Subcutaneous Pharmacokinetics Research Articles

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson’s disease

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson’s disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting “on demand” therapy for patients with Parkinson’s disease experiencing motor fluctuations.

Modeling the subcutaneous pharmacokinetics of antibodies co-administered with rHuPH20.

Predicting the subcutaneous (SC) pharmacokinetics (PK) of antibodies in humans is challenging, with clinical data currently being the only reliable data source for modeling SC absorption and bioavailability. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that facilitates SC delivery of high-dose, high-volume therapeutics. Numerous monoclonal antibodies have been co-administered SC with rHuPH20 in a clinical setting, establishing an extensive PK database. The goal of this work is to demonstrate how aggregated clinical data can be leveraged in a universal modeling framework for characterizing SC antibody PK, resulting in parameterization that can be used in predictive simulations of new antibodies. Data for 10 individual antibodies co-administered SC with rHuPH20 were obtained from publicly available sources. PK modeling of each antibody was conducted using the same model structure, but uniquely parameterized. The model structure consisted of a two-compartment model to capture linear kinetics, plus a target-binding mechanism to accommodate nonlinear kinetics driven by antibody-target complex formation and elimination. The clinical PK profiles for all antibodies were accurately described using the universal modeling framework. The SC PK parameters of absorption and bioavailability were consistent across the range of antibody and target properties evaluated. SC administration with rHuPH20 yielded a 30% increase in absorption rate on average and similar or better bioavailability. These parameter values can serve as initial conditions for model-based PK predictions for new antibodies co-administered SC with rHuPH20 to enable evaluation of optimal SC dose and schedule regimens prior to and during clinical development.

Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PKof nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation.

A model of subcutaneous pramlintide pharmacokinetics and its effect on gastric emptying: Proof-of-concept based on populational data

Pramlintide, an amylin analog, has been coming up as an agent in type 1 diabetes dual-hormone therapies (insulin/pramlintide). Since pramlintide slows down gastric emptying, it allows for easing glucose control and reducing the burden of meal announcements. Pre-clinical in silico evaluations are a key step in the development of any closed-loop strategy. However, mathematical models are needed, and pramlintide models in the literature are scarce. This work proposes a proof-of-concept pramlintide model, describing its subcutaneous pharmacokinetics (PK) and its effect on gastric emptying (PD). The model is validated with published populational (clinical) data. The model development is divided into three stages: intravenous PK, subcutaneous PK, and PD modeling. In each stage, a set of model structures are proposed, and their performance is assessed using the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC). In order to evaluate the modulation of the rate of gastric emptying, a literature meal model was used. The final pramlintide model comprises four compartments and a function that modulates gastric emptying depending on plasma pramlintide. Results show an appropriate fit for the data. Some aspects are left as open questions due to the lack of specific data (e.g., the influence of meal composition on the pramlintide effect). Moreover, further validation with individual data is necessary to propose a virtual cohort of patients.

Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

168TiP KEYNOTE-A86: Phase III, randomized, open-label study of first-line subcutaneous (SC) vs intravenous (IV) pembrolizumab with platinum doublet chemotherapy in metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC)

IV pembrolizumab is approved for several tumor types, including squamous and nonsquamous NSCLC. Because most patients prefer SC vs IV dosing, a SC formulation of pembrolizumab was developed, and was found to have similar pharmacokinetics (PK) to the IV formulation in the phase 1 KEYNOTE-555 study. The phase 3, randomized, multicenter, open-label KEYNOTE-A86 study (NCT04956692) evaluates the PK, safety, and efficacy of first-line SC vs IV pembrolizumab plus chemotherapy in metastatic squamous or nonsquamous NSCLC.

