Cumulative AUC Research Articles

Cumulative and Incremental Value of Sarcopenia Components on Predicting Adverse Outcomes

ObjectivesTo examine the incremental value of sarcopenia components, following the diagnosis algorithm of the Asian consensus, on predicting adverse outcomes. DesignA prospective cohort study. Setting and ParticipantsFour thousand community-dwelling Chinese adults (2000 men) aged 65 years or older in Hong Kong (mean age = 72.5 ± 5.2). MethodsSARC-F was used as the initial predictor of 9 adverse outcomes. In step 2, muscle strength (ie, grip strength) and/or functions (ie, chair-stand, walking speed) were added on top of SARC-F. In step 3, height-, weight-, and body mass index–adjusted appendicular skeletal mass (ASM) measured by dual-energy x-ray absorptiometry (DXA) were added separately to all models formulated in step 2. The areas under the receiver operating characteristic curve (AUCs) were calculated for the models formulated in all steps. Each cumulative AUC would be compared with the AUC yielded in the previous step to evaluate the incremental prediction value. ResultsOn top of SARC-F, assessing grip strength, walking speed, or 5-time chair-stand significantly increased the AUC for most adverse outcomes. In particular, assessing both grip strength and gait speed yielded the highest AUC in most prediction models (AUC = 0.539-0.770) and significantly increased the AUC for all outcomes except for recurrent falls. With both muscle strength and function assessed, adding ASM failed to significantly increase the AUC except for 2 conditions. In the 2 conditions, however, a higher height-adjusted ASM was associated with a higher risk of having worsened physical limitations [OR 1.25, 95% confidence interval (CI) 1.12-1.40] and decline in the physical quality of life (OR 1.18, 95% CI 1.06-1.33) in women. Conclusions and ImplicationsAssessing muscle strength and function provides additional power to predict adverse outcomes on top of SARC-F. Further assessment of muscle mass with DXA provides no extra constructive value ito bettering the prediction regardless of the adjustment parameters. Alternative technologies to measure muscle mass might be required.

733. Pharmacokinetic–Pharmacodynamic (PK–PD) Analyses for Alanine Aminotransferase (ALT) Using Phase 3 Data From Omadacycline (OMC)-Treated Patients

BackgroundOMC, an aminomethylcycline structurally related to tetracycline agents, was recently approved by the US FDA for the treatment of adult patients with ABSSSI (IV-to-PO and PO regimens) and CABP (IV-to-PO regimen). To better understand exposure-related concerns for ALT increase, PK-PD relationships for ALT were evaluated using data from OMC-treated patients enrolled in three Phase 3 studies.MethodsRepeated-measures multiple linear regression was used to evaluate factors predictive of ALT, including different OMC total-drug AUC measures prior to each ALT, with interactions and covariates selected stepwise. Using a final AIC-optimized model, predicted percent probabilities of ALT elevation >1, 1.5, 2, 3, 5, and 10 × upper limit of normal (ULN) at any time post-baseline and up to 2 days after the end of therapy were calculated among analysis patients for fixed post-baseline OMC AUC measures, and among simulated patients after IV-to-PO and PO dosing regimens.ResultsThe final model, developed using data from 327 patients with PK, included increased prior cumulative AUC among males, increased baseline gamma-glutamyl transferase, and study (ABSSSI, PO only) as factors predictive of increased ALT (P < 0.0001). However, the model-predicted impact of OMC across fixed average daily AUC values on ALT elevation endpoints of >1, 1.5, 2, 3, 5, and 10 × ULN was minimal (Figure 1), even for males despite the interaction with AUC (Figure 2). Among all patients, the estimated increases in percent probabilities for the 90th percentile of AUC relative to zero AUC were 5.81, 5.20, 1.53, 0.61, 0.31, and 0%, respectively, and ≤11.5, 7.76, 8.33, 1.31, 1.31, and 0%, respectively, across single variable patient subsets. Percent probabilities of ALT elevation endpoints were within 2.84% when comparing simulated and observed patients after administration of OMC IV-to-PO and PO dosing regimens (Figure 3).ConclusionA statistically significant relationship between an increase in ALT and increase in OMC AUC for males in the presence of other factors was found. However, increases in model-predicted ALT elevation endpoints across fixed OMC AUC values, or among simulated patients after administration of OMC IV-to-PO and PO dosing regimens relative to observed patients, were minimal. Disclosures All authors: No reported disclosures.

