Pharmacokinetics-Bridging Between Autoinjectors and Prefilled Syringes for Subcutaneous Injection: Case Examples Revealing a Knowledge Gap.

Comparative pharmacokinetics (PK) studies have efficiently served as the bridge between autoinjectors and prefilled syringes given the underlying principles that comparable exposure could translate to comparable efficacy and safety. This article discusses approaches used to address uncertainties associated with the observation of noncomparable PK leading to the successful introduction of new autoinjector devices for monoclonal antibody and Fc-fusion protein products. Information from seven case examples suggests a knowledge gap that warrants attention in autoinjector development.

Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of Cetuximab in Pancreatic Cancer Tumor Models.

Therapeutic antibodies have shown little efficacy in the treatment of pancreatic ductal adenocarcinomas (PDAC). Tumor desmoplasia, hypovascularity, and poor perfusion result in insufficient tumor cell exposure, contributing to treatment failure. Smoothened inhibitors of hedgehog signaling (sHHi) increase PDAC tumor permeability, perfusion, and drug delivery, and provide a tool to develop a quantitative, mechanistic understanding as to how the temporal dynamics of tumor priming can impact intratumor distribution of monoclonal antibodies (mAb). A linked pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to integrate the plasma and tumor PK of a sHHi priming agent with its effects upon downstream stromal biomarkers Gli1, hyaluronic acid, and interstitial fluid pressure in PDAC patient-derived xenograft (PDX) tumors. In parallel, in situ tumor concentrations of cetuximab (CTX: anti-epidermal growth factor receptor; EGFR) were quantified as a marker for tumor delivery of mAb or antibody-drug conjugates. A minimal, physiologically-based pharmacokinetic (mPBPK) model was constructed to link sHHi effects upon mechanistic effectors of tumor barrier compromise with the intratumor distribution of CTX, and CTX occupancy of EGFR in tumors. Integration of the mPBPK model of mAb deposition and intratumor distribution with the PK/PD model of tumor responses to priming not only identified physiological parameters that are critical for tumor antibody distribution, but also provides insight into dosing regimens that could achieve maximal tumor disposition of therapeutic antibodies under conditions of transient PDAC tumor permeability barrier compromise that mechanistically-diverse tumor priming strategies may achieve.

Monitoring mAb proteoforms in mouse plasma using an automated immunocapture combined with top-down and middle-down mass spectrometry.

Monoclonal antibodies (mAbs) have established themselves as the leading biopharmaceutical therapeutic modality. Once the developability of a mAb drug candidate has been assessed, an important step is to check its in vivo stability through pharmacokinetics (PK) studies. The gold standard is ligand-binding assay (LBA) and liquid chromatography-mass spectrometry (LC-MS) performed at the peptide level (bottom-up approach). However, these analytical techniques do not allow to address the different mAb proteoforms that can arise from biotransformation. In recent years, top-down and middle-down mass spectrometry approaches have gained popularity to characterize proteins at the proteoform level but are not yet widely used for PK studies. We propose here a workflow based on an automated immunocapture followed by top-down and middle-down liquid chromatography-tandem mass spectrometry (LC-MS/MS) approaches to characterize mAb proteoforms spiked in mouse plasma. We demonstrate the applicability of our workflow on a large concentration range using pembrolizumab as a model. We also compare the performance of two state-of-the-art Orbitrap platforms (Tribrid Eclipse and Exploris 480) for these studies. The added value of our workflow for an accurate and sensitive characterization of mAb proteoforms in mouse plasma is highlighted.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Anti-IFNAR1 Monoclonal Antibody QX006N: A First-in-Human Single Ascending Dose Study in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVE: QX006N is a novel, humanized, IgG4κ monoclonal antibody targeting IFNAR1, developed for the treatment of systemic lupus erythematosus. This study aims to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of QX006N when administered intravenously to healthy Chinese individuals. METHODS: A double-blind, randomized, placebo-controlled, single-ascending-dose, phase I clinical trial was conducted comprising five cohorts (n = 10 per cohort, except n = 5 for the first cohort). Subjects in each cohort were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of QX006N (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 6.0 mg/kg, or 10.0 mg/kg) or placebo for 30 minutes. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. The serum concentration of QX006N was measured using the enzyme-linked immunosorbent assay method, and the anti-drug antibodies were detected using the electrochemiluminescence assay method. RESULTS: QX006N demonstrated a favorable safety and tolerability profile throughout the study. All treatment-emergent adverse events were of Grade 1-2 (CTCAE Version 5.0), and no serious adverse events, deaths, or drug discontinuations because of treatment-emergent adverse events were observed. All drug-related treatment-emergent adverse events showed no clear dose-related trends. Following an intravenous infusion of QX006N at doses that ranged from 0.3 mg/kg to 10 mg/kg, the half-life increased from 24.7 to 208 hours in a dose-dependent manner, while clearance decreased from 0.0828 to 0.0065 L/h. The maximum concentration exhibited nearly dose-proportional increases, and the area under the curve displayed a more than dose-proportional increment with non-linear pharmacokinetic characteristics. The incidence of anti-drug antibodies was observed to increase over time for doses that ranged from 1.0 mg/kg to 10.0 mg/kg of QX006N, reaching its peak at day 57 (range 62.50-87.50%). Conversely, the incidence of anti-drug antibodies in the QX006N 0.3-mg/kg and placebo cohorts remained low. CONCLUSIONS: QX006N demonstrated acceptable safety, tolerability, and pharmacokinetic characteristics in healthy subjects when administered as a single intravenous infusion at doses that ranged from 0.3 mg/kg to 10.0 mg/kg. Based on the pharmacokinetic and safety outcomes, a recommended effective dose of 300 mg is proposed for future phase Ib studies. CLINICAL TRIAL REGISTRATION: This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20212834.

