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American Society for Clinical Pharmacology and Therapeutics Abstracts of papers, *Current Considerations in the Clinical Pharmacology of Biologics Pre-conference Atlanta Marriott Marquis, Atlanta, Georgia, March 18, 2014 Abstracts of papers, *2014 Annual Meeting Atlanta Marriott Marquis, Atlanta, Georgia, March 18 – 22, 2014 BP-001 EVALUATION OF THE EFFECTS OF BLINATUMOMABMEDIATED CYTOKINE ELEVATIONS ON CYTOCHROME P450 ENZYMES USING A PHYSIOLOGY-BASED PHARMACOKINETIC (PBPK) MODEL. Y. Xu,1 Y. Hijazi,2 A. Wolf,2 B. Wu,1 Y. Sun,1 M. Zhu1; 1Amgen Inc., Thousand Oaks, CA, 2Amgen Research (Munich) GmbH, Munich, Germany. Y. Xu: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. Y. Hijazi: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Research (Munich) GmbH. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. A. Wolf: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Research (Munich) GmbH. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. B. Wu: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. Y. Sun: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. M. Zhu: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/ employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. BACKGROUND: Blinatumomab is an investigational CD19/ CD3 bispecific T-cell engaging (BiTE®) antibody for the treatment of leukemia and lymphoma. Transient elevation of cytokines (IL-6, IL-10, IFN-γ, IL-2, and TNF-α) within 48 hrs of initial continuous

IV infusion of blinatumomab has been observed in some patients. We evaluated the effect of transient cytokine elevation, particularly IL-6, on suppression of CYP450 (CYP) enzymes. METHODS: IL-6 serum profiles in patients were described with a one-compartment PK model. PBPK simulator (Simcyp®) was used to predict IL-6 effects on CYP450-sensitive substrates. Effects of clinically relevant concentrations of blinatumomab and cytokine cocktails on CYP activities were tested using human hepatocytes. RESULTS: In patients who had cytokine elevation, observed IL-6 peak levels were in the range of 125 (quantification limit) to 59,231 pg/mL. The predicted IL-6 elevation-mediated change in AUC for substrates of CYP3A (midazolam, simvastatin), 1A2 (theophylline, caffeine) and 2C9 (warfarin) was 50 µg/mL in most patients. Cmin values were below the target concentration of 50 µg/mL in 1/57 and 4/57 patients in the induction and maintenance phases, respectively. The approved dosing strategy generally resulted in drug exposure within the target range. In turn, this was linked to efficacy in aHUS patients. Observed data show that Ec Cmin>50 µg/ mL resulted in functional complement inhibition in all aHUS patients. CONCLUSION: The PK of Ec in PNH patients was successfully leveraged to optimize dosing strategy in aHUS patients. This dosing recommendation resulted in drug exposures in pediatric and adult aHUS patients within the target range. The PK knowledge in PNH and aHUS patients is being further leveraged to optimize dosing in other complement-mediated rare diseases.

BP-005 PK/PD MODELING OF ECULIZUMAB AND FREE COMPLEMENT COMPONENT PROTEIN C5 IN PEDIATRIC AND ADULT PATIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS). C. Lathia,1 N. Kassir,2 M.S. Mouksassi,2 B. Jayaraman,2 J.F. Marier,2 C.L. Bedrosian1; 1Alexion Pharmaceuticals, Cheshire, CT, 2Pharsight, Montreal, QC, Canada. C. Lathia: 2. I am a paid consultant/employee for Alexion Pharmaceuticals. N. Kassir: 2. I am a paid consultant/employee for Pharsight. M.S. Mouksassi: 2. I am a paid consultant/employee for Pharsight. B. Jayaraman: 2. I am a paid consultant/employee for Pharsight. J.F. Marier: 2. I am a paid consultant/employee for Pharsight. C.L. Bedrosian: 2. I am a paid consultant/employee for Alexion Pharmaceuticals. BACKGROUND: Eculizumab (Ec) is an approved first-in-class terminal complement inhibitor. It binds to and blocks the cleavage of complement protein, C5, which in turn inhibits complementmediated hemolysis. A population pharmacokinetic/pharmacodynamic

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(PK/PD) model was developed to establish the link between serum concentrations of Ec and free C5 concentrations in patients with aHUS. METHODS: Clinical trials were performed in a total of 57 pediatric and adult patients with aHUS using the dosing regimen described in the US Package Insert. PK/PD modeling of Ec and free C5 was performed (NONMEM V7.2). RESULTS: A PK/PD model including a maximum inhibitory (Imax) function was used. Typical maximum C5 inhibition was 93.5%. The Hill constant (2.31) suggests a very steep PK/PD relationship as depicted in the figure below. Mean trough concentrations of Ec during the induction and maintenance phases resulted in 91.8% and 92.8% inhibition of free C5, respectively. Free C5 concentrations were reduced significantly at Ec concentrations >50 μg/mL and decreased further as Ec concentrations approached 100 μg/mL. CONCLUSION: Ec dosing in aHUS patients results in more than 90% binding of free C5 levels, across the entire range of concentrations. This dosing regimen, which resulted in >90% inhibition of C5, is associated with efficacy in aHUS patients.