Cardiovascular Health in Pediatric Heart Transplant Patients

Purpose Ideal “cardiovascular health” (CVH) - optimal levels of 7 metrics: diet, physical activity (PA), nonsmoking, BMI, BP, lipids, & glucose - is associated with greater longevity and quality of life in adults. Pediatric heart transplant (HT) patients (pts) may be at risk for suboptimal CVH due to immunosuppression and comorbidities. Hypotheses HT pts’ CVH scores will be lower compared to the general US pediatric population (GP), will diminish over time, and will correlate with complications. Methods Single-center retrospective study of HT pts from 2003-2014 that survived 1 year post-transplant (PT). Five CVH metrics were collected at listing, 1, 3 and 5 years PT; PA & diet were not available. CVH score was calculated as the sum of individual metrics: ideal=2; intermediate=1 and poor=0; CVH score 8-10 points = high (favorable). We compared the latest PT year with the NHANES weighted dataset representing the GP, adjusted for age, sex & race/ethnicity. Cumulative AUC CVH scores were calculated PT and dichotomized as high (favorable) > 33 and low Results We included 110 HT pts; 56% male, median age 6 years (range 0.1-21). NHANES 2007-2016 had 19,081 participants. Most HT pts had high CVH scores at listing, 1, 3 and 5 years PT: 73, 74, 87 and 75%, respectively. Figure 1A shows differences in the distribution of CVH metrics between HT pts and the GP. Figure 1B shows the most recent CVH score distribution; there were differences in the distribution of CVH scores in age groups (p=0.02). HT pts with low (vs. high) cumulative CVH scores had a HR of 2.95 (p=0.002) for the composite adverse outcome of chronic kidney disease, coronary allograft vasculopathy, relisting or death. Conclusion CVH scores in pediatric HT pts were stable over time with younger pts more likely to have high CVH. Compared to the GP, HT pts had lower ideal glucose but higher ideal lipids. Low cumulative CVH scores were associated with ∼3-fold higher risks of adverse outcome. Future interventions to improve CVH in HT pts, such as targeted counseling, should be considered.

First Results of a Prospective I/II Clinical Trial in Adult Patients Using TCR Alpha/Beta Depleted Stem Cell Transplantation from Matched Related and Unrelated Donors

Introduction: We report the first analysis of a multicenter prospective single-arm phase I/II study that assesses the safety and feasibility of transplantation of TCRalpha/beta depleted stem cells from matched related or unrelated donors using the CliniMACS plus System (Miltenyi Biotec, Germany) in combination with a non-myeloablative conditioning in adult patients (trial nr NL48606.000.14). The conditioning regimen consisted of ATG (Thymoglobulin®) 1.5mg/kg i.v. days -12 to -9; fludarabine i.v. 40 mg/m2 days -5 to -2 and busulfan i.v. (Busivex®) days -5 to -2 (cumulative AUC of 80-90mg*h/L), followed by 28 days of mycophenolic acid. All 35 subjects were eligible to address the primary endpoint which is the incidence of acute GVHD at day 100.Results: 2 centers enrolled 10 female and 25 male patients (median age 59 years, range 19 - 69 years), including 9 AML, 4 ALL, 2 CML, 5 MM, 1 NHL, 10 MDS, 4 MPN. Diseases were in CR (n=17), VGPR (n=1), PR (n=5) or non-remission (n=12). 4 subjects had one or more previous allogeneic SCTs. Donors included 4 MRD, 24 10/10 matched MUD and 7 9/10 matched MUD. 8 male patients received stem cells of female donors. The median number of CD34+ cells and αβ TCR cells/kg was 6.1x 10^6 (range, 1.9-10) and 14.5x10^3 (range, 0-136), respectively. One primary graft failure was observed. Primary engraftment of ANCs > 500 cells/μL was reached at a median of 14 days (range 9 - 48 days) and of platelets > 20 at a median of 17 days (range 10 - 99) days.The median time of follow-up of this first analysis was 190 days (range 110-400 days). 3/35 patients developed acute GVHD grade III-IV during the first 100 days, 9/35 patients developed acute GVHD grade II-IV and 16/35 patients grade I-IV at day 100. At day 100 the cumulative incidence (CI) of CMV was 31%, of EBV 36% and of BK cystitis 20%. The combined CI of CMV/EBV/BK infections with a CTC-AE grade III-V was 53% at day 100.Immune reconstitution was rapid with a median of 227 (range 34 - 1626) CD3+ cells/µl on day 100 but varied substantially between patients. The median numbers of CD3/CD4+ and CD3/CD8+ at day 100 post transplant were 60 (range 30 - 120) and 124 (range 5 - 1450) cells/µl. The median numbers of NK were 289 (range 32-1140) at day 30 and 128 (range 24 - 1228) cells/µl at day 100 post transplant. The median numbers of γδ T cells were 38 (range 4-143) at day 30 and 50 (range 8-556) cells/µl at day 100 post transplant.26 out of 35 patients were alive, 2 patients died of a relapse, 2 of GVHD and 5 of infectious complications. Kaplan Meier estimates of the OS are 88% (+/- 6%) at day 100 and 68% (+/- 9%) at 1Y. Kaplan Meier estimates of the EFS are 77% (+/- 7%) at day 100 and 52% (+/- 10%) at 1Y. 2 patients developed a relapse before day 100 and 5 patients before 1Y. It is noted that the outcome of 5 patients with MM was very poor in this cohort (3 patients developed a relapse and 2 patients died of complications).Conclusion: Allo-SCT of αβ T cell depleted PBMCs form matched related or unrelated donors, in combination with early ATG and a non-myeloablative conditioning regimen, resulted in favorable rates of primary engraftment (34/35), a CI of aGVHD II-IV of 26% with only minimal immuno-suppression and an encouraging early disease control (Fig 1). OS survival was mainly impacted by NRM (Fig 1), by which the majority of complications were of infectious nature. While all patients with MM suffered from NRM or relapse, all other disease categories had a rather favorable outcome. Reducing inter-individual variations in immune reconstitution early after transplantation will be key to further improve outcomes. [Display omitted] DisclosuresMinnema:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Servier: Consultancy. Kuball:Novartis: Research Funding; Miltenyi Biotec: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gd T cells and receptors and isolation strategies, Research Funding.