A Multi-Center, Phase 1b Study to Assess the Safety, Pharmacokinetics and Efficacy of Subcutaneous Isatuximab Plus Pomalidomide and Dexamethasone, in Patients with Relapsed/Refractory Multiple Myeloma

A Multi-Center, Phase 1b Study to Assess the Safety, Pharmacokinetics and Efficacy of Subcutaneous Isatuximab Plus Pomalidomide and Dexamethasone, in Patients with Relapsed/Refractory Multiple Myeloma

P-207: A multi-center, phase 1b study to assess the safety, Pharmacokinetics and efficacy of subcutaneous Isatuximab plus Pomalidomide and Dexamethasone, in patients with Relapsed/Refractory Multiple Myeloma

<h3>Background</h3> Intravenous (IV) isatuximab (Isa) + pomalidomide and dexamethasone (Pd) is an approved regimen for the treatment of adults with relapsed/refractory multiple myeloma (RRMM). Subcutaneous (SC) delivery would optimize convenience of administration. <h3>Methods</h3> This multicenter, open-label, Phase 1b study evaluated the safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa + Pd in patients (pts) with RRMM who had received ≥2 lines including lenalidomide and a proteasome inhibitor. Pts were randomized 2:1 to Cohorts 1a (SC–1000 mg) or 1b (IV–10 mg/kg) and, after evaluation of Isa SC safety, PK and CD38 Receptor Occupancy (RO), randomized to Cohorts 2a (SC–1400 mg) or 2b (IV). SC was delivered through a syringe pump. Primary endpoints assessed safety including dose-limiting toxicity (DLT), injection site reactions (ISR), and PK parameters. Key secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and CD38 RO. <h3>Results</h3> 34 pts were randomized and treated: 12 pts Isa IV 10 mg/kg + Pd, 12 pts Isa SC1000 + Pd, 10 pts Isa SC1400 + Pd. On March 31, 2021, 7 pts (58%) IV, 4 pts (33%) SC1000, and 7 pts (70%) SC1400 remained on study treatment. At study entry, International Staging System (ISS) stage II–III was 58% in IV, 33% in SC1000 and 60% in SC1400 pts. Due to sequential accrual, the median follow-up was longer in IV (15.1 months [mos]) and SC1000 (14.8 mos) cohorts than SC1400 (8.8 mos). Infusion reactions were infrequent (≤10% across cohorts, all Grade (G) 2), and only at first injection. Local tolerability of SC injection was very good with only a single episode of G2 ISR in SC1400 cohort. Similar occurrence of ≥G3 treatment emergent adverse events (TEAE), treatment-related TEAE, and neutropenia occurred across cohorts. One DLT was reported in each SC cohort: G4 neutropenia (SC1000) and G3 pulmonary infection (SC1400). No maximum tolerated dose was identified. ORR, ≥VGPR, and complete response were 67%, 33%, and 17% in the IV cohort; 67%, 42%, and 25% in the SC1000 cohort and 80%, 40%, and 20% in the SC1400 cohort, respectively. 8 mos PFS-free rate was 73% in the IV and SC1000 cohorts and 89% in the SC1400 cohort. Mean Ctrough after the 4th weekly administration was higher in the SC cohorts (339 µg/mL for SC1000, 338 µg/mL for SC1400) vs 235 µg/mL for IV cohort. High CD38 receptor saturation by Isa on bone marrow plasma cells was reached for both SC doses; mean CD38 RO was 76% in IV, 80% in SC1000, and 81% in SC1400. <h3>Conclusions</h3> The safety of Isa SC at 1000 mg and 1400 mg + Pd was consistent with the known safety profile associated with IV administration, with no new safety signals identified. Local tolerability of SC Isa was very good. Efficacy results were comparable with the Phase 3 ICARIA study. Higher Ctrough at 4 weeks (PK best predictor of Isa efficacy) was achieved following SC administration compared with IV. Isa SC administration appears to be a promising and convenient option. Funded by Sanofi.

Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: Liraglutide, insulin aspart and insulin detemir

Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Göttingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. Furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in Göttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). Finally, more superficial injections resulted in faster absorption, higher Cmax/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model.