BACKGROUND: LPZ is a first-in-class investigational drug currently being developed for the treatment of GA secondary to age-related macular degeneration. LPZ is an antibody (Ab) binding fragment of a humanized monoclonal Ab against factor D (FD), a rate-limiting enzyme in the alternative complement pathway that has been implicated in GA. A TMDD model was derived to describe the serum and aqueous PKPD of intravitreally (ITV) dosed LPZ for understanding Phase II results and guiding future studies. METHODS: A TMDD model was developed using serum (sampled at screening, day 1 and 7, and month 1, 2, 3, 6, 9, 12, 15, and 18 post-dose) and aqueous data (pre-dose, month 6 and 12 postdose) in Phase I and II studies. Preclinical LPZ and FD data were used to guide PKPD prediction in human retina. Model was used to predict target engagement in aqueous, vitreous and retina for various regimens. RESULTS: Visual and numerical predictive check suggested that the time course of LPZ-FD interaction was well described by a combined ocular/serum TMDD model using quasi steady state approximation that takes into account fast turnover kinetics of FD, first order target degradation, drug clearance, complex internalization and transfer rate between ocular and serum tissues. The model parameter estimates were supported by published studies. Model simulations showed that complete target engagement was achieved at the site of action (retina) with the 10 mg monthly regimen and partially achieved with 10 mg every other month (EOM). CONCLUSION: With a maximally achievable concentration/ ITV injection volume formulation of 10 mg monthly, complete target inhibition was predicted. The less frequent regimen (EOM) resulted in partial target engagement and less than maximal efficacy, supporting the use of 10 mg monthly regimen in future studies.

BP-007

BP-006 SELECTION OF DOSING REGIMEN USING A PKPD MODEL INCORPORATING TARGET MEDIATED DRUG DISPOSITION (TMDD) OF LAMPALIZUMAB (LPZ) IN GEOGRAPHIC ATROPHY (GA) PATIENTS. K.N. Le,1 L. Gibiansky,2 J. Good,1 T. Davancaze,1 A. Morimoto,1 K. Loyet,1 M. van Lookeren Campagne,1 E. Strauss,1 R. Graham,1 J. Jin,1 J. Visich1; 1Genentech, South San Francisco, CA, 2Quantpharm LLC, North Potomac, CA. K.N. Le: 1. This research was sponsored by Genentech. 2. I am a paid consultant/ employee for Genentech. 6. The following product discussed is not labeled for the use under discussion or is still investigational Lampalizumab. L. Gibiansky: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. J. Good: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. T. Davancaze: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. A. Morimoto: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. K. Loyet: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. M. van Lookeren Campagne: 1. This research was sponsored by Genentech. 2. I am a paid consultant/ employee for Genentech. E. Strauss: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. R. Graham: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. J. Jin: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech. J. Visich: 1. This research was sponsored by Genentech. 2. I am a paid consultant/employee for Genentech.

A SYSTEMS PHARMACOLOGY MODEL TO CHARACTERIZE THE EFFECT OF BLINATUMOMAB IN PATIENTS WITH ADULT B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL). I. Singh,1 T. Yuraszeck,1 M. Klinger,2 M. Reed,3 C. Friedrich,3 R. Kumar,3 S. Pagano,3 M. Zhu1; 1Amgen Inc., Thousand Oaks, CA, 2Amgen Research (Munich) GmbH, Munich, Germany, 3Rosa & Co., San Carlos, CA. I. Singh: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. T. Yuraszeck: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. M. Klinger: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Research (Munich) GmbH. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. M. Reed: 1. This research was sponsored by Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. C. Friedrich: 1. This research was sponsored by Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. R. Kumar: 1. This research was sponsored by Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. S. Pagano: 1. This research was sponsored by Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab. M. Zhu: 1. This research was sponsored by Amgen Inc. 2. I am a paid consultant/employee for Amgen Inc. 5. I am a significant stockholder for Amgen Inc. 6. The following product discussed is not labeled for the use under discussion or is still investigational blinatumomab.