Blood flow regulation and oxidative stress during submaximal cycling exercise in patients with cystic fibrosis

BackgroundThe impact of blood flow regulation and oxidative stress during exercise in cystic fibrosis (CF) has yet to be investigated. MethodsA maximal graded exercise test was conducted to determine exercise capacity (VO2 peak) and peak workload in 14 pediatric patients with mild CF (age 14±3y, FEV1 93±16 % predicted) and 14 demographically-matched controls. On a separate visit, participants performed submaximal cycling up to 60% of peak workload where brachial artery blood velocity was determined using Doppler ultrasound. Retrograde and antegrade components were further analyzed as indices of blood flow regulation. ResultsThe cumulative AUC for retrograde velocity was lower in patients versus controls (1770±554 vs. 3440±522cm, P=0.038). In addition, an exaggerated oxidative stress response during exercise occurred in patients only (P=0.004). ConclusionThese data suggest that patients with mild CF exhibit impaired blood flow regulation and an exaggerated oxidative stress response to submaximal exercise.

A 5'UTR Polymorphism in NT5E Gene Influences Outcome in Patients with Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplantation with Fludarabine Based Conditioning Regimen

Allogeneic hematopoietic stem cell transplantation (Allo-SCT) with fludarabine based reduced intensity or toxicity reduced conditioning regimen with Busulfan or Melphalan (Flu/Bu; Flu/Mel) has improved HSCT outcome in patients with AML. Limited reports on the PK of Flu in patients with malignant hematological diseases undergoing Allo-SCT suggest that Flu AUC is associated with transplant related mortality (TRM) (Long-Boyle et al, 2011). We prospectively analyzed the PK and pharmacogenetics (PG) of Flu and Bu on Allo-SCT outcome in patients with AML receiving Flu/Bu or Flu/Mel based regimen.Forty-eight adult AML patients receiving Flu/Bu(targeted) (Flu 40mg/m2 /day intravenously from day-5 to -2 and intravenous Bu 130mg/m2 /day from day-5 to-2; n=27) or Flu/Mel (Flu 30mg/m2 /day intravenously from day -6 to -2 and Mel 140mg/m2 intravenously on day -1; n=21) regimen prior to Allo-SCT between January 2012 and 2015 were enrolled in this study. Peripheral blood was collected for PK analysis at serial time points and plasma was separated and analyzed the same day (for Bu TDM). Bu dose was adjusted based on the first dose PK to achieve target cumulative total AUC (22000mmoles*min). Flu plasma levels was analyzed using LC-MS/MS and the concentration was expressed as mmol/ml. Genetic polymorphisms that influence Flu and Bu PK (NT5E 5'-UTR variant rs2295890 and GSTA1*B polymorphism) were screened using pre- HSCT genomic DNA. The influence of Flu/Bu PK and PG on clinical outcome endpoints such as overall survival (OS) and event-free survival (EFS) was evaluated using cox regression analysis.The demographics of the patients is listed in the Table. There was a significant inter-individual variation in the flu clearance (1.2mL/h/m2(0.5-4.3); 8.6 fold) and AUC (46mmol*h/ml (24-101); 4.2 fold). Fludarabine AUC trended higher in Flu/Bu group when compared to Flu/Mel group (median AUC 52 vs. 43 mmol*h/ml respectively; p=0.08). Neither of the polymorphisms significantly explained the variation in Bu or Flu PK in this cohort and none of the PK parameters was associated with EFS/OS. However, patients carrying variant genotype of the NT5E 5'UTR polymorphism (rs2295890) showed significantly better OS (p=0.016) and EFS (p=0.007) (Figure) compared to those carrying wild type genotype. We have previously reported that this variant is associated with decreased Flu Clearance in patients with aplastic anemia and thalassemia receiving Flu based conditioning regimen (Mohanan et al, December 06, 2014; 124 (21): 3884; Mohanan et al, December 03, 2015; 126 (23): 3120). Although not significant, the Flu clearance was lower in the NT5E variants in this cohort as well. It can be extrapolated that patients carrying the variant genotype of the NT5E polymorphism, have decreased relapse incidence (Wild type-8; Variants-1) and hence better EFS and OS post HSCT, due to decreased clearance and increased systemic exposure to Flu. This finding need to be validated in a larger number and in patients with other disease conditions undergoing HSCT with Flu based regimen, in order to achieve the goal of personalizing conditioning regimen. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37). Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications. Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.