Subcutaneous Administration of a Zwitterionic Chitosan-Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA-/EMA-approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two-component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.

Nivolumab and ipilimumab population pharmacokinetics in support of pediatric dose recommendations-Going beyond the body-size effect.

Body size has historically been considered the primary source of difference in the pharmacokinetics (PKs) of monoclonal antibodies (mAbs) between children aged greater than or equal to 2 years and adults. The contribution of age-associated differences (e.g., ontogeny) beyond body-size differences in the pediatric PKs of mAbs has not been comprehensively evaluated. In this study, the population PK of two mAbs (nivolumab and ipilimumab) in pediatric oncology patients were characterized. The effects of age-related covariates on nivolumab or ipilimumab PKs were assessed using data from 13 and 10 clinical studies, respectively, across multiple tumor types, including melanoma, lymphoma, central nervous system tumors (CNSTs), and other solid tumors. Clearance was lower in pediatric patients (aged 1-17 years) with solid tumors or CNST than in adults after adjusting for other covariates, including the effect of body size. In contrast, clearance was similar in pediatric patients with lymphoma to that in adults with lymphoma. The pediatric effects characterized have increased the accuracy of the predictions of the model, facilitating its use in subsequent exposure comparisons between pediatric and adult patients, as well as for exposure-response analyses to inform pediatric dosing. This study approach may be applicable to the optimization of pediatric dosing of other mAbs and possibly other biologics.

Correlation of In Vitro Kinetic Stability to Preclinical In Vivo Pharmacokinetics for a Panel of Anti-PD-1 Monoclonal Antibody Interleukin 21 Mutein Immunocytokines.

The development of therapeutic fusion protein drugs is often impeded by the unintended consequences that occur from fusing together domains from independent naturally occurring proteins, consequences such as altered biodistribution, tissue uptake, or rapid clearance and potential immunogenicity. For therapeutic fusion proteins containing globular domains, we hypothesized that aberrant in vivo behavior could be related to low kinetic stability of these domains leading to local unfolding and susceptibility to partial proteolysis and/or salvage and uptake. Herein we describe an assay to measure kinetic stability of therapeutic fusion proteins by way of their sensitivity to the protease thermolysin. The results indicate that in vivo pharmacokinetics of a panel of anti-programmed cell death protein 1 monocolonal antibody:interleukin 21 immunocytokines in both mice and nonhuman primates are highly correlated with their in vitro susceptibility to thermolysin-mediated proteolysis. This assay can be used as a tool to quickly identify in vivo liabilities of globular domains of therapeutic proteins, thus aiding in the optimization and development of new multispecific drug candidates. SIGNIFICANCE STATEMENT: This work describes a novel assay utilizing protein kinetic stability to identify preclinical in vivo pharmacokinetic liabilities of multispecific therapeutic fusion proteins. This provides an efficient, inexpensive method to ascertain inherent protein stability in vitro before conducting in vivo studies, which can rapidly increase the speed of preclinical drug development.

