologic malignancies. CP-4055 is metabolized to Ara-C, which is transformed intracellularly to active arabinosyl cytosine triphosphate (Ara-CTP) and inactive deaminated metabolite arabinosyl uracil (Ara-U). The present analysis aimed to elucidate the pharmacokinetics (PK) of Ara-CTP and identify its relationship with CP-4055, Ara-C, Ara-U and various blood parameters measured in the target patient population. Methods: Patients suffering from hematologic malignancies, including refractory/relapsing acute myeloid leukemia (AML), who participated in Phase I or II CP-4055 trials, were included in this analysis. CP-4055 monotherapy was given as an intravenous infusion over 2 h/day for 5 days, 4 h/day for 5 days or continuously over 120 hours at doses ranging from 200 to 2500 mg/m2/day. Blood samples were collected at various time-points (until 168 hours post-dose) and plasma was assayed for CP-4055, Ara-C, and Ara-U using a validated LC-MS/MS method. Ara-CTP was measured by HPLC in isolated leukemic blast cells from AML patients. Cholesterol levels were also measured. Population PK analyses were conducted using the iterative two-stage method in ADAPT 5®. First, a model was determined for cholesterol, which was incorporated into a PK model for CP-4055, Ara-C and Ara-U. Individual PK parameters from this model were fixed and then used for the analysis of Ara-CTP. For Ara-CTP modeling, 1-compartment (cpt) models were tested with various routes of formation. For all models, model discrimination was performed using standard criteria (residual variability, quality of fit graphs, Akaike information criterion test). Results: In the cholesterol analysis, 13 patients (57 concentrations) were included while 43 patients (around 27 concentrations per patient) were included in the modeling of CP-4055, Ara-C and Ara-U. A subset of 17 patients (46 concentrations) was part of the Ara-CTP analysis. Cholesterol was described by an indirect model with a rate of elimination and a rate of formation that was increased by phospholipids infused along with CP-4055. CP-4055 PK was best described by a 2-cpt model, where the central cpt was partitioned into 2 sub-cpts. The first sub-cpt represented a lipid depot cpt where liposomal-bound CP-4055 was infused, and which transferred CP-4055 into the other sub-cpt, which represented CP-4055 released from liposomes. The transfer of CP-4055 from the liposomes was unidirectional and saturable, and cholesterol level influenced the size of the second sub-cpt. Ara-CTP appeared to be formed from unbound CP-4055, presumably within cancer cells, and was also formed as expected from Ara-C which was best described by a 2-cpt model, while Ara-U followed a 1-cpt model with an elimination that was dependent upon creatinine clearance. The proposed model is depicted below. Based on the model, terminal elimination half-life values for CP-4055, Ara-C, Ara-U and Ara-CTP were around 9, 68, 5 and 3 hours, respectively, and were independent of dose and infusion time. Residual variabilities for cholesterol, CP-4055, Ara-C, Ara-U and Ara-CTP were 21.0%, 34.0%, 39.4%, 12.5% and 29.2%, respectively. Conclusions: For the first time, a population PK approach was used to describe the PK of a triphosphate metabolite in relation to a parent drug as well as other metabolites. Indeed, the novel multi-cpt model developed herein simultaneously described and explained the PK of cholesterol, elacytarabine, Ara-C, Ara-U and Ara-CTP. The inclusion of cholesterol levels in the model improved the overall quality of fit, especially for administered liposomal-elacytarabine. The proposed PK model describing Ara-CTP disposition suggests that Ara-CTP is formed not only from Ara-C but also from elacytarabine, presumably within cancer cells, although the exact mechanism is unknown. Disclosures: Seng Yue: Learn and Confirm: Employment; Clavis Pharma: Consultancy. Gandhi:Clavis Pharma: Research Funding. O'Brien:Clavis Pharma: Research Funding. Ravandi:Clavis Pharma: Research Funding. Jacobsen:Clavis Pharma: Employment, Equity Ownership. Dirven:Clavis Pharma: Employment. Hagen:Clavis Pharma: Employment, Equity Ownership. Hals:Clavis Pharma: Employment. Ducharme:Learn and Confirm: Employment, Equity Ownership; Clavis Pharma: Consultancy.