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BACKGROUND: Blinatumomab is a bispecific T cell-engaging (BiTE®) antibody that links CD3+ T cells to CD19+ B cells, resulting in T-cell-mediated cytotoxic B-cell apoptosis. We developed a mechanistic systems pharmacology model to describe the treatment effect of blinatumomab in adult B-ALL. METHODS: A systems pharmacology model of relevant biology in bone marrow and plasma was built to capture pharmacokinetics (PK); T-/B-cell and cytokine dynamics; and treatment effects. Literature and clinical data from MRD+ B-ALL patients were used for parameter calibration. Several adult virtual patients were created and sensitivity analysis was performed to test the effect of physiological factors on plausible mechanisms of complete, partial or no response to blinatumomab treatment. RESULTS: The model well described the drug PK, cytokine, and T- and B-cell dynamic profiles of MRD+ B-ALL patients treated with blinatumomab. Sensitivity analysis showed that treatment response was sensitive to malignant B-cell production rate, blinatumomab/ T-/B-cell complex binding efficiency, T-cell cytotoxicity, and drug clearance, but less sensitive to initial T- and B-cell numbers. Simulation suggests that in responders, circulating normal and malignant B cells are depleted to undetectable levels within the first two cycles of treatment, and normal B cells gradually recover to baseline levels after treatment stops. CONCLUSION: The systems pharmacology model is the first to describe the underlying pharmacology and response to blinatumomab treatment of adult B-ALL. The model can be applied to optimize blinatumomab regimens, to understand the potential response to other drugs with similar mode of action, and to support hypothesis generation and testing in discovery and clinical research.

BP-008 POPULATION PHARMACOKINETICS OF MAVRILIMUMAB IN RHEUMATOID ARTHRITIS PATIENTS. C. Wu,1 B. Wang,1 B. Yang,2 K. Kowalski,2 P. Ryan,3 A. Godwood,4 D. Saurigny,4 D. Close,4 L. Roskos3; 1Medimmune, Hayward, CA, 2Ann Arbor Pharmacometrics Group, Ann Arbor, MI, 3Medimmune, Gaithersburg, MD, 4Medimmune, Cambridge, United Kingdom. C. Wu: 2. I am a paid consultant/employee for Medimmune. B. Wang: 2. I am a paid consultant/employee for Medimmune. B. Yang: 2. I am a paid consultant/employee for Medimmune. K. Kowalski: 2. I am a paid consultant/employee for Medimmune. P. Ryan: 2. I am a paid consultant/employee for Medimmune. A. Godwood: 2. I am a paid consultant/employee for Medimmune. D. Saurigny: 2. I am a paid consultant/employee for Medimmune. D. Close: 2. I am a paid consultant/employee for Medimmune. L. Roskos: 2. I am a paid consultant/employee for Medimmune. BACKGROUND: Mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony stimulating factor (GM-CSF) receptor α, was investigated in Phase I and II trials for the treatment of rheumatoid arthritis (RA). In this study, we describe the development of a target mediated drug disposition (TMDD) model for mavrilimumab in early clinical development. METHODS: Mavrilimumab serum concentrations following single intravenous dose (0.01-10 mg/kg) or multiple subcutaneous doses of mavrilimumab (10, 30, 50 or 100 mg) once every other week were pooled for the analysis. A quasi steady state approximation of the TMDD model was used in the analysis. Covariates included in the initial full pharmacokinetic PK model were age, body weight, sex, race and time-varying immunogenicity. The final PK model was developed by selecting a subset of significant covariates based on the full model using the Wald’s Approximation Method and a subsequent confirmatory forward selection and backward elimination procedure. RESULTS: Mavrilimumab PK was adequately described by a two-compartment model with parallel linear and target-mediated nonlinear eliminations from the central compartment. Three covariate effects were retained in the PK final model, including body weight (WT) on clearance (CL) and central volume (Vc) and time-varying immunogenicity on Vc. Both CL and Vc increase with increasing WT. The typical values of the PK parameter estimates were also estimated.

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CONCLUSION: A TMDD model was developed that accurately described the time-course of mavrilimumab concentrations observed in two early clinical trials and supported the development of subsequent staged PK/PD modeling.

BP-009 REPEATED TIME TO EVENT MODELING OF THE RELATIONSHIP BETWEEN rFVIIIFc ACTIVITY AND SPONTANEOUS BLEEDING IN HEMOPHILIA. A.Y. Hang, I. Nestorov; Biogen Idec, Cambridge, MA. Y. Hang: 2. I am a paid consultant/employee for Biogen Idec. I. Nestorov: 2. I am a paid consultant/employee for Biogen Idec. BACKGROUND: rFVIIIFc is a recombinant coagulation factor VIII Fc fusion protein designed as a long-lasting version of rFVIII. In a pivotal Phase III study, A-LONG, individualized and weekly prophylactic treatments with rFVIIIFc reduced the bleeding rate by 92% and 76% compared to an episodic regimen. Our objective was to apply Repeated-Time-to-Event (RTTE) methodology to model the relationship between rFVIIIFc activity and spontaneous bleeding in subjects with episodic regimen. METHODS: 23 severe hemophilia A subjects in the episodic treatment arm of the A-LONG study and 16 patients from a Phase I/IIa study were included in the analysis. A population PK model was developed to predict rFVIIIFc activity for each individual. In the RTTE model, baseline hazard rate is assumed to be constant over time within an individual and follows a log-normal distribution. The hazard at any time is reduced by the instantaneous rFVIIIFc activity level, described by an Emax model. NONMEM with Laplacean and EM algorithms were used for estimation. RESULTS: The Laplacean estimated baseline hazard was 0.00745 (SE: 0.002) hr-1, yielding mean time to bleeding of 5.6 days. The estimated inter-subject variability (CV%) of baseline hazard is 110% (SE: 16.9%).The estimated IC50 was 0.283 (SE: 0.083) IU/dL, indicating rFVIIIFc is an effective treatment to decrease bleeding risk. Various EM algorithm based estimation methods yielded similar results. CONCLUSION: The proposed model provides a quantitative description of the effect of rFVIIIFc activity on reducing the risk of spontaneous bleeding. While low frequency of events could lead to difficulty in identifying baseline hazard and IC50 in an RTTE model, simulations suggested that data collected from on-demand regimen could provide adequate information on both parameters.