Physiologically based pharmacokinetic (PBPK) model that describes enhanced FcRn-dependent distribution of monoclonal antibodies (mAbs) by pI-engineering in mice.

We previously reported that monoclonal antibodies (mAbs) with a high isoelectric point (pI) value tended to exhibit fast plasma clearance (CL) and large steady-state volume of distribution (Vdss) in mice. However, the positive correlation between pI, CL, and Vdss cannot be described by the reported physiologically based pharmacokinetic (PBPK) models, in which FcRn-mediated transcytosis of mAbs is set to be minimal compared to convection-mediated transport. To address this issue, physiological parameters (lymph flow rate, reflection coefficient, endothelial uptake clearance, and FcRn concentration) were optimized based on the pharmacokinetic profiles of mAbs with various pI values in wild type and FcRn-deficient (beta-2-microglobulin knockout [KO]) mice. Simulations using the PBPK model developed in this study showed a positive correlation between pI, CL and Vdss observed in wild-type mice. Therefore, this model successfully characterized our hypothetical mechanism that an electrostatic positive interaction between mAbs and the endothelial membrane enhances FcRn-mediated transcytosis of mAbs, resulting in large Vdss. We sought to determine the right contribution of the two pathways of antibody distribution to the interstitial space and established a new model that could effectively capture the effect of pI on FcRn-mediated distribution of mAbs in the body.

Ethnic sensitivity assessment: Polatuzumab vedotin pharmacokinetics in Asian and non-Asian patients with previously untreated diffuse large B-cell lymphoma in POLARIX.

This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non-Asian patients with previously untreated diffuse large B-cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non-Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody-conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non-Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%-7.0% and 17.3%-19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non-Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.

A Minimal PBPK Model for Plasma and Cerebrospinal Fluid Pharmacokinetics of Trastuzumab after Intracerebroventricular Administration in Patients with HER2-Positive Brain Metastatic Localizations.

BACKGROUND: Dosing regimens of trastuzumab administered by intracerebroventricular (icv) route to patients with HER2-positive brain localizations remain empirical. The objectives of this study were to describe pharmacokinetics (PK) of trastuzumab in human plasma and cerebrospinal fluid (CSF) after simultaneous icv and intravenous (iv) administration using a minimal physiologically-based pharmacokinetic model (mPBPK) and to perform simulations of alternative dosing regimens to achieve therapeutic concentrations in CSF. METHODS: Plasma and CSF PK data were collected in two patients with HER2-positive brain localizations. A mPBPK model for mAbs consisting of four compartments (tight and leaky tissues, plasma and lymph) was enriched by an additional compartment for ventricular CSF. The comparison between observed and model-predicted concentrations was evaluated using prediction error (PE). RESULTS: The developed mPBPK model described plasma and CSF trastuzumab concentrations reasonably well with mean PE for plasma and CSF data of 41.8% [interquartile range, IQR = -9.48; 40.6] and 18.3% [-36.7; 60.6], respectively, for patient 1 and 11.4% [-10.8; 28.7] and 22.5% [-27.7; 77.9], respectively, for patient 2. Trastuzumab showed fast clearance from CSF to plasma with Cmin,ss of 0.56 and 0.85 mg/L for 100 and 150 mg q1wk, respectively. Repeated dosing of 100 and 150 mg q3day resulted in Cmin,ss of 10.3 and 15.4 mg/L, respectively. Trastuzumab CSF target concentrations are achieved rapidly and maintained above 60 mg/L from 7 days after a continuous perfusion at 1.0 mg/h. CONCLUSION: Continuous icv infusion of trastuzumab at 1.0 mg/h could be an alternative dosing regimen to rapidly achieve intraventricular CSF therapeutic concentrations.

A Quantitative Prediction Method for the Human Pharmacokinetics of Fc-Fusion Proteins.

