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Objective To describe the systemic pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion (RVO) or diabetic macular edema (DME). Design A population approach of nonlinear mixed-effect pharmacokinetics modeling based on serum concentrations of ranibizumab measured at various times after intravitreal administration. Participants Patients with RVO (n = 441) and DME (n = 435) from 4 large, randomized, phase 3 clinical trials of monthly ranibizumab intravitreal administration. Methods A 1-compartment pharmacokinetics model with first-order absorption and elimination rate constants previously developed in patients with age-related macular degeneration (AMD) was fitted separately to RVO and DME data. Population pharmacokinetic parameters and interindividual variability were estimated for each model. Baseline covariates were evaluated for potential effects on systemic pharmacokinetics. Model performance was validated using general diagnostic plots and a visual predictive check. Main Outcome Measures Ranibizumab disposition was determined in RVO and DME patients and compared with that previously seen in AMD patients. Results The AMD pharmacokinetics model correctly predicted the measured serum ranibizumab concentration data for RVO and DME patients. Most observed data points were within the simulated 90% confidence interval, indicating that systemic ranibizumab concentrations were comparable among AMD, RVO, and DME patients. No disease-related covariates were identified by the population pharmacokinetics analysis. Conclusions The systemic pharmacokinetics of ranibizumab were similar among patients with AMD, RVO, or DME. Disease-related differences and patient demographics, measured in this study, did not lead to variability in ocular elimination or in systemic exposure of ranibizumab after intravitreal administration. In all disease processes tested, ranibizumab exits the eye slowly and then is eliminated rapidly from the circulation, thus minimizing systemic exposure.

Background Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. Methods Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. Results Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. Conclusions There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. Trial registration number NCT02118831.

Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

Purpose The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. Methods Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (–30 and –15 min) and after (0–15 and 60–75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia’s correction was applied to QT measurements (QTcF) and change from baseline (ΔQTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure–response relationships between ΔQTcF and observed pertuzumab concentrations. Results Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔQTcF (90 % CI) values at 0–15 min, 60–75 min, and 72 h post-infusion were −6.96 (−13.69, −0.23), −6.35 (−13.57, 0.88), and −4.08 (−12.64, 4.48), all of which were

This retrospective analysis characterizes rituximab population pharmacokinetics in combination with fludarabine and cyclophosphamide and its effect on fludarabine and cyclophosphamide disposition in chronic lymphocytic leukemia (CLL) patients. Rituximab concentration data were well described by a 2-compartment model comprising a time-varying clearance component related to the target-mediated clearance pathway and a constant clearance component reflecting catabolic elimination pathway. Marked differences were observed compared to pharmacokinetic parameters for non-Hodgkin lymphoma (NHL) obtained previously: in CLL, time-varying clearance at time zero (CL(2)) was faster, volumes of distribution (V(1) and V(2)) were larger, and rate of change (K(des)) from the targetmediated clearance pathway to catabolic elimination was lower than NHL. Fludarabine and cyclophosphamide disposition showed no apparent change when co-administered with rituximab. A positive correlation between pharmacokinetic parameters and clinical response was observed, supporting the use of the higher rituximab dose of 500 mg/m(2) in CLL patients (vs 375 mg/m(2) in NHL) to achieve an effective clinical response.

To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a monoclonal antibody directed against the B-cell activating factor (BAFF) receptor 3 (BR3), following intravenous (IV) and subcutaneous (SC) administration in mice.Single IV doses of 0.2, 2.0 and 20 mg/kg and a single SC injection of 20 mg/kg of anti-BR3 antibody was administered to mice. Serum drug and BAFF concentrations and splenic B-cell concentrations were measured at various time points. Pooled PK profiles were described by a two-compartmental model with time-dependent nonlinear elimination, and BAFF profiles were defined by an indirect response model. Fractional receptor occupancy served as the driving function for a competitive reversible antagonism model to characterize B-cell dynamics.Noncompartmental analysis revealed a decrease in drug clearance (31.3 to 7.93 mL/day/kg) with increasing IV doses. The SC dose exhibited slow absorption (T(max) = 2 days) and complete bioavailability. All doses resulted in a dose-dependent increase in BAFF concentrations and decrease in B-cell counts. The proposed model reasonably captured complex PK/PD profiles of anti-BR3 antibody after IV and SC administration.A mechanistic model was developed that describes the reversible competition between anti-BR3 antibody and BAFF for BR3 receptors and its influence on B-cell pharmacodynamics.

Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Göttingen minipigs were compared with data obtained previously from humans. The present studies demonstrated: (1) minipig is predictive of human linear clearance; (2) the SC bioavailabilities in minipigs are weakly correlated with those in human; (3) minipig mAb SC absorption rates are generally higher than those in human and (4) the SC bioavailability appears to correlate with systemic clearance in minipigs. Given the important role of the neonatal Fc-receptor (FcRn) in the PK of mAbs, the in vitro binding affinities of these IgGs against porcine, human and cynomolgus monkey FcRn were tested. The result showed comparable FcRn binding affinities across species. Further, mAbs with higher isoelectric point tended to have faster systemic clearance and lower SC bioavailability in both minipig and human. Taken together, these data lend increased support for the use of the minipig as an alternative predictive model for human IV and SC PK of mAbs.

9521Background: IMCgp100 is a bispecific biologic comprised of a soluble T cell receptor recognizing the gp100 antigen fused to a scFV anti-CD3 and redirects T cell lysis of melanoma cells expressi...

Atacicept is a recombinant fusion protein containing the extracellular ligand-binding portion of the transmembrane activator and CAML interactor (TACI, CD267) receptor and inhibits B lymphocyte stimulator (BLyS, CD257) and a proliferation-inducing ligand (APRIL, CD256), both potent stimulators of B cell maturation, proliferation, and survival. Atacicept pharmacokinetics and pharmacodynamics were assessed in a double-blind, placebo-controlled, phase I study in patients with active, moderate to severe rheumatoid arthritis receiving atacicept either as a single subcutaneous or repeated, every other week dose. Pharmacokinetic profiles were determined by measuring serum concentrations of free atacicept and its complex with BLyS. Nonspecific immunoglobulin (Ig)M, IgG, and IgA; IgM-RF (rheumatoid factor), IgG-RF, and IgA-RF antibody levels; and B cell profiles provided markers of biological activity. Pharmacokinetic, biological activity, and relationships between atacicept dose and Ig antibody response were evaluated. Pharmacokinetic profiles of atacicept were nonlinear, influenced by saturable binding with its ligands, but were consistent and predictable. Atacicept treatment reduced Ig and RF serum concentration. IgM antibody levels were most sensitive to atacicept, followed by IgA and IgG, underlining the biological activity of atacicept in patients with rheumatoid arthritis. These findings can be used to explore dosing regimen design scenarios in future studies.

Atacicept, a recombinant fusion protein, blocks the activity of BLyS (a B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) and may be a potential treatment for B-cell-mediated diseases. This study assesses the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of atacicept. In this Phase I study, healthy male volunteers received a single subcutaneous dose of atacicept (2.1, 70, 210 or 630 mg) or placebo and were monitored over 7 weeks for injection-site pain, local tolerability, vital signs, echocardiography, haematology, coagulation, blood chemistry, serum virology, urinalysis and PK/PD markers [lymphocyte cell counts, BLyS–atacicept complex, immunoglobulin G (IgG), IgM]. Atacicept was well tolerated at all doses (n = 23). There were no clinically significant changes in vital signs or laboratory parameters during the study. Treatment-emergent adverse events (AEs) were mainly mild or moderate in severity, and all were transient, resolving without any clinical sequelae. There was no evidence of any relationship between atacicept dose and the incidence of AEs. Local tolerability was good. Serum atacicept peaked 16 h after dosing, and the area under the concentration-time curve increased in an approximately dose-related manner. The 70-, 210- and 630-mg doses of atacicept demonstrated a dose-dependent biological effect on IgM levels, which was apparent up to 210 days post-dose. There were no treatment-related effects on IgG levels or lymphocyte subpopulations. These results showed that single subcutaneous doses of atacicept were well tolerated in healthy volunteers, demonstrated non-linear PK and were biologically active, according to IgM levels.