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Age Differences in Disease Characteristics, Patterns of Care, and Outcomes of Follicular Lymphoma (FL) in the United States (US): Report From the National Lymphocare Study (NLCS)

Blood ◽

10.1182/blood.v120.21.3708.3708 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3708-3708

Author(s):

Chadi Nabhan ◽

Michelle Byrtek ◽

Shadi Latta ◽

Keith L Dawson ◽

Xiaolei Zhou ◽

...

Keyword(s):

Research Funding ◽

Age Groups ◽

Age Group ◽

Employment Equity ◽

Disease Characteristics ◽

Baseline Factors ◽

Equity Ownership ◽

Grade 3 ◽

The Impact ◽

To Receive

Abstract Abstract 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

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Impact of Amotosalen/UVA Pathogen Inactivated Platelet Components on Outcomes after Allogeneic Hematopoetic Stem Cell Transplantation: A Single Center Analysis

Blood ◽

10.1182/blood-2019-122330 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1167-1167

Author(s):

Andreas S. Buser ◽

Laura Infanti ◽

Andreas Holbro ◽

Joerg Halter ◽

Sabine Gerull ◽

...

Keyword(s):

Stem Cell ◽

Cox Regression ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Disease Status ◽

Risk Scores ◽

Employment Equity ◽

Stem Cell Source ◽

Equity Ownership ◽

The Impact

Background: Platelet component (PC) transfusion is required for allogeneic hematopoietic stem cell transplantation (HCT) recipients. Contamination with infectious pathogens (bacteria, viruses, or protozoa) and T-cells is a risk factor for transfusion-transmitted infection (TTI) and transfusion associated graft-versus-host disease (TA-GVHD). Pathogen inactivation (PI) treatment of PC with amotosalen-UVA (PI-PC, INTERCEPT Blood System, Cerus Corp) in platelet additive solution (PAS) without bacterial screening, gamma irradiation, CMV serology, and with 7-day storage has been the standard of care in Switzerland since 2011 to manage risk of TTI and TA-GVHD. PI-PC have replaced conventional PC (C-PC) prepared in PAS with gamma irradiation and 5 day storage. We previously reported platelet usage in two consecutive five year periods at the University Hospital of Basel. Mean PI-PC dose was higher (3.0 vs. 2.8 x 1011, p=0.001) and mean storage duration longer (4.2 vs. 3.4 days: p=0.001) than with C-PC. PC expiration wastage was reduced with 7-day PI-PC storage vs. 5-day storage (1.5% vs. 8.7%). For HCT recipients, days of PC support; PC use per patient; and RBC use per patient were similar, despite 24.3% lower corrected count increments (CCI) with PI-PC. Now, we report the impact of these observations on treatment related mortality (TRM) and overall survival (OS) 100 days after HCT. Patients and Methods: A two-period retrospective cohort study was conducted to evaluate PI-PC impact on outcomes of consecutive first allogeneic HCT recipients from January 2006 to December 2010 (Period 1, P1), when gamma-irradiated apheresis C-PC were used, and Period 2 (P2) from January 2011 