BACKGROUND AND OBJECTIVE: Fc fusion is an effective strategy for extending the half-lives of therapeutic proteins. This study aimed to evaluate the applicability of a human pharmacokinetics prediction method for Fc-fusion proteins by extending on reported methods for monoclonal antibodies (mAbs). METHODS: To predict human pharmacokinetic profiles following intravenous (IV) dosing, the pharmacokinetic data for 11 Fc-fusion proteins in monkeys were analysed by two approaches: a species-invariant time method with a range of allometric exponents in clearance (CL, 0.7-1.0) and a two-compartment model reported for mAbs. The pharmacokinetic profiles following subcutaneous (SC) dosing were predicted by simple dose normalisation from monkeys or using the geometric means of the absorption rate constant (Ka) and bioavailability (BA) for mAbs or Fc-fusion proteins in humans and compared. RESULTS: In the case of IV administration, the area under the curve could be predicted for more than 85% of Fc-fusion proteins within a twofold difference from the observed value using the species-invariant time method (scaling exponent for CL, 0.95). For SC dosing, incorporating the geometric means of absorption parameters for both mAbs (BA 68.2%, Ka 0.287 day-1) and Fc-fusion proteins (BA 63.0%, Ka 0.209 day-1) in humans provided better accuracy than simple normalisation from monkeys. CONCLUSION: We have successfully predicted the human pharmacokinetic profiles of Fc-fusion proteins for both IV and SC administration within twofold of the observed value from monkey pharmacokinetic data by extending on reported methods for mAbs. This method will facilitate drug discovery and development of Fc-fusion proteins.

Mirikizumab Pharmacokinetics in Patients with Moderately to Severely Active Ulcerative Colitis: Results from Phase III LUCENT Studies.

BACKGROUND AND OBJECTIVE: Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis. METHODS: Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. RESULTS: Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%. CONCLUSIONS: Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).

Relationship Between Cetuximab Target-Mediated Pharmacokinetics and Progression-Free Survival in Metastatic Colorectal Cancer Patients.

BACKGROUND AND OBJECTIVE: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS). METHODS: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an Emax model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated. RESULTS: Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R0 = 43 nM), and complex elimination rate constant (kint = 0.95 day-1). Estimated time-varying clearance parameters were time-invariant component of CL (CL0= 0.38 L/day-1), time-variant component of CL (CL1= 0.058 L/day-1) and first-order rate of CL1 decreasing over time (kdes = 0.049 day-1). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP. CONCLUSION: This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship.

Safety, tolerability, and pharmacokinetics of half-life extended SARS-CoV-2-neutralizing monoclonal antibodies AZD7442 (tixagevimab/cilgavimab) in healthy Japanese adults.

INTRODUCTION: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD7442 (tixagevimab/cilgavimab) in healthy Japanese adults. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 study, AZD7442 was administered intramuscularly (300 or 600 mg) or intravenously (300 or 1000 mg) to healthy Japanese adults. Primary endpoints were safety, tolerability, and pharmacokinetics. Anti-drug antibodies and neutralizing antibody activities were secondary endpoints. RESULTS: A total of 40 participants were randomized to receive AZD7442 (n = 30) or placebo (n = 10). Adverse events (AEs) occurred in 12 (40%) and 3 (30%) participants, respectively; there were no deaths, serious AEs, or AEs leading to study withdrawal. Tixagevimab and cilgavimab had mean half-lives of 82.1-95.9 and 77.9-92.0 days, respectively, which were generally similar regardless of administration route. SARS-CoV-2-neutralizing antibody titers were >4-fold higher than baseline levels from Day 8 to Day 211 in participants receiving AZD7442. CONCLUSIONS: AZD7442 was well tolerated in healthy Japanese adults, with predictable pharmacokinetics and an extended half-life, consistent with previous studies. CLINICALTRIALS: gov, NCT04896541.

Clinical validation of translational antibody PBPK model using tissue distribution data generated with 89Zr-immuno-PET imaging.

