Target-mediated Drug Disposition Research Articles

Safety of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis (HLH): Relationship to Treatment Exposure

▪Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which interferon gamma (IFNγ) is considered a key cytokine. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only curative therapy so far. Current conventional therapy for HLH is based on immunochemotherapies, namely etoposide and glucocorticoids; this treatment, however, is associated with opportunistic infections and severe myelotoxicity. Emapalumab, a fully human, anti-IFNγ monoclonal antibody that neutralizes IFNγ, is the only FDA-approved treatment for primary HLH patients with refractory, recurrent or progressive disease, or intolerance to conventional HLH therapy. In patients with primary HLH, the pharmacokinetics (PK) of emapalumab is highly influenced by body weight, and also by IFNγ production due to target-mediated drug disposition. In the pivotal trial (Locatelli et al NEJM 2020;382:1811-22), treatment of primary HLH patients with emapalumab was associated with a favorable safety and tolerability profile, with no unexpected safety concerns.Objective: To describe prespecified exploratory exposure-safety analyses that were performed on data from patients with primary HLH receiving emapalumab in the pivotal trial.Methods: Data from a multicenter, open-label, pivotal phase 2/3 study (NCT01818492) and its long-term follow-up study (NCT02069899) were included in this analysis. The safety of emapalumab was assessed in 34 patients (27 treatment experienced; 7 treatment naïve) with active primary HLH. Emapalumab was initiated at a dose of 1 mg/kg administered intravenously every 3 days, on a background of dexamethasone 5-10 mg/kg/day. Subsequent doses could be increased to 3, 6 and 10 mg/kg, if required, based on predefined laboratory and clinical response parameters. Treatment duration was up to 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to time of transplantation if needed. Exploratory graphical analyses were performed to determine the incidence of adverse events (AEs) as a function of the exposure parameters at the time of the AE. The relationship between emapalumab exposure and the incidence of treatment-emergent AEs, serious AEs, severe AEs, and AEs related to infections and infusion-related reactions (IRRs) was explored by logistic regression analyses. Selected parameters of renal (creatine clearance [CRCL]) and liver (total bilirubin [TBIL] and alanine aminotransferase [ALT]) function were explored graphically. Exposure parameters were obtained from the population PK/pharmacodynamic (PD) data file that was used for the population PK and PK/PD analyses. Observed individual concentration-time data were used to derive the individual exposure parameters as a function of time. The analyses considered AEs that emerged after the start of the first infusion until last infusion and prior to initiation of HSCT conditioning.Results: Exploratory graphical exposure-safety analyses did not reveal any apparent relationship between the number of AEs and exposure to emapalumab. Logistic exposure-safety regression analyses using the observed exposure to emapalumab at the time of an AE for patients experiencing an event and the highest observed exposure to emapalumab for those patients experiencing no AE, indicated that the incidence of AEs did not increase as a function of increasing emapalumab concentration. In fact, a statistically significant decrease in the incidence of severe AEs and the incidence of AEs related to IRRs was observed. No multivariate effects were identified in the multivariate regression analyses. No clear trend was observed for TBIL, ALT or CRCL as a function of the duration of emapalumab treatment. The exposure of emapalumab did not appear to influence the levels of TBIL, ALT or CRCL in individual patients during treatment.Conclusion: In this study, the exposure-safety evaluation did not reveal any significant relationships between exposure to emapalumab and observed incidence rates of AEs, serious AEs, infections, or IRRs. These findings support the primary evidence of a favorable benefit-risk profile of emapalumab across the dose range used in this fragile patient population. DisclosuresJordan: Sobi: Consultancy. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Jacqmin: Sobi: Consultancy. Laveille: Sobi: Consultancy. Snoeck: Sobi: Consultancy. de Min: Sobi: Consultancy, Ended employment in the past 24 months.

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment-A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model.