to December 2017, when apheresis and whole blood-derived PI-PC were used. The review utilized 100-day OS and 100-day TRM to determine the impact of PI-PC on HCT outcomes. Descriptive statistics were used for continuous variables and log-rank analysis for survival outcomes. Univariate analysis was performed using Pearson χ2 statistics. Multivariate Cox regression modelling analyses included: PC period (P1, P2), donor match (HLA identical/twin, matched related, matched unrelated), disease state (early, intermediate, late), and conditioning regimen (reduced intensity, myeloablative) with TRM as the outcome. This was an IRB approved single-center analysis. Results: In P1 and P2, 256 and 557 consecutive first-time allogeneic HCT recipients were included, respectively. By univariate analysis, the distribution of European Group for Bone Marrow Transplantation (EBMT) risk scores (grouped 0-2, 3-4, 5-7) and mean patient age were higher during P2 (p = 0.001 and p <0.001, respectively). Primary disease status (p = 0.039); stem cell source (p <0.001); GVHD prophylaxis with ATG (p <0.001); total body irradiation (p <0.001); and conditioning regimen (p <0.001) were different between P1 and P2. Donor match (p=0.084) and disease status (p = 0.628) were similar in P1 and P2. TRM at day 100 post HCT was significantly less (31/557, 5.5%) for PI-PC recipients in P2 vs. C-PC recipients in P1 (37/256, 14.5%, p<0.001). Overall proportion of survivors at day 100 post HCT was significantly greater for PI-PC recipients (507/557, 91.0 %) compared to C-PC recipients (209/256, 81.6%, p <0.001). By multivariate Cox regression analysis, P2 with PI-PC component support was associated with improved TRM (p = 0.001; adjusted hazard ratio 0.433; 95% confidence interval: 0.262, 0.716). Donor match (p = 0.019), disease state (p = 0.022), and myeloablative conditioning (p = 0.034) were associated with significantly poorer TRM (Table). Stem cell source was not significant (p=0.157) in the model. Hemorrhage was reported as cause of death in 1/50 (2.0%) patients during P2 with PI-PC and 4/47 (8.5%) patients during P1 with C-PCs. Conclusions: Universal implementation of PI-PC in routine with extended storage to 7 days in P2 was associated with reduced TRM and better overall survival 100 days post HCT, despite transplantation of older patients with higher EBMT risk scores. Multivariate analysis revealed an adjusted hazard ratio of 0.433 (95% C.I. 0.262, 0.716) for TRM by 100 days, suggesting better outcomes in P2. This retrospective analysis at a single site indicated that PI-PC treated with amotosalen /UVA stored up to 7 days did not have a negative impact on TRM and OS in HCT recipients, and was an integral part of improving clinical outcomes at our institution. . Table. Disclosures Heim: Novartis: Research Funding. Irsch:Cerus Corporation: Employment, Equity Ownership. Lin:Cerus Corporation: Employment, Equity Ownership. Benjamin:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership.