BP-010 A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFECTS OF RBP-8000 ON COCAINE PK AND COCAINE-INDUCED PHYSIOLOGICAL EFFECTS IN COCAINE USERS. Y. Chen, B. Zheng, Y. Liu, C. Heidbreder, P.J. Fudala, A. Nasser; Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA. Y. Chen: 2. I am a paid consultant/employee for Reckitt Benckiser Pharmaceuticals Inc. B. Zheng: 2. I am a paid consultant/employee for Reckitt Benckiser Pharmaceuticals Inc. Y. Liu: 2. I am a paid consultant/employee for Reckitt Benckiser Pharmaceuticals Inc. C. Heidbreder: 2. I am a paid consultant/ employee for Reckitt Benckiser Pharmaceuticals Inc. P.J. Fudala: 2. I am a paid consultant/employee for Reckitt Benckiser Pharmaceuticals Inc. A. Nasser: 2. I am a paid consultant/employee for Reckitt Benckiser Pharmaceuticals Inc. BACKGROUND: RBP-8000 is a double mutant cocaine esterase that rapidly metabolizes cocaine to inactive metabolites. The objectives of this study were to assess the pharmacokinetics (PK) of cocaine and cocaine-induced physiological effects (heart rate and systolic blood pressure) in the absence (placebo) and presence of 100 or 200 mg RBP-8000. METHODS: 28 cocaine users were randomized 1:1 (active: placebo) to 4 sequences and 2 treatment periods. The two periods were separated by a 72-hour washout. Subjects received a 50 mg (free base)

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IV infusion of cocaine over 10 minutes, followed by a 2-min IV infusion of 100 mg or 200 mg RBP-8000 or matched placebo. Blood samples were collected over 24 hours. Cocaine and RBP-8000 plasma concentrations were quantified using LC/MS/MS and ELISA validated methods, respectively. Cocaine PK parameters, heart rate, and systolic blood pressure were statistically compared between placebo and RBP8000 groups. RESULTS: After RBP-8000 administration, cocaine concentration dropped by 90% of peak concentration within 2 min. In RBP-8000 groups, AUC0-t of cocaine was 5% of the placebo groups. The effect of RBP-8000 was not dose proportional. However, the 200 mg RBP-8000 dose produced longer lasting effect on cocaine PK. Systolic blood pressure and pulse rate decreased to a higher extent and faster after RBP-8000 injection compared to placebo. CONCLUSION: RBP-8000 rapidly hydrolyzed plasma cocaine concentrations and significantly decreased cocaine-induced physiological effects. This study provides strong evidence in support of the use of RBP-8000 as a pharmacotherapy for cocaine intoxication.

BP-011 DEVELOPMENT AND APPLICATION OF SYSTEMS PHARMACOLOGY MODEL TO PREDICT NAUSEA RESULTED FROM ADMINISTRATION OF GLP-1 AGONISTS. V. Voronova, O. Demin Jr, S. Smirnov, O. Demin; Institute for Systems Biology SPb, Moscow, Russian Federation. V. Voronova: None. O. Demin Jr: None. S. Smirnov: None. O. Demin: None. BACKGROUND: Glucagon-like peptide 1 (GLP-1) analogues are a promising group of drugs for type 2 diabetes treatment with complex mechanism of action. GLP-1 analogues increase stomach food retention, which causes nausea. The aim of this work was to explore influence of GLP-1 analogues on gastric emptying and to link gastric food accumulation with nausea incidence during the treatment using a systems pharmacology approach. METHODS: A series of ordinary differential equations was developed to characterize movement of food in the gastrointestinal tract, synthesis and degradation of GLP-1 in blood, GLP-1 and its analogs binding to the receptors, and nausea appearance. Parameters of the model were taken from the literature or fitted against published data. RESULTS: The final model adequately describes food retention data (see Figure) and incidence of nausea during GLP-1 agonists administration with different pharmacokinetics properties. Mechanisms of nausea appearance and adaptation have been studied. CONCLUSION: It was shown that (i) long-acting GLP-1 agonists with extended treatment period and high-amplitude oscillations in concentration (Albiglutide) cause more long nausea; (ii) dose escalation during the treatment (Exenatide IR) leads to slower drug accumulation in blood and reduces nausea incidence.