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day−1 and kPint = 0.0079 day−1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

New pediatric analysis establishes novel dosing framework for the future

Pharmacists have all heard the phrase “children are not little adults.” It’s popular for a reason: it represents the dangers of simply scaling adult drug dosages to children. Adult physiology, however, has historically been used to scale pediatric dose recommendations. Currently, the most accurate way to determine the initial dosage of a drug is to use a physiologically based pharmacokinetic model (PBPK) to mathematically extrapolate drug dosing from an adult to a child population. Unfortunately, the development of a PBPK remains a challenge, as it requires a deep level of raw, quantitative, physiological data related to developmental stage, disease processes, and any other variable that can affect the pharmacokinetics of a drug. This task may have become significantly less herculean, however, thanks to an open-source, comprehensive, quantitative database, published in March 2021 in the Journal of the American Association of Pharmaceutical Scientists, on the mathematical age relationships among weight, height, organ weight, and organ blood flow—all critical parameters needed when designing a pediatric PBPK. Until recently, this kind of data have been difficult to consolidate or have been locked tightly behind proprietary software. The authors hope that by making it open-source, their database will encourage the creation of widespread pediatric PBPK models that can help predict optimal dosing for pediatric patients with both old and new drugs. One of the first steps in the clinical development for most drugs seeking a pediatric indication is to demonstrate similar exposure levels at various dosages. The first dose is informed by adult pharmacokinetic data leveraged in mathematical models that rely on assumptions regarding the drug’s pharmacokinetics. These data are then scaled down to different child age groups using allometric functions of basal metabolic rates and body weight. Although this is usually sufficient, it may be inaccurate for non-small drug molecules that do not exhibit linear kinetics with time-dependent clearance or target-mediated drug disposition. Biologics pose a particular problem. Using a PBPK model to achieve more accurate results presents a solution. The general process involves creating a simulation of a population of adults whose pharmacokinetics of a particular drug is expressed as rate-based equations. The adults are then swapped with virtual children with all other pharmacokinetic parameters being held constant and their drug exposure metrics compared. If the virtual pediatric exposures are similar to that of the virtual adult population, the presumed first-in-pediatric dose can progress to a more practical application. Chang and colleagues created a comprehensive database of physiological parameters in children from newborns to 20 years. They found a singular function that described the relationships between body weight and age, height and age, organ weight and age, and organ blood flow and age. The formula can be used to estimate any of these parameters—as they relate to age—by referencing the appropriate tables and variable values in the author’s library. The analysis also includes functions predicting pediatric organ weight and blood flow for a library of organs—including heart, lung, muscle, skin, fat, bone, bone marrow, brain, kidney, liver, intestine, pancreas, thymus, and spleen—as well as blood volume and extracellular water. In fact, Chang and colleagues published a follow-up study in June 2021 in the British Journal of Clinical Pharmacology, in which they put the database to the test using it to develop their own PBPK model to characterize monoclonal antibody (mAb) pharmacokinetics in pediatric patients. The results of the investigation were in concordance with the rest of the literature: that mAb pharmacokinetics often require higher doses or more frequent dosing in order to achieve therapeutic levels. The confirmatory results appear to demonstrate a practical application of their database for use in PKPB modeling and will hopefully serve as an accessible framework for pediatric pharmacologists—particularly for biologics—in the years to come.

An optimally designed anti-human CD40 antibody with potent B cell suppression for the treatment of autoimmune diseases

Antibodies targeting the CD40-CD40L pathway have great potential for treating autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), and inflammatory bowel diseases (IBD). However, in addition to the known difficulty in generating a purely antagonistic CD40 antibody, the presence of CD40 and CD40L on platelets creates additional unique challenges for the safety, target coverage, and clearance of antibodies targeting this pathway. Previously described therapeutic antibodies targeting this pathway have various shortcomings, and the full therapeutic potential of this axis has yet to be realized. Herein, we describe the generation and characterization of BI 655064, a novel, purely antagonistic anti-CD40 antibody that potently neutralizes CD40-CD40L-dependent B-cell stimulation without evidence of impacting platelet functions. This uniquely optimized antibody targeting a highly challenging pathway was obtained by applying stringent functional and biophysical criteria during the lead selection process. BI 655064 has favorable target-mediated drug disposition (TMDD)-saturation pharmacokinetics, consistent with that of a high-quality therapeutic monoclonal antibody.