Summary. Background: Recombinant human thrombin (rhThrombin) is being developed as a general adjunct to hemostasis. Endogenous thrombin is rapidly inactivated by complex formation with antithrombin III and other inhibitors. It follows that these inhibitors will also inactivate any rhThrombin that reaches the systemic circulation. Objectives: Study goals were to determine the pharmacokinetic characteristics of [125I]-rhThrombin and [125I]-rhThrombin complexed to endogenous inhibitors, and the tissue distribution of rhThrombin-associated radioactivity in non-human primates. Hematology, serum chemistry and coagulation status were also monitored. Methods: [125I]-rhThrombin was administered intravenously (i.v.; 3.5 U kg−1) or subcutaneously (s.c.; 350 U kg−1) to male cynomolgus monkeys. Plasma was analyzed for rhThrombin-associated radioactivity and non-compartmental analysis was used to determine the corresponding pharmacokinetic parameters. A size exclusion–high pressure liquid chromatography (SE–HPLC) method was used to quantitate rhThrombin complexes, non-complexed rhThrombin, and free [125I]. Whole-body gamma scintigraphy was used to follow radioactivity localization up to 72 h postdose. Results: No adverse events were observed following [125I]-rhThrombin administration. The pharmacokinetic profile of rhThrombin-associated radioactivity following i.v. injection was multi-exponential with an initial half-life of approximately 10 min. Following both i.v. and s.c. dosing, the terminal half-life was approximately 15 h. SE–HPLC analysis revealed that rhThrombin was rapidly complexed to antithrombin III and other inhibitors in the systemic circulation following i.v. administration. Thus, rhThrombin-associated radioactivity in the blood was complexed and presumed inactive. [125I]-rhThrombin inhibitor complexes accumulated and were eliminated in the liver following both routes of administration. Conclusions: These data suggest that rhThrombin rapidly binds to endogenous inhibitors following either i.v. or s.c. administration.

Hemostasis in humans and other animals is a complex process that controls blood loss after a vascular injury. Factor XIII (FXIII) stabilizes clots primarily by cross-linking fibrin, thus protecting a newly formed clot from fibrinolysis by plasmin. Congenital deficiencies in humans involving FXIII are associated with delayed bleeding and wound healing and severe spontaneous hemorrhaging. These symptoms can be alleviated by intravenous administration of enriched FXIII plasma fractions. Circulating plasma FXIII is found as a heterotetramer that dissociates in the presence of calcium and thrombin into an active dimer and 2 inactive monomers. The recombinant FXIII under investigation is the active dimer alone. A 3-compartment, nonlinear population pharmacokinetic model was implemented in NONMEM V and then used to analyze data from preclinical studies in cynomolgus monkeys. The model simultaneously describes endogenous production of dimer (0.622 microg kg(-1) hr(-1)) and monomer (12.1 microg kg(-1) hr(-1)), and the administration of recombinant dimer. The model incorporates the rate and extent of complexation of recombinant dimer with available endogenous monomer (6.59 mg(-1) kg hr(-1)) to form the heterotetramer. Half-lives for dimer, heterotetramer, and monomer (3.33 hours, 2.83 days, and 3.94 hours for A(2), A(2)B(2), and B, respectively) were estimated, along with their variability in the population studied.