The main objective of this manuscript was to validate the ability of the monoclonal antibody physiologically-based pharmacokinetic (PBPK) model to predict tissue concentrations of antibodies in the human. To accomplish this goal, preclinical and clinical tissue distribution and positron emission tomography imaging data generated using zirconium-89 (89Zr) labeled antibodies were obtained from the literature. First, our previously published translational PBPK model for antibodies was expanded to describe the whole-body biodistribution of 89Zr labeled antibody and the free 89Zr, as well as residualization of free 89Zr. Subsequently, the model was optimized using mouse biodistribution data, where it was observed that free 89Zr mainly residualizes in the bone and the extent of antibody distribution in certain tissues (e.g., liver and spleen) may be altered by labeling with 89Zr. The mouse PBPK model was scaled to rat, monkey, and human by simply changing the physiological parameters, and a priori simulations performed by the model were compared with the observed PK data. It was found that model predicted antibody PK in majority of the tissues in all the species superimposed over the observed data, and the model was also able to predict the PK of antibody in human tissues reasonably well. As such, the work presented here provides unprecedented evaluation of the antibody PPBK model for its ability to predict tissue PK of antibodies in the clinic. This model can be used for preclinical-to-clinical translation of antibodies and for prediction of antibody concentrations at the site-of-action in the clinic.

Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

INTRODUCTION: Subcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood. OBJECTIVE: To bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products. METHODOLOGY: We have previously developed a multiscale, multiphysics computational model to simulate lymphatic absorption and whole-body pharmacokinetics of monoclonal antibodies. The same simulation framework was applied in this study to compute the capillary absorption of solubilized small molecule drugs that are injected subcutaneously. Sensitivity analyses were conducted to probe the impact by key simulation parameters on the local and systemic exposures. RESULTS: This framework was capable of determining which parameters had the biggest impact on small molecule absorption in the SC. Particularly, membrane permeability of a drug was found to have the biggest impact on drug absorption kinetics, followed by capillary density and drug diffusivity. CONCLUSION: Our modelling framework proved feasible in predicting local transport and systemic absorption from the injection site of small molecules. Understanding the effect of these properties and how to model them may help to greatly expedite the development process.

Safety and pharmacokinetics of IBI112, an IL-23 monoclonal antibody, in Chinese healthy volunteers: a first-in-human phase 1 study.

BACKGROUND: Interleukin (IL) 23p19 monoclonal antibodies were efficacious and safe in the treatment of psoriasis. A first-in-human (FIH) study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of IBI112, a novel IL-23p19 monoclonal antibody. METHODS: In this FIH, randomized, double-blind, placebo-controlled, single-ascending-dose study, a subcutaneous (SC, 5-600 mg) or intravenous (IV, 100 and 600 mg) or placebo was administered to eligible healthy subjects. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Furthermore, non-compartment analysis and population PK modeling were conducted to characterize PK, and model-based simulation was applied to justify dose selection for psoriasis patients. RESULTS: A total of 46 subjects were enrolled, with 35 receiving IBI112 and 11 receiving placebo. No serious adverse events (SAEs) and no clinically significant adverse events were identified. After a single SC of IBI112, the median Tmax was 4-10.5 days, and the half-life (t1/2) ranged from 21.8 to 35.8 days. IBI112 exposures (Cmax and AUCinf) approached dose proportionality across 5-300 mg range. CONCLUSION: IBI112 was well tolerated and safe at SC or IV dose up to 600 mg and showed a linear PK characteristics at SC dose from 5 to 300 mg. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT04511624.

Mannose 6-phosphate receptor-targeting antibodies preserve Fc receptor-mediated recycling.

The concept of grafting mannose 6-phosphonate derivatives (M6Pn), named AMFA, on therapeutic proteins was first developed for the improvement of enzyme delivery in lysosomal storage disorders. This glycoengineering increases the cellular uptake of the protein via the cation-independent mannose 6-phosphate receptor (M6PR) which further allows their targeting to the lysosomes. In the present study, we investigated the extent to which the direct grafting of AMFA onto a drug, here a monoclonal antibody (mAb), affects the cell uptake and recycling of the antibody. The antibodies infliximab (IFX) and adalimumab (ADA), directed against the tumor necrosis factor α (TNFα), grafted with AMFA acquired an affinity for the M6PR, resulting in a >3-fold increase in drug release in cells. Subsequently, the impact of AMFA grafting to the Fc portion of mAb on its affinity for the neonatal Fc receptor (FcRn), which is the key receptor for antibody recycling, was evaluated. Whether one to three AMFA moieties were grafted, FcRn-mediated recycling of mAb was not affected. AMFA grafting did not impair the pharmacokinetics of both ADA and IFX and presented a high stability since AMFA were still bound to mAb in the plasma of mice 21 days after the treatment. In conclusion, this type of antibody engineering with a reduced number of AMFA confers M6PR targeting property and increases endocytosis, and yet appears fully compatible with FcRn binding and with antibody recycling and transcytosis.