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Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02438-12 ◽

2013 ◽

Vol 57 (8) ◽

pp. 3470-3477 ◽

Cited By ~ 14

Author(s):

Mohamed A. Kamal ◽

Scott A. Van Wart ◽

Craig R. Rayner ◽

Vishak Subramoney ◽

Daniel K. Reynolds ◽

...

Keyword(s):

Steady State ◽

Time Course ◽

Demographic Data ◽

Visual Predictive Check ◽

Compartment Model ◽

Plasma Drug ◽

First Order ◽

Drug Concentrations ◽

Population Pk ◽

The Impact

ABSTRACTOseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individualpost hocpredictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2= 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.

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Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-131481 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5768-5768

Author(s):

Adekemi Taylor ◽

Martine Allard ◽

Cecile Kresja ◽

Dana Lee ◽

Greg Slatter

Keyword(s):

Multiple Myeloma ◽

Steady State ◽

Solid Tumors ◽

Upper Bound ◽

Myeloid Leukemia ◽

Employment Equity ◽

Equity Ownership ◽

The Mean ◽

The Relationship ◽

Mdm2 Inhibitor

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

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The Combined Safety and Tolerability Profile of Vorinostat-Based Therapy for Solid or Hematologic Malignancies.

Blood ◽

10.1182/blood.v114.22.1710.1710 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1710-1710 ◽

Cited By ~ 1

Author(s):

David Siegel ◽

Pamela N Munster ◽

Eric Rubin ◽

Marian Iwamoto ◽

Simon van Belle ◽

...