Factor XIII (FXIII) is a thrombin-activated protransglutaminase responsible for fibrin clot stabilization and longevity. Deficiency in FXIII is associated with diffuse bleeding and wound-healing disorders in humans. This report summarizes results from several studies conducted in adult cynomolgus monkeys ( M. fascicularis) to evaluate the safety and pharmacokinetics of recombinant human factor XIII A2 dimer (rFXIII). Intravenous slow bolus injection of rFXIII resulted in the expected formation of the heterotetramer rA2cnB2, prolonged circulating half-life (5–7 days), and increased plasma transglutaminase activity. Recombinant FXIII was well tolerated as a single dose up to 20 mg/kg rFXIII (2840 U/kg), as repeated daily doses up to 6 mg/kg (852 U/kg) for 14 days, and as 3 repeated doses of 8 mg/kg (1136 U/kg) separated by 14 days. Overt toxicity occurred after a single intravenous injection of ≥ 22.5 mg/kg rFXIII (3150 U/kg), or with 2 doses of =12.5 mg/kg (1775 U/kg) administered within 72 hours. The rFXIII-mediated toxicity was expressed as an acute systemic occlusive coagulopathy. Evaluation of plasma samples from dosed animals demonstrated formation of cross-linked fibrin/fibrinogen oligomers and higher-order protein aggregates, which are hypothesized to be responsible for the observed vessel occlusion and associated embolic sequelae. These results demonstrate that rFXIII-mediated toxicity results from exaggerated pharmacological activity of the molecule at supraphysiological concentrations. The absence of observed toxicological effect with repeated intravenous doses up to 8 mg/kg (1136 U/kg) was used to support an initial clinical dose range of 0.014 to 0.35 mg/kg (2–50 U/kg).

Summary. Background: Factor XIII (FXIII) is a transglutaminase that cross-links fibrin and other proteins to improve clot strength and resistance to fibrinolysis. Both congenital and acquired FXIII deficiency may result in a bleeding diathesis, and plasma-derived FXIII has been used to treat many of these clinical conditions. Objectives: A clinical study was designed and performed to evaluate the safety, pharmacokinetics, and immunogenicity of recombinant FXIII (rFXIII) administration to healthy adult volunteers. Patients and method: Fifty healthy adult volunteers were enrolled in this randomized, double-blinded, placebo-controlled study. A single dose of rFXIII, ranging from 2 U kg−1 to 50 U kg−1, or placebo was administered. Safety was evaluated by capturing adverse events, clinical safety laboratory studies, and clinical score for deep venous thrombosis. Blood samples were taken for pharmacokinetic and immunogenicity analysis throughout the 28-day follow-up period. Results: Recombinant FXIII was well tolerated, with no serious adverse events or dose-related toxicities. Following a single i.v. injection of 50 U kg−1 rFXIII, the estimated terminal half-life was 270–320 h, the volume of distribution ranged from 40 to 75 mL kg−1, and FXIII activity increased 1.77% per 1 U kg−1 rFXIII administered. Increase in circulating A2B2 and decrease in free FXIII-B subunit indicate in vivo formation of FXIII heterotetramer. An immunogenic response to rFXIII or yeast, the production host, was not observed. Conclusions: Recombinant FXIII was well tolerated at doses of up to 50 U kg−1 in healthy adult volunteers. The safety, pharmacological and immunological profile of rFXIII suggests it should be studied in patients with congenital FXIII deficiency as well as evaluated as a systemic hemostat in patients with acquired FXIII deficiency or hemorrhage.

SummaryFactor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced inSaccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, doubleblind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency

The study characterizes the long-term pharmacokinetics (PK) following last dose of bevacizumab as adjuvant therapy in patients with resected stage II and III colon carcinoma in a Phase III clinical study (AVF3077s).Patients in AVF3077s received bevacizumab (5 mg/kg every 2 weeks) as adjuvant therapy for 1 year. Following the last dose bevacizumab concentration, data at 3 and 6 months were used to characterize long-term bevacizumab PK based on the population-modeling approach.The long-term bevacizumab PK were consistent with previously reported results based on short-term bevacizumab PK. The clearance (CL), central volume of distribution (V(1)), intercompartmental clearance (Q), and the peripheral volume of distribution (V(2)) were 214 mL/day, 2,830 mL, 636 mL/day, and 2,490 mL, which correspond to a disposition and elimination half-life of 1.33 and 19.1 days, respectively. The empirical Bayes estimates of median post-treatment bevacizumab drug levels at 3 and 6 months were 6.14 and 0.23 μg/mL, respectively. For test covariates, the change in CL and V(1) of bevacizumab was less than 20% of the typical value. Body weight is the important covariate explaining the inter-individual variability on CL and V(1).Long-term bevacizumab PK in this study was predictable based on short-term PK data from metastatic settings in other tumor types. An exploratory analysis demonstrated no apparent association of the tested covariates with bevacizumab PK. Further, the extended serum persistence of bevacizumab following last dose should be considered in clinical study designs and post-treatment evaluations that may be affected by bevacizumab.

Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.

Objective Etrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. Design In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). Results In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. Conclusion Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

A number of regulatory guidance documents discuss various aspects of the transition from preclinical to clinical study of a novel biopharmaceutical. This article reviews the decision processes surrounding the determination of the initial dose of a novel biopharmaceutical agent to be administered to subjects in clinical trials. Keywords: biopharmaceutical agent; dosing; regulatory framework; preclinical safety evaluation

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G1 Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating-inducing ligand. Here we determined the nonclinical safety, pharmacoki- netics and pharmacodynamics of atacicept in mice and cynomol- gus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc) bioavailability of atacicept in mice and monkeys was 76 and 92%, with a mean serum t1/2 of 44 and 179 h, respectively. In accord with its anticipated mechanism of action, repeated administration of atacicept decreased serum IgG concentrations up to 50%, IgM concentrations >99%, and circulating mature B-cell concentra- tions up to 60%. These effects were dose-related but reversible, as determined in a 25-week follow-up period. Microscopically, B cells numbers were reduced in the follicular marginal zone of the spleen and the mantle surrounding germinal centers of the lymph nodes. These data confirm the preclinical safety and the pharmacological activity of atacicept and support its clinical development.

HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (/=10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data.

Introduction P is a humanized mAb that inhibits heterodimerization of HER2. P and T bind distinct HER2 epitopes, and due to their complementary mechanisms of action they provide a more comprehensive blockade of HER2 signaling. Based on preclinical efficacy models, a steady-state trough P concentration (Ctrough) of 20 ug/ml was selected as target in pts. CLEOPATRA is a Phase III study comparing P + T + D vs placebo (Pla) + T + D in HER2-positive 1L MBC (Baselga NEJM 2012). The objectives of the substudy reported here are to characterize the P PK in the presence of T and D, and to explore potential drug - drug interactions. Methods P/Pla (840 mg loading, 420 mg maintenance) was administered on Day 1 of each cycle; T (8 mg/kg loading, 6 mg/kg maintenance) was administered on Day 2 of Cycle 1 and on Day 1 of each cycle onward following P; D (75 mg/m2, escalation to 100 mg/m2 if tolerated) was administered on Day 2 of Cycle 1 following T and on Day 1 of each cycle onward following T. All drugs were given q3w iv. Blood samples for P were collected before and after infusion at Cycles 1, 3, 6, 9, 12, 15, 18, and at treatment discontinuation. Samples for T were collected before and after infusion at Cycles 1 and 3. Samples for D were collected at Cycle 1 at 8 serial time points during and following the infusion over a 24 h period to allow calculation of Cmax, CL, Vss, t1/2, AUC0–t, and AUC0-inf. Results 37 pts (17 Pla arm, 20 P arm) were available for PK evaluation. Serum P Ctrough exceeded the target of 20 ug/ml in >90% of pts and there was no impact of T and D on P PK, compared with historical data. Mean serum T Cmax and Cmin at Cycles 1 and 3 were similar in both arms. Ratios of geometric LS means of P + T + D/Pla + T + D x100 for serum T were: Cycle 1 Cmax 90.3; Cycle 3 Cmin 95.9; Cycle 3 Cmax 81.0. D PK parameters were similar in both arms. Ratios of geometric LS means of P + T + D/Pla + T + D x100 for plasma D were: AUC0–t 104.9, AUC0-inf 101.4, Cmax 92.5. Conclusion P PK parameters were consistent with previous studies, and co-administration of T and D appears not to influence P PK in HER2-positive MBC. There was no evidence of drug - drug interactions between P and T, or between P and D, which have different clearance pathways. Disclosure J. Cortes: I am an advisory board member for Roche, Celgene and Novartis. I have received research funding from Roche, Celgene, Cephalon and Ferrer. S. Swain: Advisory Board for Genentech/Roche for EMILIA study and Avastin - uncompensated. Research funding: Genentech/Roche. T. Patel: I have an advisory board membership for Genentech/Roche to disclose and are a speaker for Genentech/Roche. I have received research funding from Genentech/Roche. N. Masuda: I have honoraria to disclose received from Chugai Pharmaceutical Co., Ltd. V. McNally: I am a Roche employee and hold Roche shares. J. Visich: I am an employee of Genentech. J. Baselga: Dr Baselga reports the following relationships with relation to the topic of this abstract: Roche, Sanofi Aventis, Consulting/Scientific Advisory Board. Roche, Sanofi Aventis, Honoraria for speaking engagements. All other authors have declared no conflicts of interest.