BP-012 CLINICAL PHARMACOKINETICS OF INTRATHECALLY ADMINISTERED HGT-1410 IN PATIENTS WITH SANFILIPPO SYNDROME TYPE A (MPS IIIA). J. Chung, R. Pfeifer, P. Haslett, M. Mascelli, T.G. McCauley; Shire, Lexington, MA J. Chung: 1. This research was sponsored by Shire. R. Pfeifer: None. P. Haslett: None. M. Mascelli: None. T.G. McCauley: None. BACKGROUND: HGT-1410 (recombinant human heparan N-sulfatase) via intrathecal (IT) administration is undergoing clinical development for the treatment of patients with mucopolysaccharidosis (MPS) IIIA, a lysosomal storage disease (LSD), with central nervous system (CNS) manifestations. METHODS: Study HGT-SAN-055 enrolled patients ≥3 years of age with a documented diagnosis of MPS IIIA who were untreated with investigational products for MPS IIIA, to provide a total of 12 evaluable patients (3 dose groups, 4 patients per group). The dose regimen was monthly IT administration via an Intrathecal Drug Delivery Device (IDDD) at doses of 10, 45, and 90 mg/patient. PK sampling was performed following first (week 2) and final (week 22) doses. RESULTS: While determination of a comprehensive PK profile in CSF was not clinically feasible, HGT-1410 levels were evaluated indirectly by measuring systemic serum HGT-1410 concentrationtime profiles. Following IT administration, a gradual translocation of HGT-1410 from cerebrospinal fluid (CSF) to the venous system was observed. IT administration of HGT-1410 exhibited biphasic serum concentration-time profiles across all 3 dose groups. Anti-HGT-1410 serum antibodies were detected in 2 of 12 patients at Week 2 (baseline) and 6 of 12 patients at Week 22. Dose-proportionality was observed in antibody negative but not in antibody positive patients, suggesting the presence of anti-HGT-1410 antibodies altered the PK characteristics of HGT-1410. CONCLUSION: This study described the serum pharmacokinetic characteristics of HGT-1410 following IT administration in patients with MPSIIIA. Serum exposure is proportional to the dose in antibody negative patients and no clear pattern in antibody effect on serum HGT-1410 exposure.

BP-013 LBEC0101, AN ETANERCEPT BIOSIMILAR, SHOWED COMPARABLE TOLERABILITY AND PHARMACOKINETIC PROFILES TO THOSE OF ETANERCEPT IN HEALTHY MALE VOLUNTEERS. H. Chung, L. Ahn, Y. Choi, S. Shin, I. Jang, K. Yu, H. Lee; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. H. Chung: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. L. Ahn: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. Y. Choi: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. S. Shin: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. I. Jang: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. K. Yu: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. H. Lee: 1. This research was sponsored by LG Life Sciences, Ltd., Korea. BACKGROUND: LBEC0101, a biosimilar of etanercept, is a fusion protein of the ligand-binding portion of the human tumor necrosis factor receptor II, linked to the Fc portion of human immunoglobulin G1. The objective of this study was to compare the tolerability and pharmacokinetic characteristics of LBEC0101 with those of etanercept, a reference product. METHODS: A randomized, double-blind, two-treatment, twoperiod, two-sequence, crossover study was conducted in 48 healthy male volunteers. In each period, a single subcutaneous injection of LBEC0101 or etanercept at 25 mg was administered and serial blood samples were collected up to 648 hours after injection for

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pharmacokinetic analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum concentrations of the study drugs and their pharmacokinetic parameters were derived using the non-compartmental method. Tolerability was evaluated throughout the study. RESULTS: A total of 43 subjects (89.6%) completed the study with no clinically relevant safety issues. The mean values of the maximum plasma concentrations (Cmax) and the area under the concentration-time curve from time 0 to the last measurable time point (AUClast) for etanercept were 1.71 μg/mL and 348.14 h*μg /mL, respectively. The corresponding values for LBEC0101 were 1.77 μg/mL and 345.86 h*μg/mL, respectively, leading to the geometric mean ratios (90% confidence intervals) of LBEC0101 to etanercept of 1.02 (0.92-1.13) and 0.96 (0.87-1.06) for Cmax and AUClast, respectively. CONCLUSION: LBEC0101 and etanercept were both well tolerated at 25 mg in healthy male volunteers. LBEC0101 is bioequivalent to etanercept as assessed by the conventional criteria of [0.8-1.25]. LBEC0101 may be developed further as a clinically effective alternative to etanercept.