Subcutaneous Daratumumab Plus Standard Treatment Regimens in Patients with Multiple Myeloma across Lines of Therapy: Pleiades Study Update

Subcutaneous Daratumumab Plus Standard Treatment Regimens in Patients with Multiple Myeloma across Lines of Therapy: Pleiades Study Update

Pharmacokinetic (PK) and Pharmacodynamic (PD) Studies of RUC-4 Succinate, a Novel αIIbβ3 Pure Antagonist for First Point of Contact Treatment of ST Segment Elevated Myocardial Infarction (STEMI)

We are developing the novel αIIbβ3 pure antagonist, RUC-4, for first point of contact treatment of ST Segment Elevated Myocardial Infarction (STEMI) in combination with aspirin. We have chosen the subcutaneous (SC) route to facilitate its delivery by ambulance and emergency room personnel, and potentially by self-administration. In preparation for initiating human studies, we have conducted preclinical studies of: 1. the pharmacokinetics (PK) and pharmacodynamics (PD) of RUC-4 succinate administered IV, IM, and SC to non-human primates (NHP); 2. the impact of in vitro aspirin on the RUC-4 IC50 in human platelet-rich plasma (PRP); and 3. the effect of different anticoagulants on the IC50 of RUC-4 in human PRP.Non-human primates (Macaca fascicularis; NHPs) received RUC-4 at 1.0, 1.96, and 3.86 mg/kg IV, IM, and SC. Blood samples for IV PK studies were collected at 0, 1, 5, 15, 30, 120, and 270 min; samples for IM and SC PK studies were collected at 0, 5, 15, 30, 45, 120, and 270 min and ~27 hrs, the latter only for animals that received 3.86 mg/kg IM. There were 2 animals per group and 2 groups per dose, so no more than 4-5 samples were collected from a single animal. Platelet aggregation was performed with 5 µM ADP on citrated PRP from the NHPs that received RUC-4 IM. All doses of RUC-4 administered IM and SC were well tolerated, but animals demonstrated variable temporary bruising. None of the animals developed thrombocytopenia despite receiving up to 4 doses of RUC-4 over 3 months. The PK data are shown in the Table; both IM and SC RUC-4 reached dose-dependent peak levels within 5-15 min, with T1/2 s between 0.28 and 0.56 hrs. The bioavailability of RUC-4 IM and SC ranged between 0.60-0.88 at doses of 1.93 and 3.86 mg/kg; there was greater variability in bioavailability at 1 mg/kg (1.2 IM and 0.55 SC). Platelet aggregation studies demonstrated >80% inhibition of the initial slope of aggregation in response to ADP in all samples in which the whole blood RUC-4 concentration was ≥ ~8 nM, with partial inhibition at lower concentrations.Since aspirin is the standard-of-care for initial treatment of STEMI, we plan to administer RUC-4 + aspirin. To assess aspirin-RUC-4 interactions, we compared the RUC-4 IC50 in untreated human citrated PRP to the RUC-4 IC50 in PRP pre-treated with 0.83 mM aspirin for 10 min at 22°C. This aspirin dose completely inhibited platelet aggregation to 1.5 mM arachidonic acid in each donor, indicating inhibition of thromboxane A2 production. In studies on 5 donors using 5 μM ADP as the agonist, the RUC-4 IC50 was 40 ± 9 nM in untreated PRP and 37 ± 5 nM in aspirin-treated PRP (p=0.50).Previous studies demonstrated that citrate anticoagulation can variably enhance the antiplatelet effect of some αIIbβ3 antagonists (Phillips et al., Circulation 96:1488, 1997: Kereiakes et al., J Thromb Thrombolysis 12:123, 2001). We therefore compared the IC50 of RUC-4 in human blood anticoagulated with citrate (0.38%), heparin (15.8 U ml), and PPACK (300 nM) when stimulated with a thrombin receptor activating peptide (T6; TRAP) at 20 µM. The resulting IC50 values were 66 ± 25, 111 ± 7, and 122 ± 17, respectively (n=4; p=0.05 for citrate vs PPACK and p=0.04 for heparin vs citrate). With 20 µM ADP activation, the IC50 values for blood anticoagulated with citrate and PPACK (100 µM) were 54 ± 13 and 102 ± 12 nM (p=0.001).In summary: 1. In accord with our studies with RUC-4 free base (Li et al., ATVB 34: 2321, 2014), IM RUC-4 succinate achieves peak blood levels in NHP within 5 min, resulting in >80% inhibition of platelet aggregation that persists for several hrs at a dose of 3.86 mg/kg. 2. SC RUC-4 achieves peak blood levels within 5-15 min; while the peak concentrations are lower than those with IM RUC-4 at the same doses, the blood levels are more sustained, with levels equivalent to the IM values producing ≥80% inhibition of initial slope persisting for several hrs. 3. Aspirin at a concentration that eliminates arachidonic acid-induced platelet aggregation does not affect the IC50 for RUC-4; 4. Assaying RUC-4 IC50 in human PRP from blood anticoagulated with citrate yields a value ~50% of that obtained with PRP prepared from blood anticoagulated with agents that do not affect divalent cation levels. Thus, the values in the presence of citrate may overestimate the in vivo antiplatelet effect. We conclude that the PK and PD of SC RUC-4 are favorable for short-term, high-potency inhibition of platelet aggregation as part of first point of care treatment of STEMI. [Display omitted] DisclosuresNedelman:Biomere: Employment, Equity Ownership. Coller:Centocor: Patents & Royalties: Abciximab; CeleCor: Consultancy, Equity Ownership; Rockefeller University: Patents & Royalties: RUC-4; Platelet Biogenesis: Consultancy; Accumetrics: Patents & Royalties: VerifyNow Assays; Scholar Rock: Consultancy, Equity Ownership.

Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model.

Monoclonal antibodies (mAbs) are commonly administered by subcutaneous (SC) route. However, bioavailability is often reduced after SC administration. In addition, the sequential transfer of mAbs through the SC tissue and lymphatic system is not completely understood. Therefore, major objectives of this study were a) To understand absorption of mAbs via the lymphatic system after SC administration using physiologically based pharmacokinetic (PBPK) modeling, and b) to demonstrate application of the model for prediction of SC pharmacokinetics (PK) of mAbs. A minimal PBPK model was constructed using various physiological parameters related to the SC injection site and lymphatic system. The remainder of the body organs were represented using a 2-compartment model (central and peripheral compartments), with parameters derived from available intravenous (IV) PK data. The IV and SC clinical PK data of a total of 10 mAbs were obtained from literature. The SC PK data were used to estimate the lymphatic trunk-lymph node (LN) clearance. The mean estimated lymphatic trunk-LN clearance obtained from 37 SC PK profiles of mAbs was 0.00213 L/h (0.001332 to 0.002928, 95% confidence intervals). The estimated lymphatic trunk-LN clearance was greater for the mAbs with higher isoelectric point (pI). In addition, the estimated clearance increased with decrease in the bioavailability. The minimal PBPK model identified SC injection site lymph flow, afferent and efferent lymph flows, and volumes associated with the SC injection site, lymphatic capillaries and lymphatic trunk-LN as important physiological parameters governing the absorption of mAbs after SC administration. The model may be used to predict PK of mAbs using the relationship of lymphatic trunk-LN clearance and the pI. In addition, the model can be used as a bottom platform to incorporate SC and lymphatic in vitro clearance data for mAb PK prediction in the future.

Prolonged Half-Life and Improved Recovery of Recombinant Factor IX-XTEN Fusion Proteins in Hemophilia B Mouse Model