Ustekinumab Dosing Individualization in Crohn's Disease Guided by a Population Pharmacokinetic-Pharmacodynamic Model.

Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

425P Cetuximab could be administered once every two weeks instead of once weekly

Cetuximab (ERBITUX®), an anti-EGFR monoclonal antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The pharmacokinetics (PK) of cetuximab has a nonlinear elimination due to the turnover of EGFR. (1) Target-mediated drug disposition (TMDD) models (2,3) have been commonly used to describe target-mediated pharmacokinetics (TMPK) of monoclonal antibodies.

A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab.

A model to quantitatively characterize the effect of evinacumab, an investigational monoclonal antibody against angiopoietin‐like protein 3 (ANGPTL3) on lipid trafficking is needed. A quantitative systems pharmacology (QSP) approach was developed to predict the transient responses of different triglyceride (TG)‐rich lipoprotein particles in response to evinacumab administration. A previously published hepatic lipid model was modified to address specific queries relevant to the mechanism of evinacumab and its effect on lipid metabolism. Modifications included the addition of intermediate‐density lipoprotein and low‐density lipoprotein compartments to address the modulation of lipoprotein lipase (LPL) activity by evinacumab, ANGPTL3 biosynthesis and clearance, and a target‐mediated drug disposition model. A sensitivity analysis guided the creation of virtual patients (VPs). The drug‐free QSP model was found to agree well with clinical data published with the initial hepatic liver model over simulations ranging from 20 to 365 days in duration. The QSP model, including the interaction between LPL and ANGPTL3, was validated against clinical data for total evinacumab, total ANGPTL3, and TG concentrations as well as inhibition of apolipoprotein CIII. Free ANGPTL3 concentration and LPL activity were also modeled. In total, seven VPs were created; the lipid levels of the VPs were found to match the range of responses observed in evinacumab clinical trial data. The QSP model results agreed with clinical data for various subjects and was shown to characterize known TG physiology and drug effects in a range of patient populations with varying levels of TGs, enabling hypothesis testing of evinacumab effects on lipid metabolism.

Infliximab Treatment Does Not Lead to Full TNF-α Inhibition: A Target-Mediated Drug Disposition Model.

Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration-time data. Estimated baseline TNF-α amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day-1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition.

A Target-Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults.

SPI‐62 is a selective and potent small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1). SPI‐62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose‐dependent volume of distribution, nonlinear PK following the first dose, and dose‐proportional PK at steady state, as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI‐62 is the saturable binding of SPI‐62 to its pharmacological target HSD‐1, a phenomenon known as target‐mediated drug disposition (TMDD). Because of the nonlinear and complex PK of SPI‐62, the relationship among SPI‐62 dose, exposure, and response is no longer intuitive and consequently dose selection can be challenging. To facilitate dose selection and clinical trial design, in the current study population PK analysis was performed to characterize SPI‐62 dose‐exposure relationship in humans quantitatively. SPI‐62 PK was best characterized by a 2‐compartment TMDD model with 3 transit absorption compartments. The model was successfully established to explain the substantial and unusual nonlinear PK of SPI‐62 in humans, and it provided adequate fitting for both single‐ and multiple‐dose data. Our modeling work has provided a strong foundation for dose selection in future SPI‐62 clinical trials.

IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate (ADC) Demonstrates Initial Antileukemia Activity in Patients with Relapsed or Refractory Acute Myeloid Leukemia

IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate (ADC) Demonstrates Initial Antileukemia Activity in Patients with Relapsed or Refractory Acute Myeloid Leukemia

SYNT001: A Humanized IgG4 Monoclonal Antibody That Disrupts the Interaction of FcRn and IgG for the Treatment of IgG-Mediated Autoimmune Diseases

IntroductionThe neonatal crystallizable fragment receptor (FcRn) contributes in a variety of ways to pathogenic processes associated with many autoimmune diseases that are mediated by IgG and IgG immune complexes, including warm autoimmune hemolytic anemia (WAIHA). FcRn does so by protecting IgG, presumably including pathogenic autoantibodies, from catabolism. In addition, FcRn regulates innate and adaptive responses initiated by IgG immune complexes. These properties make FcRn a potential target for immune therapy. SYNT001 is a humanized, de-immunized IgG4 monoclonal antibody with a stabilizing hinge mutation designed to block the interaction between FcRn and the Fc portion of IgG molecules, at both acidic and neutral pH, in order to disrupt the associated pathways related to IgG homeostasis and innate and adaptive immunity. This first-in-human, proof-of-concept study evaluated the safety, tolerability, and biological effects of SYNT001 in healthy volunteers.MethodsWe performed a single-ascending-dose, randomized, double-blind, placebo-controlled, phase 1a trial at a single site in the US. Healthy male subjects aged 18 to 55 years were to receive 1, 3, 10, 30, or 60 mg/kg SYNT001 intravenously (IV) or placebo in a 6:2 ratio per dose cohort. To avoid exposure of healthy subjects to low levels of IgG, the study included a stopping rule if ≥1 subject exhibited serum total IgG (tIgG) levels below the lower limit of normal following SYNT001 dosing. To provide an appropriate pharmacodynamic range in order to observe responses, eligible subjects were required to have tIgG levels greater than or equal to the midpoint of the normal range (≥1200 mg/dL). The primary objective was evaluation of safety. The pharmacokinetics and pharmacodynamics of SYNT001 were also assessed. The study was reviewed and approved by the site's Institutional Review Board and all subjects provided written informed consent.ResultsSYNT001 was administered to 23 subjects (6 subjects in each of the 1, 3, or 10 mg/kg dose groups and 5 in the 30 mg/kg dose group) and 8 subjects received placebo. The tIgG stopping rule was reached before the final subject in the 30 mg/kg cohort was enrolled; thus, dose escalation to 60 mg/kg was halted. Exposure (AUC0-inf and Cmax) increased with ascending SYNT001 doses in a greater than dose-proportional manner, t1/2 increased with dose, and the Vd for SYNT001 was less than the estimated plasma volume at all doses. Semilog plots suggested that elimination from serum occurred by target-mediated drug disposition via FcRn at lower serum concentrations. Treatment-emergent adverse events (TEAEs) were reported in 9 subjects, including 8 treated with SYNT001 and 1 treated with placebo. Headache was the most commonly reported TEAE, occurring in all 8 SYNT001-treated subjects who reported a TEAE. No other TEAE was reported by more than one SYNT001-treated subject. One TEAE of severity grade 2 (moderate), a headache in the 10 mg/kg cohort, was reported; all other TEAEs were severity grade 1 (mild). There were no grade 3 or 4 TEAEs or serious AEs. No significant changes in urinalysis, hematology, or blood chemistries, including albumin, IgA, and IgM, were reported. The nadir of an approximately 50% reduction in tIgG levels in the 30 mg/kg dose group occurred 5 days post-dosing. The tIgG effect was durable; on Day 28, the mean percent change of total IgG from baseline was −8.9%, 4.3%, −4.4%, and −27.9% in the 1, 3, 10, and 30 mg/kg dose groups, respectively. The magnitude, but not the duration, of the nadir differed for each IgG subclass with IgG3 (70% decrease from baseline) > IgG1 (55%) > IgG4 (45%) > IgG2 (35%) at the 30 mg/kg dose. SYNT001 administration also resulted in a dose-dependent decrease in circulating immune complexes (CIC), with up to a 50% decrease from baseline in the 30 mg/kg group and an effect lasting more than a week.ConclusionsSYNT001 was well tolerated and produced rapid, durable, and clinically significant reductions in all IgG subclasses and CIC in healthy volunteers. Both the level and duration of the pharmacodynamic effect provide strong support for the potential efficacy of SYNT001 as a therapeutic agent in the treatment of IgG-mediated autoimmune diseases such as WAIHA. Accordingly, a phase 1b study of SYNT001 in WAIHA patients is underway (www.clinicaltrials.gov ID: NCT03075878). DisclosuresBlumberg:Syntimmune, Inc.: Employment, Equity Ownership. Humphries:Syntimmune, Inc.: Consultancy. Lasseter:Syntimmune, Inc.: Research Funding; Clinical Pharmacology of Miami: Employment. Blumberg:Syntimmune, Inc.: Equity Ownership.