Abstract 1742 Poster Board I-768 Introduction In the randomized Phase III study REACH, the combination of rituximab (R) (375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6) and fludarabine (F) (25mg/m2 X 6 cycles) and cyclophosphamide (C) (250 mg/m2 X6 cycles) was shown to improve clinical response and prolong PFS in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL) compared with F and C alone. The use of 500 mg/m2 as the dose of R in R-FC was guided by previous published data in CLL patients treated with R monotherapy demonstrating a probable dose-response relationship of a higher response rate at the higher dose levels (O'Brien JCO 2001, Byrd JCO 2001) and also by the data of high number of circulating malignant cells in CLL population (characteristic of CLL) which indicated that R might exhibit a higher clearance rate in CLL compared to observed clearance rates in NHL. Prior to the REACH study, the pharmacokinetics (PK) of R have not been thoroughly studied in the CLL population. As sub-study in REACH trial, a complete PK analysis of R was performed in CLL patients using a population PK analysis. This approach allowed not only the characterization of R PK in CLL patients, but also allowed for an opportunity to perform comparison of the PK differences between indications (CLL and NHL) and provided data-driven validation for the need of high R in CLL patients. Patients and Methods The PK of R were described with plasma concentrations from 21 CLL patients who received R-FC, using nonlinear mixed-effects modeling (NONMEM VI) software. A two-compartment model with time-varying clearance was validated using a bootstrap and visual predictive check method. The concentration vs. time profiles after given different dosages of R in NHL and CLL patients were predicted using the final models based on the observed data. Results R concentration data in CLL patients were well described by a two-compartment model with time-varying clearance, which has been used to describe R concentration data in NHL. Total clearance is comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2) that decreases following a first-order decay rate from its initial value following the first infusion. The term Kdes represents the actual rate of change from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1). The typical population estimates of R nonspecific clearance (CL1), and central compartment volume of distribution (V1) are similar between CLL and NHL (171 vs. 138 mL/day; 2310 vs. 2710 mL, respectively). However, the specific clearance (CL2) in CLL was much faster than that in NHL (1280 vs. 577 mL/day), and the rate of change (Kdes) from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1) is two times lower for CLL patients compared to NHL patients (0.024 vs. 0.046 /day) and this suggests that it takes longer time for receptor saturation for CLL patients compared to NHL patients. The results of the simulation exercise showed that in the early cycles of the R-FC regimen, trough concentrations (Ctrough) and drug exposure (AUC) in CLL patients given 500 mg/m2 would be lower than those for NHL patients given 375 mg/m2 dose regimen. By the final cycles, the Ctrough and AUC of R are similar in NHL given 375 mg/m2 and CLL given 500 mg/m2. Conclusions Retrospective population PK analysis of R in CLL patients using non linear mixed effect modeling confirmed an increased R clearance during the early cycle of treatment as compared to NHL patients. This increased clearance is potentially due to a higher number of malignant cells in circulation for CLL patients, thus a larger dominance of the faster receptor-mediated clearance component in these patients, which overcome the lower CD20 density in CLL. The dose regimen of 500mg/m2 in CLL patients allows for reaching steady state AUC which is similar to the steady state AUC achieved with doses of 375mg/m2 given in NHL patients. Disclosures Li: Genentech: Employment. Zhi:Hoffmann-La Roche Inc.: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment. Valente:Genentech: Employment, Equity Ownership. Visich:Genentech: Employment.