INTRODUCTIONProphylactic treatment for hemophilia B patients is the therapy of choice to improve quality of life and minimize annual bleeding rates and damage to joints. A new generation of extended half-life (EHL) FIX replacement products has been generated to improve patient care by reducing treatment burden. The factors include the currently marketed rFIXFc, as well as rFIX attached to PEG or albumin. The latter two are in clinical trials. All FIX preparations are administered by intravenous dosing, which can be particularly challenging for young patients and patients with limited venous access; these difficulties are reduced, but not eliminated, by the less frequent dosing achieved with EHL rFIX therapies. In the current study, we evaluate an XTEN-recombinant protein technology in order to develop EHL rFIX-XTEN molecules that are suitable for both acute treatment, as well as prophylactic subcutaneous dosing in hemophilia B, and could potentially further reduce the burden of treatment. XTEN are unstructured polypeptide sequences that consist of a limited set of natural amino acids (Pro, Ala, Gly, Glu, Ser, Thr). Fusion of XTEN to proteins alters its hydrodynamic properties and reduces the rate of clearance and degradation of the fusion protein. These XTEN fusion proteins are produced using recombinant technology, without the need for chemical modifications, and degraded by natural pathways.MATERIALS AND METHODSRecombinant FIX and FIXFc molecules were expressed as the natural Arg338Leu (R388L, Padua) variant with improved activity. XTEN polypeptides are fused to either the C-terminus of rFIX or inserted into the EGF2 domain or activation peptide (AP) domain of rFIX or rFIXFc. The fusion proteins were prepared by transient expression in human HEK293 cells followed by affinity purification. Hemophilia B (HemB) mice were dosed by either intravenous or subcutaneous injection with a single bolus of 50 or 200 IU/kg of the rFIX- or rFIXFc-fusion proteins. Plasma activity levels were determined over time using a FIX activated partial thromboplastin time assay (aPTT). PK parameters were determined using non-compartmental modeling with Phoenix WinNonlin 6.2.1 (Pharsight).RESULTSInsertion of XTEN sequences with increasing length (42, 72, 144 or 288 amino acids long) at either C-terminus of rFIX-R338L or in the AP domain showed a size dependent increase in plasma recovery up to 60% following intravenous bolus dosing. Combinations of XTEN insertions in the EGF2 or AP domain with Fc-mediated half-life extension in rFIXFc-R338L, extended the half-life as well as increased the plasma recovery. The AUC/D for rFIX-CT-XTEN.288 and rFIXFc-AP-XTEN.72 were 8.5 and 14.5 fold improved when compared to intravenously dosed rFIX, respectively.Following a subcutaneous dose of either rFIXFc-AP-XTEN.72 or rFIX-CT-XTEN.288, we observed 28 and 40-fold improved AUC/D; 15- and 30-fold improved Cmax/D and 3-fold increased bioavailability. When compared to rFIXFc the improvement in pharmacokinetic parameters was 6- and 9-fold improved AUC/D; 3- and 10-fold Cmax/D and 1.5- and 2-fold improved bioavailability for FIXFc-AP-XTEN.72 and rFIX-CT-XTEN.288, respectively.Taken together, subcutaneous dosing of rFIX-CT-XTEN.288 and rFIXFc-AP-XTEN.72 in HemB mice showed improved AUC/D when compared to intravenous dosing of rFIXFc.CONCLUSIONSrFIXFc-AP-XTEN.72 and rFIX-CT-XTEN.288 show greatly improved subcutaneous pharmacokinetics in HemB mice compared to both rFIX and rFIXFc. These promising preclinical subcutaneous dosing data in HemB mice suggests the potential of once weekly or every two weeks prophylactic subcutaneous dosing of FIX-XTEN molecules in patients. In addition, the molecules have potential for acute treatment by intravenous dosing. Further studies are ongoing to address the efficacy and allometric scaling in preclinical animal models. Disclosuresvan der Flier:Biogen: Employment. Liu:Biogen: Employment. Liu:Biogen: Employment, Equity Ownership, Honoraria, Research Funding. Mercury:Biogen: Employment. Ismail:Biogen: Employment. Seth-Chhabra:Biogen: Employment, Equity Ownership, Honoraria, Patents & Royalties, Research Funding. Kulman:Biogen: Employment. Schellenberger:Amunix Operating Inc: Employment. Light:Biogen: Employment, Equity Ownership. Peters:Biogen: Employment.

Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-IgTM) molecule that specifically and potently neutralizes both IL-1α and IL-1β

Interleukin-1 (IL-1) cytokines such as IL-1α, IL-1β, and IL-1Ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. IL-1α and IL-1β bind to IL-1R1 complexed to the IL-1 receptor accessory protein and induce similar physiological effects. Preclinical and clinical studies provide significant evidence for the role of IL-1 in the pathogenesis of osteoarthritis (OA), including cartilage degradation, bone sclerosis, and synovial proliferation. Here, we describe the generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) of the IgG1/k subtype that specifically and potently neutralizes IL-1α and IL-1β. In ABT-981, the IL-1β variable domain resides in the outer domain of the DVD-Ig, whereas the IL-1α variable domain is located in the inner position. ABT-981 specifically binds to IL-1α and IL-1β, and is physically capable of binding 2 human IL-1α and 2 human IL-1β molecules simultaneously. Single-dose intravenous and subcutaneous pharmacokinetics studies indicate that ABT-981 has a half-life of 8.0 to 10.4 d in cynomolgus monkey and 10.0 to 20.3 d in rodents. ABT-981 exhibits suitable drug-like-properties including affinity, potency, specificity, half-life, and stability for evaluation in human clinical trials. ABT-981 offers an exciting new approach for the treatment of OA, potentially addressing both disease modification and symptom relief as a disease-modifying OA drug.

PEGylation does not significantly change the initial intravenous or subcutaneous pharmacokinetics or lymphatic exposure of trastuzumab in rats but increases plasma clearance after subcutaneous administration.

The lymphatic system plays a major role in the metastatic dissemination of cancer and has an integral role in immunity. PEGylation enhances drainage and lymphatic uptake following subcutaneous (sc) administration of proteins and protein-like polymers, but the impact of PEGylation of very large proteins (such as antibodies) on subcutaneous and lymphatic pharmacokinetics is unknown. This study therefore aimed to evaluate the impact of PEGylation on the sc absorption and lymphatic disposition of the anti-HER2 antibody trastuzumab in rats. PEG-trastuzumab was generated via the conjugation of a single 40 kDa PEG-NHS ester to trastuzumab. PEG-trastuzumab showed a 5-fold reduction in HER2 binding affinity, however the in vitro growth inhibitory effects were preserved as a result of changes in cellular trafficking when compared to native trastuzumab. The lymphatic pharmacokinetics of PEG-trastuzumab was evaluated in thoracic lymph duct cannulated rats after iv and sc administration and compared to the pharmacokinetics of native trastuzumab. The iv pharmacokinetics and lymphatic exposure of PEG-trastuzumab was similar when compared to trastuzumab. After sc administration, initial plasma pharmacokinetics and lymphatic exposure were also similar between PEG-trastuzumab and trastuzumab, but the absolute bioavailability of PEG-trastuzumab was 100% when compared to 86.1% bioavailability for trastuzumab. In contrast to trastuzumab, PEG-trastuzumab showed accelerated plasma clearance beginning approximately 7 days after sc, but not iv, administration, presumably as a result of the generation of anti-PEG IgM. This work suggests that PEGylation does not significantly alter the lymphatic disposition of very large proteins, and further suggests that it is unlikely to benefit therapy with monoclonal antibodies.

Subcutaneous pharmacokinetics of the cardiac hormone vessel dilator.

Vessel dilator, a hormone synthesized in the heart, eliminates 71% of human small-cell lung cancers and 67% of human breast cancers growing in mice when given subcutaneously (s.c.) via osmotic pumps. The pharmacokinetics of s.c. administered vessel dilator have not been evaluated previously. In the present study, the pharmacokinetics of vessel dilator following s.c. bolus (ScB) or 3h s.c. infusion (ScI) were compared with those following i.v. bolus (IvB) administration in male Fischer 344 rats. The half-life (t½ ) of vessel dilator after ScI, IvB and ScB was 54, 43 and 30min, respectively. The tmax for vessel dilator after IvB, ScB and ScI administration was 1.5, 23 and 156min, respectively, whereas the corresponding Cmax values were 3749, 887 and 471ng/L (normalized against the dose used for ScB and IvB). The area under the curve (AUC0-∞ ) for vessel dilator was 1166, 880 and 1652ngh/mL (normalized) following IvB, ScB and ScI administration, respectively. The volume of distribution for vessel dilator was 2.38, 0.92 and 1.08L following IvB, ScB and SCI administration, respectively; corresponding clearance values were 1.69, 1.50 and 0.78L/h, respectively. Plasma concentrations of vessel dilator after each of the three methods of administration mirrored their predicted concentration-time profiles. We conclude that vessel dilator administered via ScI has a significantly greater AUC and t½ and slowed clearance compared with IvB or ScB administration (P<0.001), suggesting that s.c. infusion is the preferred method of administration, based on pharmacokinetics, to treat cancers.