Keyword(s):

Cancer Patients ◽

Advanced Cancer ◽

Hematologic Malignancies ◽

Tolerability Profile ◽

Employment Equity ◽

Advisory Committees ◽

Common Drug ◽

Equity Ownership ◽

Grade 3 ◽

Dose Modifications

Abstract Abstract 1710 Poster Board I-736 Introduction Treatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. Methods Safety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events) In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval) A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was <10 msec at every timepoint, no patient had a QTcF change-from-baseline value >30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE) A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients (<5.8%) reported TEE as a serious AE (SAE), 47 (<2.6%) of which were recorded as being related to vorinostat, and 4/47 (<0.3%) TEE SAEs were fatal. Conclusions In this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. Disclosures Siegel: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

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Steady-State Imatinib Trough Levels as Well as Dose Interruptions Are Associated with Clinical Response (CCyR and MMR) and Adverse Events (AEs) in Patients with Chronic Myeloid Leukemia (CML) Receiving IM as Frontline Therapy.

Blood ◽

10.1182/blood.v114.22.2213.2213 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2213-2213

Author(s):

Richard A. Larson ◽

Yen Lin Chia ◽

Camille Granvil ◽

François Guilhot ◽

Brian J. Druker ◽

...

Keyword(s):

Steady State ◽

Clinical Response ◽

Cumulative Dose ◽

Research Funding ◽

Risk Scores ◽

Employment Equity ◽

Risk Patients ◽

Equity Ownership ◽

Grade 3 ◽

Trough Levels

Abstract Abstract 2213 Poster Board II-190 Background: Correlations between IM trough plasma levels (Cmin) and clinical response have been previously reported [Picard et al. Blood 2007; Larson et al. (IRIS) Blood 2008; Guilhot et al. (TOPS) ASH 2008]. This analysis correlates IM Cmin on Day 29 of initial treatment with complete cytogenetic response (CCyR) and major molecular responses (MMR) at 12 months and with cumulative Grade 3&4 toxicity over 12 months based on data pooled from 2 studies, IRIS (400 mg qd) and TOPS (400 mg bid (800 mg/daily) vs 400 mg qd), in newly diagnosed, previously untreated, Ph+ CML-CP. Methods: Steady-state Cmin was defined as predose blood level collected within ±3 hours of the scheduled dosing time on Day 29 without any dose interruptions within 5 days prior to PK sampling. The correlation between IM Cmin and CCyR and MMR at 12 months was studied by two approaches: 1) analysis of outcomes by quartile groups based on patients' IM Cmin levels; 2) logistic regression analysis with Cmin as a continuous variable plus Sokal risk scores and cumulative days with any dose interruptions during the initial 12 months. Safety parameters included Grade 3&4 AEs, as well as all frequently-occurring (>10%) AEs of any grade that occurred during the 12 months. Patients with missing covariates were excluded. Results: Steady-state IM Cmin trough levels were available in 526 patients: 319 in IRIS and 207 from TOPS. At the time of assessment most patients received either 400 mg or 800 mg; 8 patients received reduced doses (6 at 300 mg; 2 at 600 mg). The median IM Cmin [25-75% quartiles] for 400 mg in the pooled dataset was 943 ng/mL [688-1280 ng/mL], and that for 800 mg was 2910 ng/mL [2333-3900 ng/mL]. IM Cmin showed large inter-patient variability for both 400 mg and 800 mg dose groups (52.7% and 39.9%, respectively). Both CCyR and MMR rates at 12 months were significantly correlated with IM Cmin on Day 29. Besides Cmin on Day 29, Sokal risk scores and cumulative dose interruptions (due either to treatment-related toxicities or non-adherence) were significant covariates for 12 month CCyR and MMR. Patients with high Sokal scores (H) had lower CCyR and MMR rates than those with low Sokal scores (L), 64% (H), 69% (intermediate (I)), and 83% (L), respectively, for CCyR, and 37%, 48%, and 59%, respectively, for MMR. Response rates at 12 months were significantly lower for patients with cumulative dose interruptions > 28 days (in the first 12 months): 45% vs 76% for CCyR, and 27% vs 48% for MMR. Modeling predicts that at a Cmin level of 1000 ng/mL and assuming no or minimal dose interruptions, the CCyR at 12 months would be 85%, 78%, and 68% for L, I, and H Sokal risk patients, respectively, and for MMR 55%, 45% and 36%, respectively. If the Cmin were 2000 ng/mL, the CCyR at 12 months would be 93%, 89%, and 83% for L, I, and H Sokal risk patients, respectively, and for MMR 65%, 55% and 44%, respectively. The predicted CCyR and MMR would be lower if there were dose interruptions. Patients who had Grade 3&4 AEs over first 12 months period (n=136) had a higher IM Cmin on Day 29 (median [25-75% quartiles], 1985 [982-2943] ng/mL vs 1010 [728-1468] ng/mL, P<0.001), than those without (n=390) as well as longer cumulative dose interruptions (20 [8-41] days vs 0 [0-2] days, P<0.001), lower CCyR rate (66%; 77/117 vs 75%; 277/369, P=0.05), and lower MMR rate (37%; 49/131 vs 48%; 155/323, P=0.006). Most Grade 3&4 AEs were treatment-related hematologic AEs with median times to onset between 50-63 days. Regression analysis showed the correlation between hematologic Grade 3&4 AEs and IM Cmin level for the population (Figure). Among all-grade non-hematologic AEs, rash and vomiting were associated with higher IM Cmin levels. Conclusion: IRIS+TOPS pooled data confirmed earlier findings that higher steady-state IM levels correlate with better CCyR and MMR responses but also with more Grade 3&4 treatment-related toxicities. Dose interruptions compromise CCyR and MMR rates at 12 months. IM Cmin levels provide additional information together with clinical response and tolerability to inform dose changes for individual patients. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding. Chia:Novartis: Employment. Granvil:Novartis: Employment. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Nedelman:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment, Equity Ownership.