Concizumab (Anti-TFPI) Exposure-Response Modeling in Patients with Hemophilia A

Concizumab (Anti-TFPI) Exposure-Response Modeling in Patients with Hemophilia A

Influence of Baseline Disease Characteristics and Exposure to Obinutuzumab on Clinical Outcome in Patients with Previously Untreated Advanced Follicular Lymphoma Treated with Obinutuzumab-Based Immunochemotherapy in the GALLIUM Trial

▪IntroductionObinutuzumab (G), a humanized type II glycoengineered anti-CD20 therapeutic monoclonal antibody (mAb), exhibits target mediated drug disposition, a situation where pharmacokinetics (PK) is considered as a surrogate marker of CD20 occupancy. The recommended dose and schedule of G in the treatment of patients (pts) with B cell malignancies was determined based on safety, efficacy, and PK profile to ensure full target saturation throughout the entire dosing period (Cartron et al , 2016). Understanding the relationships between clinical outcome and G exposure is confounded by the underlying relationships between exposure, tumor burden (which changes over time), CD20 target density and disease biology. In this analysis, we evaluated the sources of variability including exposure to G in outcome amongst pts with previously untreated (1L), advanced follicular lymphoma (FL) who received G-based immunochemotherapy in the GALLIUM trial (NCT01332968).Material and MethodsThe GALLIUM trial is described elsewhere (Marcus R et al , ASH 2016). Serum G concentrations collected during Induction and Maintenance in 408 pts with 1L, G-treated FL were analyzed and included in a population PK analysis. For each patient, predicted Cmean values were computed from the PK model, as the ratio of cumulative area under the curve (AUC) over the duration of the Induction period. Tertiles of Cmean (low, medium, high) were used to reflect variability in exposure among pts.A multivariate regression analysis (Cox analysis) was used to investigate the effect of various factors such as exposure (Cmean), and baseline patient and disease characteristics on PFS (e.g FLIPI score, ECOG status, bone marrow involvement, presence of bulky disease (>7cm), polymorphism of Fcg receptor IIb/IIc, Ann Arbor stage).In this analysis, we also specifically evaluated the relationship between body weight (BW) and exposure and the correlation with PFS using a univariate semi-parametric Cox proportional hazard model of BW.Results:Among pts with available PK data (n=408) solely those who received at least 50% of the planned induction cycles of G (ie ≥4 cycles of G-CHOP/CVP (n=189 pts), ≥3 cycles of G-Benda (n=212 pts); total n = 401) were included in the PFS analysis.In GALLIUM, similarly to most mAbs, the main factors associated with lower G exposure in FL pts were higher BW, but also high tumor burden at baseline (BSIZ), and male gender (Gibiansky et al , CPT Pharmacometrics Syst Pharmacol., 2014). In addition, age, serum albumin level and chemotherapy backbone were also influential (E. Gibiansky et al , PAGE, 2016; Table I).A Cox analysis showed that PFS was negatively impacted by high BSIZ and presence of the Fcγ polymorphism IIa/IIb 232TT single nucleotide polymorphism. In pts treated with G-Benda, the PFS benefit was similar across G exposure categories. In pts treated with G-CHOP (n=130) or G-CVP (n=59), G exposure seems to be associated with PFS outcome, especially in pts with high BSIZ. Sample size was smaller compared to G-Benda pts, therefore G-CHOP and G-CVP pts were grouped in the analysis (Fig 1).Kaplan-Meier (KM) plots of PFS by baseline BW categories (≤90 Kg, >90kg) were performed (HR = 1.52 with 95% CI: 0.91, 2.54) (Fig. 2). A separation in PFS was observed between pts with BW £ 90 kg and > 90 kg; however, the 95% CI was large and included the value of 1. This indicates that the apparent visual separation in the KM curves of PFS between the BW categories is not statistically significant.ConclusionExposure to G is highly variable among pts; however this variability does not correlate with clinical outcome in pts treated with G-Benda. In these pts differences in exposure cannot be considered as the primary determinant of inferior clinical outcome. Intrinsic patient and disease characteristics (e.g., tumor burden) are likely relevant contributors to differences in PFS. PET and Minimal Residual Disease are also prognostic for outcome and additional results will be provided at the time of presentation. In pts treated with G-CHOP or G-CVP, lower exposure is associated with shorter PFS; however it remains unknown whether exposure is a cause or rather a consequence of poorer prognosis (Matts Kagedal et al , PAGE 2017). Sample size was smaller and the comparative efficacy of Benda vs CHOP/CVP is under debate. [Display omitted] DisclosuresJamois:Roche: Employment, Other: GALLIUM was sponsored by F. Hoffmann-La Roche Ltd.. Gibiansky:Roche: Consultancy. Gibiansky:Roche: Consultancy. Buchheit:Roche: Employment. Baumlin:Roche: Employment. Sahin:Roche: Employment, Equity Ownership. Cartron:Sanofi, BMS, Jansen, celgene, Roche, Gilead: Equity Ownership; Celgene: Consultancy, Employment; Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Marcus:Roche: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Celgene: Other: Support for meeting attendance . Strefford:Roche: Research Funding. Meneses-Lorente:Roche Products Ltd: Employment. Frey:Roche: Employment. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership.