BP-014 PHARMACOKINETICS OF MOXETUMOMAB PASUDOTOX, AN INVESTIGATIONAL IMMUNOTOXIN TARGETING CD22, IN PATIENTS WITH RELAPSED OR REFRACTORY HAIRY CELL LEUKEMIA. B. Wang,1 L. Chang,1 R.J. Kreitman,2 R. Ibrahim,3 T. Goswami,3 I. Pastan,2 M. Liang,1 L. Roskos1; 1MedImmune, Hayward, CA, 2National Cancer Institute/National Institutes of Health, Bethesda, MD, 3MedImmune, Gaithersburg, MD.B. Wang: 1. This research was sponsored by MedImmune. L. Chang: 1. This research was sponsored by MedImmune. R.J. Kreitman: 1. This research was sponsored by MedImmune. R. Ibrahim: 1. This research was sponsored by MedImmune. T. Goswami: 1. This research was sponsored by MedImmune. I. Pastan: 1. This research was sponsored by MedImmune. M. Liang: 1. This research was sponsored by MedImmune. L. Roskos: 1. This research was sponsored by MedImmune. BACKGROUND: Moxetumomab pasudotox is an immunotoxin composed of murine anti-CD22 variable domains (Fv) linked to a truncated form of Pseudomonas exotoxin. METHODS: In a Phase I, multicenter, dose escalation study, patients with relapsed or refractory hairy cell leukemia (HCL) received three intravenous infusions of moxetumomab pasudotox on Days 1, 3 and 5 of each 28-day treatment cycle. The starting dose was 5 μg/kg and subsequent cohort dose-escalation followed a standard 3+3 design with an expanded cohort at 50 μg/kg. Blood samples were collected at designated time points for pharmacokinetic (PK) and immunogenicity evaluations. Plasma concentrations of moxetumomab pasudotox were determined using a validated sandwich enzyme-linked immunosorbent assay (ELISA). The presence of anti-drug antibodies was detected by a screening assay followed by a solid-phase ELISA-based neutralizing assay. Noncompartmental analysis was performed on the individual PK data. RESULTS: The elimination half-life of moxetumomab pasudotox was 1 to 3 hours. In 12 HCL subjects receiving 50 µg/kg moxetumomab pasudotox, the first-dose mean area under the concentration-time curve (AUC) increased from 539 ng.h/mL at Cycle 1 to 2250 ng.h/mL at Cycle 5. Reduction in systemic clearance to a similar residual value of 10 to 20 mL/kg/h on repeated dosing suggests all doses depleted CD22+ cells. Within the first dosing cycle, increased AUC from Day 1 to Day 5 may be predictive of best disease response. The presence of anti-drug antibodies (ADA) was associated with reduced PK exposure in some subjects. CONCLUSION: Overall results from this Phase I study supported a development decision to initiate a pivotal trial for moxetumomab pasudotox in patients with advanced HCL.

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BP-015 PHARMACOKINETICS OF PEGINTERFERON BETA-1A DELIVERED BY SINGLE-USE AUTOINJECTOR AND PREFILLED SYRINGE. X. Hu, Y. Cui, A. Ali Seddighzadeh, S. Hung; Biogen Idec, Cambridge, MA. X. Hu: 1. This research was sponsored by Biogen Idec. 2. I am a paid consultant/employee for Biogen Idec. 5. I am a significant stockholder for Biogen Idec. 6. The following product discussed is not labeled for the use under discussion or is still investigational Peginterferon beta-1a. Y. Cui: 1. This research was sponsored by Biogen Idec. 2. I am a paid consultant/employee for Biogen Idec. 5. I am a significant stockholder for Biogen Idec. 6. The following product discussed is not labeled for the use under discussion or is still investigational Peginterferon Beta-1a. A. Ali Seddighzadeh: 1. This research was sponsored by Biogen Idec. 2. I am a paid consultant/ employee for Biogen Idec. 5. I am a significant stockholder for Biogen Idec. 6. The following product discussed is not labeled for the use under discussion or is still investigational Peginterferon Beta-1a. S. Hung: 1. This research was sponsored by Biogen Idec. 2. I am a paid consultant/ employee for Biogen Idec. 5. I am a significant stockholder for Biogen Idec. 6. The following product discussed is not labeled for the use under discussion or is still investigational Peginterferon beta-1a. BACKGROUND: Peginterferon beta-1a demonstrated efficacy to treat multiple sclerosis (MS) in a Phase III study (n=1512), in which prefilled syringe (PFS) was used as delivery device. Autoinjector (AI) can simplify administration process and reduce injection burden. This study was to characterize pharmacokinetics of peginterferon beta-1a delivered subcutaneously by either device to support the development of AI. METHODS: This was an open-label, two-sequence, crossover study with a 3-week washout period. Subjects were randomized into two groups (1:1). Group 1 was treated with PFS (Day 1) followed by AI (Day 22); Group 2 was treated with a reversed sequence. Thirty subjects were planned to have 24 evaluable subjects (not powered to establish bioequivalence). PK samples were collected at predose and up to 240 hours post-dose following each dosing. Drug concentration was measured using enzyme-linked immunosorbent assay. PK parameters were calculated using non-compartmental analysis. RESULTS: Twenty-four subjects received both PFS and AI treatments. One subject was excluded from the summary analysis because no drug was detectable after PFS injection on Day 22 and high- titer anti-PEG antibody was detected at pre-dose. The exposure was similar between the two devices. The geometric mean AUCinf, Cmax, and t1/2 was 41.0 h·ng/mL, 427 pg/mL, and 39.9 h, respectively, following AI injection; the geometric mean AUCinf, Cmax, and t1/2 was 38.3 h·ng/mL, 365 pg/mL, and 46.0 h, respectively, following PFS injection. The percent difference in geometric means were 7.14% for AUCinf, 17.1% for Cmax, and -13.3% for t1/2. The safety profiles of the two devices were similar. CONCLUSION: These data demonstrated PK similarity between AI and PFS, supporting the development of the AI to improve treatment convenience.