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Effects of Selectin Antagonist GMI-1070 on the Activation State of Leukocytes In Sickle Cell Patients Not In Crisis

Blood ◽

10.1182/blood.v116.21.2672.2672 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2672-2672

Author(s):

Scott I Simon ◽

Shannon Chase ◽

Sandra K Larkin ◽

Frans Kuypers ◽

Lori Styles ◽

...

Keyword(s):

Steady State ◽

Sickle Cell ◽

Fold Increase ◽

Employment Equity ◽

Blood Samples ◽

High Affinity ◽

Equity Ownership ◽

First Time ◽

Time Point

Abstract Abstract 2672 It is hypothesized that activated leukocytes play key roles in sickle cell vaso-occlusion by adhering to inflamed venules and capturing circulating platelets and sickle red blood cells. GMI-1070 is a small molecule selectin antagonist which was recently reported to reverse acute vascular occlusion in a humanized sickle cell disease (SCD) mouse model (Chang et al, Blood 2010) presumably by inhibiting E-selectin and its effects on downstream signaling of leukocyte activation. Sickle cell patients express elevated levels of soluble E-selectin (Kato et al, Brit J Haem 2005) activated polymorphonuclear neutrophils (PMN) (Lum et al Amer J Hem 2004) and platelet/monocyte aggregates (PMA) (Wun et al Clin Lab Haem 2002). In this study, the activation state of leukocytes from whole blood samples of sickle cell patients not in crisis before and after infusion of GMI-1070 was evaluated ex vivo. Isolated PMN from normal, healthy volunteers were strongly activated by binding soluble E-selectin/hIg in vitro as determined by a 7-fold increase of the integrin MAC1 (CD11b) and an 8-fold increase in expression of the high affinity form of CD18 detected by antibody 327C. Addition of GMI-1070 completely blocked upregulation of MAC1 and 327C at 50μg/ml and showed pronounced inhibition (79% MAC1; 75% 327C) at 10μg/ml. These in vitro concentrations are consistent with blood levels of GMI-1070 found in sickle cell patients 4 and 8 hours after dosing. A phase 1/2 study was conducted on 10 adult subjects with SCD at steady state. GMI-1070 was given IV at 20mg/kg as a loading dose and at 10 hours a final dose of 10mg/kg was given. Blood samples were drawn from these adults pre-infusion and at 8, 24, and 48 hours after the initial infusion. In some subjects, a blood sample was also drawn at 4 hours post infusion. Activation of PMN's in whole blood samples from subjects was assessed by upregulation of MAC-1, expression of the high affinity CD18 and the loss of CD62L due to shedding of L-selectin determined by flow cytometric analysis of cell surface labeling with fluorescently conjugated antibodies. Of 4 subjects tested, 3 showed increased surface expression of L-selectin, 3 showed decreased expression of MAC-1, and 2 showed decreased expression of high affinity CD11b at the first time point tested (4 or 8hr) after dosing with GMI-1070 suggesting an inhibition of PMN activation in these patients. A functional consequence of monocyte activation is the formation of platelet/monocyte aggregates due to expression of high affinity integrins. Platelet-monocytes aggregates (PMA) in blood were detected using anti-CD11c for monocytes and anti-CD41a for platelets. Treatment of samples with lipopolysaccharide (LPS) was used for positive controls. Intracellular IL-1β was used as a marker of activated monocytes. In 5 patients out of 6 tested with this assay, PMA in the subject's blood were decreased at the first time point after dosing (8hr). These results are consistent with an effect of GMI-1070 on inhibition of activation given its IC50 value for E-selectin (4.3μM), the blood concentration in subjects after dosing, and the serum half life (7.7hr) in steady state sickle cell adults. Conclusions: GMI-1070 significantly inhibited E-selectin-mediated activation of PMNs in vitro as determined by expression of the integrin MAC-1 and high affinity CD18 at 10μg/ml. Similar concentrations of GMI-1070 in sickle cell subjects' blood at 4 and 8 hours after dosing also resulted in a lowered activation state of PMNs identified by reduced expression of cell surface integrin molecules as well as the inhibition of shedding of L-selectin in some cases. A more functional measure of leukocyte activation is the aggregation of platelets on monocyte cell surfaces. In 5 of 6 subjects tested, GMI-1070 reduced PMA 8 hours after dosing. Thus, GMI-1070 not only inhibits E-selectin, but also blocks the expression of downstream integrin adhesion molecules that together play crucial roles in vaso-occlusion by promoting the adhesion to platelets and erythrocytes in the formation of occlusions that block blood flow. The effects of GMI-1070 on the activation state of leukocytes via the inhibition of functional adhesion molecules in steady state sickle cell subjects supports the further evaluation of treatment with GMI-1070 during vaso-occlusive episodes. Disclosures: Simon: GlycoMimetics: Research Funding. Chase:GlycoMimetics:.Kuypers:GlycoMimetics Inc.: Research Funding. Styles:GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics Inc.: Consultancy, clinical trial sponsorship. Thackray:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Off Label Use: The drug (GMI-1070) is not approved for any clinical indication.

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A 2-Part Phase I Study in Patients with Solid or Hematologic Malignancies: Dose Proportionality of Subcutaneous (SC) Azacitidine (AZA) and Pharmacokinetics of SC AZA in Patients with Severe Renal Impairment,

Blood ◽

10.1182/blood.v118.21.3480.3480 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3480-3480

Author(s):

Eric Laille ◽

Alain C. Mita ◽

Sanjay Goel ◽

Nashat Y. Gabrail ◽

Joseph Schwarz ◽

...

Keyword(s):