Target‐mediated drug disposition modeling of an anti‐TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics

BackgroundMG1113 is a human monoclonal antibody of tissue factor pathway inhibitor (TFPI) under development for prophylaxis for hemophilia patients with or without inhibitors against factor VIII products, which have been used for the treatment of hemophilia. Because TFPI is a negative regulator in the extrinsic coagulation pathway, neutralization of TFPI function by MG1113 can potentially increase coagulation activity by bypassing the intrinsic coagulation pathway, which factor VIII activates. ObjectivesThis study aims to determine the correlation between pharmacokinetics (PK) and pharmacodynamics (PD) after administering MG1113 to monkeys and to predict the PK and PD of MG1113 in humans by the Target‐Mediated Drug Disposition (TMDD) model using the results from monkeys. MethodsThe PK profile of MG1113 and the PD effect on the free TFPI level were evaluated after intravenous (IV) and subcutaneous (SC) administrations of MG1113 (2.5, 5, and 10 mg/kg) to male cynomolgus monkeys. After setting up the PK/PD model on monkeys, PK parameters on humans were calculated using allometric scaling, and then clinically effective doses were predicted applying the TMDD model. Results and ConclusionsMG1113 showed nonlinear PK after both IV and SC administrations at the dosing range from 2.5 to10 mg/kg. The concentrations of MG1113 versus TFPI could be characterized a dose‐response relationship using a TMDD model. The TMDD modeling and simulation built in this study were used to simulate various dosage regimens of MG1113 to apply to the first‐in‐human study design, and moreover expected to be referred to establish the dose for further clinical trials.

Population Pharmacokinetics of Ropeginterferon Alfa-2b: A Comparison Between Healthy Caucasian and Chinese Subjects.

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations. Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b. Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations. Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

An Extended Model Including Target Turnover, Ligand-Target Complex Kinetics, and Binding Properties to Describe Drug-Receptor Interactions.