The Lymphatic System Plays a Major Role in the Intravenous and Subcutaneous Pharmacokinetics of Trastuzumab in Rats

Therapeutic monoclonal antibodies are currently delivered mainly via the intravenous route, since large volumes are often required to deliver a therapeutic dose. Administration via the subcutaneous route would have several therapeutic advantages; the absorption mechanisms for antibodies dosed subcutaneously are poorly understood. This study was conducted to develop a better understanding of the mechanisms governing the subcutaneous absorption and trafficking of monoclonal antibodies. Specifically, the role of the lymphatic system in the absorption and prolonged plasma exposure of trastuzumab was explored in thoracic lymph duct-cannulated rats after SC and IV dosing. A population pharmacokinetic model was developed in S-ADAPT to simultaneously fit all plasma and lymph concentrations and to predict the pharmacokinetics in nonlymph duct-cannulated animals. The estimated absolute bioavailability of trastuzumab after SC administration in rats was 85.5%. Following SC administration, 53.1% of the trastuzumab dose was absorbed via a first-order process (mean absorption time: 99.6 h) into the peripheral lymph compartment and 32.4% of the dose was absorbed by a Michaelis-Menten process into the central compartment. Recovery in thoracic lymph over 30 h was 26.7% after SC and 44.1% after IV administration. This study highlights for the first time the significant role of the lymphatic system in maintaining the long plasma exposure of trastuzumab, with the model predicting an extensive distribution of this monoclonal antibody into the lymph following SC and IV administration. This extensive direct absorption from the SC injection site into lymph may enable novel therapeutic strategies for the treatment of lymph resident metastatic cancer.

Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats

ObjectiveTo describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (IV), intramuscular (IM) and subcutaneous (SC) buprenorphine in cats. Study designRandomized, prospective, blinded, three period crossover experiment. AnimalsSix healthy adult cats weighing 4.1 ± 0.5 kg. MethodsBuprenorphine (0.02 mg kg−1) was administered IV, IM or SC. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p < 0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the IV data was described using a model combining biophase equilibration and receptor association-dissociation kinetics. ResultsTT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after IV and IM administration, respectively (p < 0.05). Maximum increase in TT (mean ± SD) was 9.3 ± 4.9 °C at 60 minutes (IV), 4.6 ± 2.8 °C at 45 minutes (IM) and 1.9 ± 1.9 °C at 60 minutes (SC). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after IV administration compared to IM and SC, respectively. IV and IM buprenorphine concentration-time data decreased curvilinearly. SC PK could not be modeled due to erratic absorption and disposition. IV buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t1/2ke0 = 47.4 minutes) and receptor binding (kon = 0.011 mL ng−1 minute−1). Persistence of thermal antinociception was due to slow receptor dissociation (t1/2koff = 18.2 minutes). Conclusions and clinical relevanceIV and IM data followed classical disposition and elimination in most cats. Plasma concentrations after IV administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the IV route should be preferred over the IM and SC routes when buprenorphine is administered to cats.

Final Results of the BP22333 Study Demonstrate Non-Inferior Pharmacokinetics (PK) and Safety of Subcutaneous (SC) Administration of Rituximab Compared with Intravenous (IV) Administration As Maintenance Therapy in Patients with Follicular Lymphoma (FL)