Renal Function ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment ◽

Hematologic Malignancies ◽

Dose Proportionality ◽

Employment Equity ◽

Post Dose ◽

Equity Ownership ◽

To Receive

Abstract Abstract 3480 Background: The recommended starting dose for all patients receiving SC AZA is 75 mg/m2 daily for 7 days in 28-day cycles. If no response is observed, the dose may be increased to 100 mg/m2. Conversely, if cytopenias do not adequately resolve between dosing cycles, AZA dose may be reduced. Similarly, because AZA and its metabolites are primarily excreted by the kidneys, patients with renal impairment may require monitoring for elevations of BUN or serum creatinine (cr), in which case the next AZA treatment cycle should be delayed until values return to baseline and the next AZA dose should be reduced by 50% (Vidaza® prescribing information, 2011). Currently, the pharmacokinetics (PK) of SC AZA in reduced (<75 mg/m2) or increased (100 mg/m2) doses, and AZA exposure at the recommended dose in patients with renal impairment, are unknown. Objectives: To assess the dose proportionality of AZA PK after single SC doses ranging from 25 to 100 mg/m2, and to determine the effect of renal impairment on AZA PK after single and multiple (5 days) SC doses of 75 mg/m2. Also, the safety and tolerability of AZA in patients with severe renal impairment were determined. Methods: This 2-part multicenter, randomized, open-label study included patients with solid or hematologic malignancies. Part 1 was a 4-treatment, parallel-group evaluation of the dose proportionality of SC AZA in patients with normal renal function (cr clearance [CLcr] >80 mL/min/1.73 m2, Cockcroft-Gault equation adjusted for body surface area). Patients were randomized to receive a single dose of 25-, 50-, 75-, or 100-mg/m2 SC AZA. Blood and urine samples were collected before dosing and at various time points up to 8 hours post-dose. The 75 mg/m2 dosing group in Part 1 received an additional 4 days of AZA treatment and blood and urine were collected from these patients on the same schedule on Day 5. For Part 2, patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) received SC AZA 75 mg/m2 for 5 consecutive days. PK parameters were determined using non-compartmental methods. Patients could continue to receive treatment with AZA (75 mg/m2/d SC x 7d q 28 days) in an extension phase for up to 6 cycles (patients were followed for safety only). Results: At the time of this analysis, 21 patients were enrolled and were included in safety evaluations, with PK data available for 18 patients. At baseline, median ages of patients with normal renal function (n=17) or severe renal impairment (n=4) were 61 years (range: 38–76) and 71 years (range: 54–90), respectively. Of patients with normal renal function, 12 (70%) had solid tumors, 4 had MDS (RAEB-t [n=2], RA, RARS), and 1 had multiple myeloma. Of patients with severe renal impairment, 2 (50%) had solid tumors, 1 had CMML, and 1 had MDS (RA). In Part 1, 14 patients were randomized to either 25 mg/m2 (n=4), 50 mg/m2 (n=4), 75 mg/m2 (n=3), or 100 mg/m2 (n=3). Mean [±SD] AUC0-∞ in the 25-, 50-, 75-, and 100 mg/m2 dose groups were 490 [146], 895 [300], 1270 [480], and 1410 [212] ng*hr/mL, respectively. Preliminary results show AZA is dose proportional across the 25–100 mg/m2dose range (Figure 1). In Part 2, on Days 1 and 5 of 5 consecutive days of SC AZA administration, AZA was rapidly absorbed by patients with severe renal impairment, reaching Cmax within 0.75 hours post-dose. AZA concentration decreased thereafter in a pseudobiphasic manner (Figure 2). Similar profiles were observed in patients with normal renal function who received the same dose. Mean [±SD] AUC0-∞ values after a 75 mg/m2 SC AZA dose on Day 1 were 1270 [480] ng*hr/mL in patients with normal renal function and 1630 [913] ng*hr/mL in patients with severely impaired renal function. On Day 5, mean AUC0-∞ values were 901 [92] and 1280 [728] ng*hr/mL, respectively. Similar observations were noted for Cmax. No accumulation of AZA was noted on Day 5 in either group. High inter-patient variability was noted in both groups (% coefficient of variation up to ∼82%). Patients with or without renal impairment did not show unusual or unexpected adverse events. Conclusions: AZA is dose-proportional over the 25–100 mg/m2 dosing range. PK parameters from patients with severe renal impairment treated with multiple doses of AZA 75 mg/m2 SC were comparable to those obtained from patients with normal renal function. Treatment with AZA 75 mg/m2 SC over multiple days was safe and well tolerated in this small group of patients with normal renal function or severe renal impairment. Disclosures: Laille: Celgene Corporation: Employment, Equity Ownership. Goel:Celgene: Research Funding. Schwarz:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

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