Since the beginning of this century, target-mediated drug disposition has become a central concept in modeling drug action in drug development. It combines a range of processes, such as turnover, protein binding, internalization, and non-specific elimination, and often serves as a nucleus of more complex pharmacokinetic models. It is simple enough to comprehend but complex enough to be able to describe a wide range of phenomena and data sets. However, the complexity comes at a price: many parameters. In this chapter, we present an overview of the temporal development of the compounds involved after different types of drug doses and offer convenient handles for dissecting data sets in a sophisticated manner in order to estimate the values of these parameters, such as rate constants and pertinent concentrations.

Safety and PK/PD of ALLO-647, an anti-CD52 antibody, with fludarabine (Flu)/cyclophosphamide (Cy) for lymphodepletion in the setting of allogeneic CAR-T cell therapy.

2527 Background: Allogeneic chimeric antigen receptor (CAR) T cell therapy holds promise in addressing logistical/manufacturing challenges of autologous CAR T cell therapy. ALLO-501 (anti-CD19; uses Cellectis technologies) and ALLO-715 (anti-BCMA) are allogeneic CAR T cell products whose a) disrupted TCRα constant gene may reduce GvHD risk, and b) edited CD52 gene may permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells. Methods: The ongoing ALPHA (ALLO-501) and UNIVERSAL (ALLO-715) trials include patients (pts) with relapsed/refractory large B-cell or follicular lymphoma and multiple myeloma, respectively. The lymphodepletion regimen included ALLO-647 (39 mg [low dose, LD; n = 33], 60 mg [n = 12], or 90 mg [high dose, HD; n = 27]) with Flu 30 mg/m2/d x 3d +/- Cy 300 mg/m2/d x 3d (Flu+Cy, n = 66; Cy, n = 6) (ALLO-647/Flu +/- Cy) before CAR T infusion. A mixed-effects population pharmacokinetic (PK) model was fit to ALLO-647 concentration vs. time data. Pharmacodynamic (PD) effects on host T cells, IL15, and CAR T cell expansion were also studied. Results: As of the data cut, 72 pts were treated. Common Grade ≥3 AEs were neutropenia (71%), thrombocytopenia (42%), anemia (39%), and lymphopenia (28%). Neutrophil, hemoglobin, and platelet counts did not differ by ALLO-647 dose, suggesting these dim-CD52+ cells were unaffected. Gr ≥3 infections were seen in 21% pts; 33 had infusion-related reactions (IRR; Gr 1: 13%; Gr 2: 32%; Gr 3: 1.4%). IRR incidence and severity were higher with HD ALLO-647. The optimal PK model included a saturable (concentration-dependent) elimination pathway; clearance varied as a function of baseline lymphocyte count (LC). Serum ALLO-647 levels increased with dose; median modelled Cmax was 4,224 and 14,139 ng/mL for LD and HD, respectively. With ALLO-647/Flu +/- Cy, all but 2 pts reached a LC nadir < 0.05x109 cells/L, typically by D-3. Duration of lymphodepletion was typically longer with HD ALLO-647. Median duration of T-cell suppression ( < 10 cells/µl) was ̃ 8.5 and 13.6 days from CAR T infusion, respectively, for LD and HD ALLO-647. With HD, T cell counts were < 10 through D+28 in 17 pts and > 10 in 2. In 68 evaluable pts, compared to LD, HD ALLO-647 was associated with higher D0 serum IL15 levels, which have been linked to improved clinical response (eg, Kochenderfer JCO 2017). Higher CAR T expansion was also observed post D+14 with HD ALLO-647 compared to LD, creating an opportunity for clinical response. Conclusions: ALLO-647/Flu +/- Cy had a tolerable safety profile and produced a deep and durable window of lymphocyte depletion. ALLO-647 exhibited target-mediated drug disposition; clearance increased with higher baseline LC. HD was associated with higher IL15 levels and better CAR T expansion, suggesting dose responses. Enrollment in both studies is ongoing; updated safety and PK/PD data will be presented. Clinical trial information: NCT04093596.

Progress in the Development of Anti-tissue Factor Pathway Inhibitors for Haemophilia Management.