A phase I study comparing the biosimilarity of the pharmacokinetics and safety of recombinant humanized anti-vascular endothelial growth factor monoclonal antibody injection with Avastin® in healthy Chinese male subjects.

BACKGROUND: The biosimilar landscape for malignancies continues to grow, with several biosimilars for reference product bevacizumab currently available. Bevacizumab has been shown to be well tolerated; however, the safety of recombinant humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody injection remains unclear. This study aimed to compare the pharmacokinetics (PK), safety, and immunogenicity of recombinant humanized anti-VEGF monoclonal antibody injection to that of Avastin® in healthy Chinese male volunteers. METHODS: A randomized, double-blind, single-dose, and parallel-group study was performed on 88 healthy men who randomly (1:1) received either the test drug as an intravenous infusion of 3 mg/kg or Avastin®. The primary PK parameter was area under the serum concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0-t). Secondary endpoints included maximum observed serum concentration (Cmax), AUC from 0 extrapolated to infinity (AUCinf), safety, and immunogenicity. Serum bevacizumab concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). RESULTS: The baseline characteristics were similar among the two groups. The 90% confidence interval (CI) for the geometric mean ratio of AUC0-t, Cmax and AUCinf between the test group and reference group were 91.71%-103.18%, 95.72%-107.49% and 91.03%-103.43%, respectively. These values were within the predefined bioequivalence margin of 80.00%-125.00%, demonstrating the biosimilarity of the test drug and Avastin®. Eighty-one treatment-emergent adverse events were reported, with a comparable incidence among the test group (90.91%) and the reference group (93.18%). No serious adverse events were reported. The incidence of ADA antibodies in the two groups was low and similar. CONCLUSION: In healthy Chinese men, PK similarity of recombinant humanized anti-VEGF monoclonal antibody injection to Avastin® was confirmed, with comparable safety and immunogenicity. Subsequent studies should investigate recombinant humanized anti-VEGF monoclonal antibody injection in patients setting. TRIAL REGISTRATION: Registered 08/10/2019, CTR20191923.

Application of population physiologically based pharmacokinetic modelling to optimize target expression and clearance mechanisms of therapeutic monoclonal antibodies.

AIMS: To use population physiologically based pharmacokinetic (PopPBPK) modelling to optimize target expression, kinetics and clearance of HER1/2 directed therapeutic monoclonal antibodies (mAbs). Thus, to propose a general workflow of PopPBPK modelling and its application in clinical pharmacology. METHODS: Full PBPK model of pertuzumab (PTZ) was developed in patient population using Simcyp V21R1 incorporating mechanistic targeted-mediated drug disposition process by fitting known clinical PK and sparse receptor proteomics data to optimize target expression and kinetics of HER2 receptor. Trastuzumab (TTZ) PBPK modelling was used to validate the optimized HER2 target. Additionally, the simulator was also used to develop a full PBPK model for the HER1-directed mAb cetuximab (CTX) to assess the underlying targeted-mediated drug disposition-independent elimination mechanisms. RESULTS: HER2 final parameterisation coming from the PBPK modelling of PTZ was successfully cross validated through PBPK modelling of TTZ with average fold error (AFE), absolute AFE and percent prediction error values for area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of 1.13, 1.16 and 16, and 1.01, 1.07 and 7, respectively. CTX PBPK model performance was validated after the incorporation of an additional systemic clearance of 0.033 L/h as AFE and absolute AFE showed an acceptable predictive power of AUC and Cmax with percent prediction error of 13% for AUC and 10% for Cmax . CONCLUSIONS: Optimisation of both system and drug related parameters were performed through PBPK modelling to improve model performance of therapeutic mAbs (PTZ, TTZ and CTX). General workflow was proposed to develop and apply PopPBPK to support clinical development of mAbs targeting same receptor.