BP-016 PHARMACOKINETIC AND EXPOSURE-RESPONSE ANALYSES OF PERTUZUMAB PLUS TRASTUZUMAB AND DOCETAXEL DURING NEOADJUVANT TREATMENT OF HER2+ EARLY BREAST CANCER. A.L. Quartino,1 H. Li,2 J.Y. Jin,1 D. Wada,2 G. Ross,3 L. Gianni,4 J. Visich,1 B. Lum,1 A. Garg1; 1Genentech Inc., South San Francisco, CA, 2Quantitative Solutions Inc., Menlo Park, CA, 3Roche Products Ltd, Welwyn Garden City, United Kingdom, 4Oncologia Medica, San Raffaele Cancer Centre, Milan, Italy. A.L. Quartino: 2. I am a paid consultant/employee for Genentech Inc. 4. I hold a patent for F. Hoffmann-La Roche Ltd. H. Li: 2. I am a paid consultant/employee for Genentech Inc. J.Y. Jin: 2. I am a paid consultant/employee for Genentech Inc. 5. I am a significant stockholder for F. Hoffmann-La Roche Ltd. D. Wada: 2. I am a paid consultant/employee for Genentech Inc. G. Ross: 2. I am a paid

volume 95 supplement 1 | mar 2014 | www.nature.com/cpt

ABSTRACTs

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consultant/employee for F.Hoffmann-La Roche Ltd. L. Gianni: 2. I am a paid consultant/employee for F.Hoffmann-La Roche Ltd, Genentech. J. Visich: 2. I am a paid consultant/employee for Genentech Inc. 5. I am a significant stockholder for F. Hoffmann-La Roche Ltd. B. Lum: 2. I am a paid consultant/employee for Genentech Inc. 5. I am a significant stockholder for F. Hoffmann-La Roche Ltd. A. Garg: 2. I am a paid consultant/employee for Genentech Inc. 5. I am a significant stockholder for F. Hoffmann-La Roche Ltd. BACKGROUND: Pertuzumab (Ptz) in combination with trastuzumab (T) and docetaxel (D) is approved for the treatment of first line HER2-positive metastatic breast cancer. NEOSPHERE was a 4-arm study evaluating the efficacy and safety of neoadjuvant/ adjuvant treatment in HER2-positive early breast cancer (EBC). The primary efficacy endpoint was pathological complete response (pCR) evaluated at Cycle 4. The aims of the analyses were to: (i) compare PK in NEOSPHERE to historical data; (ii) explore potential PK drugdrug interactions (DDI); (iii) explore the exposure-response (ER) relationship between Ptz Cmin and pCR. METHODS: Limited PK data was obtained from Ptz (n=139) and T (n=135) patients. PK data for each antibody was compared with simulations from previous population PK (popPK) models after correcting for differences in covariates. DDI between Ptz, T and D were examined by empirical Bayes estimates of individual PK parameters by analysis of variance (ANOVA) (p20 µg/mL. CONCLUSION: This ER analysis supports 20 μg/mL as the target Cmin during Ptz treatment and further supports the appropriateness of the Ptz 840 mg loading dose followed by a 420 mg maintenance dose q3w regimen in neoadjuvant EBC.