The unprecedented progress in addressing unmet needs in haemophilia care to date includes developing several novel therapies that rebalance haemostasis by restoring thrombin generation in patients with haemophilia A or B with and without inhibitors. These novel therapies are FVIII mimetics, antithrombin interference RNA therapy and several monoclonal antibodies directed against the tissue factor pathway inhibitor (anti-TFPI). In this review, we provide an update on the progress made in developing anti-TFPI therapie. Phase 1 data from the three anti-TFPI studies showed acceptable safety profiles, and currently, available phase 2 data are encouraging. While these data support these molecules' further development progression, there is uncertainty on several aspects of their evolution. Two of the three anti-TFPIs have shown drug-related thrombosis, with one study consequently terminated. None of the thrombotic events is predictable with current monitoring tools, and none correlate with known coagulation parameters. All three anti-TFPIs undergo target mediated drug disposition, which impacts the formulation of dosing regimen fo these therapies. They would require more frequent dosing than some of the extended half-life clotting factor products and antithrombin RNAi therapy. There is no assay to measure the TFPI as the physiological levels are very low, which makes monitoring the impact of the anti-TFPI a challenge. The anti-TFPIs have several advantages, including their bioavailability when administered subcutaneously, their stable pharmacokinetics and their ability to prevent bleeds in haemophilia A or B patients with and without inhibitors. Whether these advantages can be realized will depend on the outcome of the currently ongoing studies.

Comparisons of basic target-mediated drug disposition (TMDD) and ligand facilitated target removal (LFTR)

In the well-known model for basic Target-Mediated Drug Disposition (TMDD), drug binds to the target and the resulting drug-target complex is removed by a first order process, leading to loss of both drug and target. In the present note we study what happens when, instead, drug is returned to the free drug pool so that it can a new target molecule. What results is a mechanism in which the drug, here referred to as the ligand, facilitates the removal of the target,and then returns to the free ligand pool. Accordingly the process will be referred to as Ligand-Facilitated Target Removal (LFTR). It is shown through simulations and mathematical analysis how the two models differ and how their signature profiles typically appear. We also derive a useful parameter of both models, the in vivo potency EC50 (L50) which contains both ligand-target binding properties (kon,koff), target turnover (kdeg) and ligand-target complex kinetics (ke(RL)). Thus, this parameter contains a conglomerate of properties and is therefore potentially more informative about relevant (clinical) exposure than the binding affinity (Kd) alone. The derived potency parameter EC50 may therefore be used as a more robust ranking parameter among small and large drug molecules in drug discovery. Subsequently the LFTR model is applied to experimentally obtained literature data and the relevant parameters are estimated.

Pharmacokinetics and Determination of Tumor Interstitial Distribution of a Therapeutic Monoclonal Antibody Using Large-Pore Microdialysis.

R7072 is a fully human monoclonal antibody (mAb) exerting anti-tumor activity via blockade of insulin like growth factor 1 receptor. The tumoral interstitial concentrations are anticipated to be better surrogates of active site concentrations than commonly used serum concentrations for pharmacokinetic-pharmacodynamic correlation of anti-tumor mAbs. Previously, a large-pore microdialysis technique for measuring tissue interstitial concentrations of R7072 in non-tumor bearing mice was established. In the current studies, the serum pharmacokinetics of R7072 were assessed and tissue interstitial concentrations were measured by large-pore microdialysis following intravenous and intraperitoneal administration of R7072 in tumor bearing mice. R7072 exhibited nonlinear pharmacokinetics in the studied dose range. Tumor and subcutaneous interstitial concentration data suggested some delay in tissue distribution after dosing. A dose-dependent increase in the ratio of tumor interstitial to serum concentration was observed indicating target-mediated drug disposition in tumor tissue. However, subcutaneous interstitial to serum concentration ratios were similar across the doses as observed previously in non-tumor bearing mice. A two-compartment population pharmacokinetic model with subcutaneous and tumor as open-loop compartments comprising of parallel linear and non-linear elimination from serum, linear disposition from subcutaneous interstitium and non-linear disposition from tumor interstitium was developed to simultaneously describe the pharmacokinetic data from all matrices.