Abstract 1618: Carboplatin therapeutic monitoring in preterm and full-term neonates

Abstract Background: Administration of the most appropriate dose of chemotherapy to neonates with cancer is particularly challenging and in many cases is not standardized based on any scientific rationale. We report on the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life and use the data generated to provide guidance for the treatment of future patients. Patients and methods: Carboplatin therapeutic monitoring was performed to achieve target drug exposures (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma over an 8 year period. Carboplatin was administered over 3 days of treatment with therapeutic drug monitoring utilized to target AUC values of 5.2 - 7.8mg/ml.min. Results: AUC values achieved following therapeutic monitoring were within 15% of the target value for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on the initial mg/kg dosing schedule implemented. Carboplatin clearance values determined across three consecutive courses of chemotherapy in two patients increased from 3.4 to 7.1ml/min and 7.2 to 16.5 ml/min, representing increases of 210% and 230% over periods of 7 and 8 weeks respectively. Complete remission was observed in all seven patients treated for retinoblastoma and in one patient with neuroblastoma, with no renal toxicity reported and only one patient experiencing ototoxicity. Conclusion: The study highlights the benefits of utilising therapeutic drug monitoring to achieve cumulative target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of the marked increases in drug clearance observed over consecutive courses of chemotherapy. Reducing the likelihood of sensorineural hearing loss may be particularly relevant in the case of neonates with retinoblastoma, where it is likely to have an even greater impact on the quality of life of a child who may also have some degree of visual impairment. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform the treatment of future patients. Acknowledgements: Work supported by Cancer Research UK, the North of England Children's Cancer Research Fund and the Experimental Cancer Medicine Centre Network. Citation Format: Gareth J. Veal, Julie Errington, James Hayden, David Hobin, Dermot Murphy, Rachel A. Dommett, Deborah A. Tweddle, Helen Jenkinson, Susan Picton. Carboplatin therapeutic monitoring in preterm and full-term neonates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2015-1618

Carboplatin therapeutic monitoring in preterm and full-term neonates

IntroductionAdministration of the most appropriate dose of chemotherapy to neonates is particularly challenging and frequently not standardised based on any scientific rationale. We report the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life. MethodsCarboplatin therapeutic monitoring was performed to achieve target drug exposures area under the plasma concentration–time curve (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma treated over an 8year period. Carboplatin was administered over 3days with therapeutic drug monitoring utilised to target cumulative AUC values of 5.2–7.8mg/mlmin. ResultsAUC values achieved were within 15% of target values for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on initial mg/kg dosing schedules. Carboplatin clearance determined across three consecutive chemotherapy courses in two patients increased from 3.4 to 7.1ml/min and from 7.2 to 16.5ml/min, representing increases of 210–230% over several weeks of treatment. Complete remission was observed in 8/9 patients, with no renal toxicity reported and only one patient experiencing ototoxicity. ConclusionThe study highlights the benefits of utilising therapeutic drug monitoring to achieve target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of marked increases in drug clearance observed over consecutive chemotherapy courses. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform future treatment.

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates.

In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.

The effects of whole grain high-amylose maize flour as a source of resistant starch on blood glucose, satiety, and food intake in young men.

The objective of this study was to determine the dose response effect of whole grain high-amylose maize (HAM) flour as a source of resistant starch (RS) on blood glucose, appetite and short-term food intake. In a repeated-measures crossover trial, healthy men (n = 30, 22.9 ± 0.6 y, BMI of 22.6 ± 0.3 kg/m(2)) were randomly assigned to consume 1 of 3 cookies once a week for 3 wk. Cookies were control (100% wheat flour), low-dose (63% wheat flour,37% HAM flour), and high-dose (33% wheat flour, 67% HAM flour) providing 53.5, 43.5, and 36.3 g of available carbohydrate, respectively. Ad libitum food intake was measured 120 min at a pizza meal, blood glucose and subjective appetite were measured after consumption of the cookie (0 to 120 min) and after the pizza meal (140 to 200 min). Blood glucose concentrations were lower at 30 and 45 min after high-dose treatment, and at 120 min after both high- and low-dose treatments compared to control (P < 0.05). Blood glucose AUC before the pizza meal (0 to 120 min) was 44% and 14% lower, and higher by 43% and 41% after the pizza meal (140 to 200 min) compared with control. Yet despite the higher response following the meal, cumulative AUC (0 to 200 min) was still 22% lower after the high-dose treatment (P < 0.05). All treatments equally suppressed subjective appetite and there was no effect on food intake. In conclusion, HAM flour as a source of RS and incorporated into a cookie was associated with better glycemic control in young men.