BP-017 POPULATION PHARMACOKINETICS AND EVALUATION OF FIXED DOSING FOR PERTUZUMAB, A HER2 TARGETED MONOCLONAL ANTIBODY, IN CANCER PATIENTS. A. Garg,1 J. Li,1 A. Quartino,1 J. Jin,1 D.R. Wada,2 H. Li,2 J. Cortes,3 V. McNally,4 J. Visich,1 B. Lum1; 1Genentech, Inc., South San Francisco, CA, 2Quantitative Solutions Inc., Menlo Park, CA, 3Vall d’Hebron University Hospital, Barcelona, Spain, 4Roche Products, Welwyn Garden City, United Kingdom. A. Garg: 1. This research was sponsored by Genentech, Inc. 2. I am a paid consultant/employee for Genentech, Inc. 5. I am a significant stockholder for Roche. J. Li: 2. I am a paid consultant/employee for Medimmune. A. Quartino: 2. I am a paid consultant/employee for Genentech, Inc. 5. I am a significant stockholder for Roche. J. Jin: 2. I am a paid consultant/employee for Genentech, Inc. 5. I am a significant stockholder for Roche. D.R. Wada: 2. I am a paid consultant/employee for Genentech, Inc. H. Li: 2. I am a paid consultant/employee for Genentech, Inc. J. Cortes: 2. I am a paid consultant/employee for Roche. V. McNally: 2. I am a paid consultant/employee for Roche. J. Visich: 2. I am a paid consultant/ employee for Genentech, Inc. 5. I am a significant stockholder for Roche. B. Lum: 2. I am a paid consultant/employee for Genentech, Inc. 5. I am a significant stockholder for Roche. BACKGROUND: Pertuzumab is a humanized monoclonal antibody (mAb) with a novel mechanism of action, which targets dimerization of the HER2 receptor with other HER-family members (HER1, HER3 and HER4), and works cooperatively with trastuzumab, another HER2-targeted mAb. Pertuzumab in combination with trastuzumab and docetaxel is indicated for patients with HER2+ first line metastatic breast cancer. A population PK analysis was conducted to characterize pertuzumab PK across clinical trials in multiple tumor

types, to assess the impact of covariates that may impact PK, and to evaluate fixed dosing of pertuzumab. METHODS: Pertuzumab was administered every 3 weeks as an IV infusion, as a weight-based dose (0.5-25 mg/kg), or as a fixed dose (840 mg loading followed by 420 mg maintenance or 1050 mg without a loading dose). Data from 12 Phase I/II/III clinical studies, comprising 481 patients and 4,525 samples, were pooled for this analysis using NONMEM 7. RESULTS: Serum pertuzumab PK was described by a twocompartment linear model with first-order elimination. The elimination clearance (CL), central compartment volume (Vc), and terminal halflife were 0.235 L/day, 3.11 L, and 18.0 days, respectively. Baseline serum albumin and lean body weight were significant covariates affecting PK, explaining only a small percentage of inter-individual variability, and therefore do not require dose modification. Simulations comparing fixed and body-weight adjusted dosing, showed comparable distributions of steady-state Cmin, and confirmed the adequacy of the fixed dosing of pertuzumab. CONCLUSION: A population PK model was developed for pertuzumab. The analysis supports the use of fixed, non-weight-based dosing to achieve the desired pertuzumab exposure in most patients, irrespective of any covariates.

BP-018 C-REACTIVE PROTEIN ANTISENSE SELECTIVELY AND POTENTLY INHIBITS CRP INCREASE FOLLOWING ENDOTOXIN CHALLENGE IN HUMANS. R.J. Noveck; Duke University School of Medicine, Durham, NC. R.J. Noveck: 1. This research was sponsored by ISIS Pharmaceuticals, Inc. BACKGROUND: C-Reactive Protein (CRP) plays an active role in inflammation and elevated CRP has been implicated in the pathophysiology of multiple diseases. This study evaluated the effects of pretreatment with an antisense inhibitor of CRP (ISIS-CRPRx) on the acute phase response induced by endotoxin challenge. METHODS: Healthy adult males (N=35) were randomized 2 active: 1 placebo into 2 cohorts of a double-blind, placebo-controlled, study and received 6 doses of ISIS-CRPRx (400 or 600 mg ISIS 329993) or placebo IV on Day 1, 3, 5, 8, 15 and 22. On Day 26, eligible subjects received endotoxin (2 ng/kg IV). During the challenge, subjects were monitored closely and key inflammatory markers were measured serially. RESULTS: ISIS-CRPRx was well tolerated with no serious adverse events. Endotoxin elicited a pro-inflammatory response as expected. CRP increased following endotoxin >30-fold from baseline in placebo subjects (Figure). ISIS-CRPRx blunted the endotoxin-induced increase in CRP by 36% (400 mg) and 64% (600 mg), p

Abstracts of the American Society for Clinical Pharmacology and Therapeutics 2014 Annual Meeting, March 18-22, 2014, Atlanta, Georgia.

Abstracts of the American Society for Clinical Pharmacology and Therapeutics 2014 Annual Meeting, March 18-22, 2014, Atlanta, Georgia. - PDF Download Free
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