Development of Risperidone PLGA Microspheres

The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone, with an eventual goal of avoiding combination therapy for the treatment of schizophrenia. Two PLGA copolymers (50 : 50 and 75 : 25) were used to prepare four microsphere formulations of Risperidone. The microspheres were characterized by several in vitro techniques. In vivo studies in male Sprague-Dawley rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst followed by sustained release of the active moiety. Additionally, formulations prepared with 50 : 50 PLGA had a shorter duration of action and lower cumulative AUC levels than the 75 : 25 PLGA microspheres. A simulation of multiple dosing at weekly or 15-day regimen revealed pulsatile behavior for all formulations with steady state being achieved by the second dose. Overall, the clinical use of Formulations A, B, C, or D will eliminate the need for combination oral therapy and reduce time to achieve steady state, with a smaller washout period upon cessation of therapy. Results of this study prove the suitability of using PLGA copolymers of varying composition and molecular weight to develop sustained release formulations that can tailor in vivo behavior and enhance pharmacological effectiveness of the drug.

Pharmacokinetics Of a Generic Formulation Of Intravenous Busulfan (BUCELON 60™) In Patients Undergoing Hematopoietic Stem Cell Transplantation

High-dose Busulfan (Bu) in combination with cyclophosphamide or fludarabine is widely used conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) for various hematological malignant and non-malignant disorders. Intravenous (i.v) formulation of Bu, along with targeted dose adjustment has resulted in reliable systemic exposure (due to its predictable pharmacokinetics (PK)) while minimizing toxicity and treatment failure. We have previously demonstrated the population pharmacokinetics of oral Bu in thalassemia patients undergoing HSCT (Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 3349) and factors predicting or influencing the outcomes. Since 2010, a generic form of i.v Bu (BUCELON 60™, Celon Labs, India) with targeted dose adjustment has been used at our center, for HSCT with all Bu based conditioning regimen. There is no report on the PK of Bucelon in patients undergoing HSCT. The objectives of the present study were to evaluate the PK of Bucelon in patients undergoing HSCT, compare the systemic exposure to i.v Bucelon vs. previous reports in patients with various hematological diseases and report the toxicity and outcome after i.vBucelon in our patient cohort.Ninety five patients diagnosed with various haematological disorders receiving high dose i.v Bu as combination chemotherapy between June 2010 and July 2013 was included. Seventy three patients received single daily (Q24H-130mg/m2/day) while 22 had 6 hourly doses (Q6H-0.8mg/kg/dose) of Bu. Patient demographics are shown in Table. Peripheral blood samples were collected at different time points (0, 3, 4, 5 & 7hr in Q24H and 0,2,3,4 & 6hr in Q6H) on day 1 and day 3 and plasma Bu concentration were analyzed using an LC-ESI MS/MS method (Salamun DE et al.2013). An AUC of 5000-5500µmoles (cumulative AUC target: 20000 to 22000µmoles) in Q24H or 900-1350µmoles in Q6H was targeted. The effect of pharmacogenetic factors on the PK/systemic exposure of i.v Bucelon were evaluated. The PK parameters estimated were: AUC, Clearance (CL) and volume of distribution (V) after the 1st dose of Bucelon and after dose adjustment. The median day 1 AUC was 4180µmoles*min (1713-10456) and 599.5µmoles*min (307-1456) in Q24H and Q6H respectively. The median CL and V are 4.19L/h (0.81-21.55) 17.5589L/h (2.51-243.90) in Q6H and 41.83L/h (2.47-144.84) and 156.3L/h (6.5-454.51) in Q24H respectively. We analyzed the effect of polymorphisms in the drug metabolizing genes (GST, CYP) on the first dose AUC of Bu in these patients. Out of the eight polymorphisms in GSTA1, GSTM1, GSTT1, GSTP1, CYP2B6*6, CYP2C19*2, CYP2C19*3, CYP3A4*1B analyzed, GSTM1 positive patients in Q6H showed a significantly lower median Bucelon AUC, 589µmoles*min (307-1456) than when compared to GSTM1 null patients (median AUC, 963µmoles*min (670-1240) (P=0.0122) Figure). None of the other polymorphisms were found to influence the 1st dose Bucelon AUC in patients receiving once daily or Q6H dose. However, the median day 1 AUC is found to be much less compared to previous report on patients with thalassemia major receiving Q6H i.v Bu: 599.5µmoles*min (307-1456) vs. 971µmoles*min (630-1621) as well as in malignant conditions receiving Q24H dose of i.vBu: 4180µmoles*min (1713-10456) vs. 5113μmoles*min (2796 - 9355). [Display omitted] [Display omitted] When we analyzed the regimen related toxicity in these patients, 10 of the 95 (10.5%) developed sinusoidal obstruction syndrome (SOS) of which 3 was severe. Eight patients (8.4%) had not engrafted or rejected and 5 (5.2%) relapsed, 13 patients (13.7%) developed Grade III-IV GVHD and 3 had Hemorrhagic Cystitis. There was no significant difference in the cumulative AUC between those who develop toxicities and those who did not.We report the PK of i.v Bucelon, a generic formulation of i.v Bu for the first time in patients undergoing HSCT. Since the systemic exposure to Bucelon seems to be lower in similar age, disease matched cohort, this may mean that targeted adjustment of Bu is necessary when we use i.vBucelon as conditioning regimen for HSCT. The lower systemic exposure could be due to population difference in PK or due to the drug formulation, or a combination of both, which needs to be validated further. Disclosures:No relevant conflicts of interest to declare.

AB0268 Lack of correlation between golimumab exposure and selected safety events following intravenous or subcutaneous administration in an integrated analysis of phase 3 data in rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis

BackgroundFor anti-TNFα agents, infections&malignancies are key safety concerns of interest. It is unknown whether safety events are driven by peak (Cmax), trough (Cmin), average (Cavg) conc or by total systemic...

Phase II Study of CD4+-Guided Pentostatin Lymphodepletion and Pharmacokinetically Targeted Busulfan as Conditioning for Hematopoietic Cell Allografting

One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4+ lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3+ donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m2 i.v. on days −28, −21, and −14 when the CD4+ cell count was >100 cells/μL and on days −4 and −3 regardless of CD4+ level. Rituximab 375 mg/m2 was administered to patients with CD20+ malignancies on days −21, −14, −7, +1, and +8. Busulfan 200 mg/m2 i.v. was administered on days −4 and −2 at a dose to target a cumulative AUC dose of 16,000 (±10%) μmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4+ cell count decrease from baseline (day −28) was 52% to day −21, 66% to day −14, 62% to day −7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3+ donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.

Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor

For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

Defining An Optimal Therapeutic Range for Busulfan (Bu) Administered with Pre-and Post-Transplant Cyclophosphamide (Cy) In HLA-Matched Related and Unrelated Bone Marrow Transplantation (BMT).

AbstractAbstract 3474We have recently reported on a novel conditioning strategy comprised of standard dose busulfan (Bu) with cyclophosphamide (Cy) 50 mg/kg/dose for two doses pre-transplant with an additional two doses administered post-transplant, as sole GVHD prophylaxis. Preliminary data suggest that this strategy may reduce toxicity of alloBMT and maximize its antitumor efficacy. Given the evidence suggesting that an optimal therapeutic range of Bu systemic exposure may exist, the goal of this study was to examine the correlation between Bu area under the concentration versus time curve (AUC) and clinical outcomes in 131 consecutive patients, ages 21– 66 years, with advanced hematologic malignancies who received HLA-matched related (72 patients) and unrelated (59 patients) allografts. Bu was administered orally (1 mg/kg/dose, n= 72) or intravenously (0.8 mg/kg/dose, n= 59) every 6 hours for a total of 16 doses with pharmacokinetic adjustment to a target AUC range of 800–1400 umol*min/L. If first dose pharmacokinetics were not possible, an AUC was calculated on the first available dose. The median first dose AUC was 993 umol*min/L (range, 482–1875) for all patients (median PO = 1083; median IV= 860; P=.0001). On the basis of targeted first-dose AUC, 19 patients (13% PO and 17% IV) required dose escalation, whereas 12 patients (11% PO and 7% IV) required dose reduction. Median total cumulative AUC was 15992 umol*min/L (range, 10795–24739) with PO median of 17160 and an IV median of 13880 (P<.0001). AUC was initially entered into a proportional hazards model using a restricted cubic spline transformation to allow for non-linearity. We found that overall survival (OS) and event-free survival (EFS) were higher in patients with a first dose AUC of 800–1000 umol*min/L as compared to those with a lower or higher AUC for first dose [EFS HR=0.55 (0.33, 0.93); P=.03 and OS HR=0.52 (0.28, 0.95); P=.03]. Similarly, we found that OS and EFS were higher in patients having a total cumulative AUC between 13500 and 17000 umol*min/L as compared to those with lower or higher total AUC values [EFS HR= 0.60 (0.37, 0.95); P=.03 and OS HR= 0.56 (0.33, 0.96); P=.04]. Furthermore, we found that risk of non relapse mortality (NRM) and relapse were lower in patients having first dose AUC values in the range of 800–1000 umol*min/L [NRM HR= 0.35 (0.11, 1.19); P= 0.09 and relapse HR= 0.75 (0.42, 1.35); P= 0.34]. In addition, we found the risk of NRM and relapse were lower in patients having total cumulative AUC values in the range of 13500– 17000 umol*min/L [NRM HR= 0.75 (0.30, 1.85); P= 0.53 and relapse HR= 0.63 (0.37, 1.07); P= 0.09]. Moreover, patients outside our identified optimal therapeutic range at first dose and total cumulative AUC were at an increased risk for NRM [HR=1.5 (0.62, 3.61); P= 0.37] and relapse [HR= 1.64 (0.98, 2.74); P= 0.06], as well as reduced OS [HR= 2.05 (1.22, 3.42); P= 0.01) and EFS [HR= 1.80 (1.15, 2.83); P =0.01] as compared to patients within our newly identified range for first AUC, total cumulative AUC, or both. These results suggest that an optimal therapeutic range with Bu administration exists for both toxicity and relapse and can be achieved with either conventional PO or IV Bu administration. Disclosures:Off Label Use: Cyclophosphamide as conditioning for allogeneic bone marrow transplantation and as Graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Luznik:Otsuka Pharmaceutical: Research Funding.

Modelling the occurrence and severity of enoxaparin-induced bleeding and bruising events.

To develop a population pharmacokinetic-pharmacodynamic model to describe the occurrence and severity of bleeding or bruising as a function of enoxaparin exposure. Data were obtained from a randomized controlled trial (n = 118) that compared conventional dosing of enoxaparin (product label) with an individualized dosing regimen. Anti-Xa concentrations were sampled using a sparse design and the size, location and type of bruising and bleeding event, during enoxaparin therapy, were collected daily. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed effects techniques. The final model was used to explore how the probability of events in patients with obesity and/or renal impairment varied under differing dosing strategies. Three hundred and forty-nine anti-Xa concentrations were available for analysis. A two-compartment first-order absorption and elimination model best fit the data, with lean body weight describing between-subject variability in clearance and central volume of distribution. A three-category proportional-odds model described the occurrence and severity of events as a function of both cumulative enoxaparin AUC (cAUC) and subject age. Simulations showed that individualized dosing decreased the probability of a bleeding or major bruising event when compared with conventional dosing, which was most noticeable in subjects with obesity and renal impairment. The occurrence and severity of a bleeding or major bruising event to enoxaparin, administered for the treatment of a thromboembolic disease, can be described as a function of both cAUC and subject age. Individualized dosing of enoxaparin will reduce the probability of an event.

Pharmacokinetics of oral deforolimus (AP23573, MK-8669)

14555 Background: Deforolimus is a non-pro drug rapamycin analog which specifically inhibits mTOR. Intravenous deforolimus has shown promising anti-tumor activity in a variety of malignancies. We tested the safety and tolerability of oral deforolimus in a comprehensive phase I study. A PK model was developed to characterize the concentration-time profile of deforolimus following oral administration on different dosing schedules. Subsequently the PK results were compared to historical IV data. Our data show oral deforolimus to be bioavailable, with a safety and tolerability profile similar to IV deforolimus. Methods: The trial was an open label dose-finding study for adults with advanced/refractory solid tumors. Tolerability and anti-tumor results are reported in a companion abstract. Seven dosing regimens (QDx4 qd and bid QW, QDx5 QW± a loading dose, QDx6 QW, QDx21 Q28D, and QDx28) were investigated. Multiple PK samples were taken on Days 1, 15 and 21 of a 28 day cycle. Trough samples were collected on Days 2, 4, 8, 11, 15, 16 and 22. Deforolimus levels were determined by LC/MS/MS. PK modeling was performed using WinNonLin®. Results: A 2-compartment PK model incorporating a lag time for absorption best described deforolimus PK in the 129 evaluable patients of the 147 who received treatment. Following oral administration, deforolimus has a rapid exponential decline followed by a slower linear phase of elimination. Cmax occurred at 2–3 hours; the median terminal half life is 35–70 hours. Mean estimated AUC and Cmax increased in a less than dose-proportional manner. Absolute bioavailability derived from prior IV data was ∼20%. AUCs (μg*hr/mL) at MTD over a cycle are shown below for six regimens. Conclusions: Oral deforolimus has a comparable half life to the IV form and exhibits similar nonlinear PK behavior (JCO 2005 23, 16S: 3043). A 40 mg QDx5/week schedule offers a high cumulative AUC while maintaining convenience and tolerability. This schedule has been selected for further evaluation in SUCCEED: a global phase 3 trial in patients with metastatic sarcomas. Dosing Cohort (n) Mean AUC0–28 days SD QD×21 15mg (11) 17.9 11.9 QD×28 10mg (13) 14.6 8.8 QD×4 50mg qw (12) 31.2 14.1 QD×5 60 loading/30 mg qw (7) 25.8 9.8 QD×5 qw 40mg (20) 34.6 16.6 QD×6 qw 30mg (13) 36.3 18.6 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ariad Ariad, Cognigen Corporation ARiad Ariad

Plasma levels, tissue distribution, and excretion of radioactivity after single-dose administration of ( 3H)-oleic acid added to D-004, a lipid extract of the fruit of Roystonea regia, in rats

Background: D-004, a lipid extract of the fruit of Roystonea regia, contains a mixture of fatty acids—mainly oleic, lauric, palmitic, and myristic acids, with oleic acid being among the most abundant—that has been found to reduce the risk for prostatic hyperplasia (PH) induced with testosterone (T) in rats. The pharmacokinetic profile of D-004 has not been reported. Objective: The objective of this study in rats was to assess plasma levels, tissue distribution, and excretion of total radioactivity (TR) after single-dose administration of oral D-004 radiolabeled with ( 3H)-oleic acid, as a surrogate for the pharmacokinetics of D-004. Methods: This experimental study was conducted at the Pharmacology Department, Center of Natural Products, National Center for Scientific Research, Havana, Cuba. Single doses of suspensions of ( 3H)-oleic acid 0.16 μCi/mg mixed with D-004 400 mg/kg (radioactive dose/animal 7.2 μCi) were given orally to male Wistar rats weighing 150 to 200 g assigned to the treated or control group. Three rats were euthanized at each of the following times: 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 48, 72, 96, and 144 hours after study drug administration. After administration, the rats euthanized at the last experimental time point were housed individually in metabolism cages. Urine and feces samples were collected daily. At each time point, blood samples were drawn and plasma samples were obtained using centrifugation. After euthanization, tissue samples (liver, lungs, spleen, brain, kidneys, adipose tissue, muscle, stomach, small and large intestines, adrenal glands, heart, testes, prostate, and seminal vesicles) were quickly removed, washed, blotted, and homogenized. Plasma (100 μL), tissue aliquots (100 mg), feces (10 mg), and urine (100μL) were dissolved and TR was measured. Samples were assayed in duplicate. Results were expressed in μgEq of radio-labeled oleic acid per milliliter of plasma or urine or gram of tissue or feces. Plasma, tissue, feces, and urine samples of rats that did not receive ( 3H)-oleic acid were used as controls. Excretion was expressed as the percentage of the radioactivity excreted via each route with respect to the total radioactive dose administered to each rat. Results: A total of 50 rats were included in the experiment (mean age, 4 weeks; mean weight, 310 g). Absorption was rapid; mean C max was 195.56 (31.12) μgEq/mL, and mean T max was 2 hours. Thereafter, a biphasic decay of TR was found: a rapid first phase (t 1/2α, 1.33 hours), followed by a slower second elimination phase (t 1/2β, 36.07 hours). Radioactivity was rapidly and broadly distributed throughout the tissues, with more accumulating in the prostate than elsewhere. In the first 8 hours, accumulation of TR was greatest in the prostate, followed by the liver, small intestine, and plasma. Subsequently, TR increased in the small intestine, while it decreased in the liver and plasma. In contrast, over the periods of 24 and 144 hours after administration, TR increased in the adipose tissue, while it decreased in the other tissues and plasma. During those intervals, TR was greatest in the prostate, followed by adipose tissue. Mean peak radioactivity in the prostate (562.41 μgEq/g) was reached at 4 hours and decreased slowly thereafter. The prostate had the highest values of t 1/2β and cumulative AUC compared with the other tissues and plasma. Mean (SD) TR was similar in feces (33.48% [4.90%]) and urine (28.96% [5.32%]), with total excretion being 62.40% (5.90%) of the administered dose. Conclusions: In this experimental study, after single-dose administration of oral D-004 radiolabeled with ( 3H)-oleic acid in rats, TR was rapidly and widely distributed across the tissues, with the prostate having the highest accumulation of radioactivity. Excretion of TR was limited, with similar amounts being excreted in feces and urine. The broad distribution of radiolabeled oleic acid and/or its metabolites suggests (SD) pharmacokinetic rationale for the effectiveness of D-004 in reducing the risk for PH induced with T in rats.