AbstractAbstract 1641Rituximab has proven efficacy and tolerability for treating B-cell malignancies. IV rituximab administration can take several hours, consuming considerable healthcare resources. A SC rituximab formulation has been developed which may shorten administration time, increase patient (pt) convenience, and potentially reduce IV administration-associated costs. Rituximab efficacy depends on CD20 binding, and Ctrough rituximab levels reflect rituximab exposure throughout the therapy cycle; therefore, achieving a non-inferior Ctrough level with SC dosing is expected to provide comparable efficacy to IV dosing. BP22333 (NCT00930514) is a two-stage phase Ib study assessing PK and tolerability of SC vs IV maintenance rituximab in pts with first-line or relapsed FL. Stage 1 dose-finding results (Salar et al, ASH 2010, abstract 2858; Salar et al, EHA 2012, abstract 0794) identified a fixed dose of 1400 mg for formal Ctrough non-inferiority testing in Stage 2. We report Stage 2 data.The Stage 2 objective was to demonstrate non-inferiority of simulated Ctrough of rituximab SC and IV, using a non-inferiority test with a lower boundary of 0.8 for the 90% confidence interval (CI). Secondary endpoints include SC vs IV rituximab safety and area under the serum concentration-time curve. Eligible pts (N = 157) were aged ≥18 years with an ECOG performance status of ≤ 2, and histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment. Eligible pts must have achieved a complete or partial response following IV rituximab-based induction therapy for FL and have received ≥1 cycle of IV rituximab maintenance within 16 weeks of completing induction. Pts (N = 154) were randomized 1:1 to receive SC rituximab (1400 mg) or IV rituximab (375 mg/m2) for their remaining maintenance cycles, stratified by 2-monthly (q2m) vs 3-monthly (q3m) regimen. Study arms were balanced for age, sex, body surface area, FL grade at diagnosis, induction therapy and number of maintenance doses prior to study entry. As of May 11, 2012, 13 SC pts had withdrawn (7 for progressive disease [PD], 4 for AEs, 1 at investigator’s decision, 1 for ineligibility) and 17 IV pts had withdrawn (10 for PD, 4 for AEs, 3 for ineligibility). Median treatment duration on-study was 14.8 months (range, 0–19) in the SC arm and 13.8 months (range, 0–19) in the IV arm.The primary endpoint of the study was met. Geometric mean Ctrough,SC:Ctrough,IV ratios were 1.24 and 1.12, respectively, for q2m and q3m, and lower limits of the two-sided 90% CI (1.02 and 0.86, respectively) exceeded the protocol-specified non-inferiority limit (Ctrough,SC:Ctrough,IV ratio of 0.8). Therefore, 1400 mg SC rituximab was concluded to be non-inferior to 375 mg/m2 IV rituximab administration.AE incidence and intensity were generally balanced; 79% of pts in each arm experienced AEs. Serious AEs were observed in 12% and 14% of pts in the SC and IV arms, respectively; none occurred in > 1 pt in either arm. Grade 3/4 AEs occurred in 18% and 17% of pts in the SC and IV arms, respectively; the only grade 3/4 AEs occurring in > 1 pt in either arm were neutropenia (2 pts in each arm) and arthralgia (2 pts in the IV arm). Administration-related reactions (ARRs) were the most frequent AE and had a higher incidence in the SC arm (reported in 31% of SC vs 4% of IV pts). ARRs were mostly local reactions; the most common in the SC arm were: erythema (13%), injection site erythema (5%), and myalgia (5%). Further safety data will be presented.PK data for SC and IV rituximab administration demonstrate non-inferiority of 1400 mg rituximab SC administration to that of the approved IV rituximab maintenance regimen for both q2m and q3m schedules. The overall AE profiles were similar for SC and IV rituximab administration, with the exception of local ARRs, which had a higher incidence in the SC arm compared with the IV arm, reflecting the expected change in the ARR profile with SC administration. Induction and maintenance therapy using the 1400 mg SC rituximab dose is being assessed in the phase III BO22334 study. Disclosures:Salar:Roche: Consultancy. Off Label Use: Subcutaneous (SC) administration of rituximab as maintenance therapy in patients with follicular lymphoma (FL). Larouche:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brewster:Roche: Employment, Equity Ownership. Catalani:Roche: Employment, Equity Ownership. McIntyre:Roche: Employment. Sayyed:Roche: Employment. Haynes:Roche: Consultancy, Honoraria.

Pharmacokinetics (PK) and Pharmacodynamics (PD) of Subcutaneous Versus Intravenous Administration of Bortezomib in Patients with Relapsed Multiple Myeloma: Effects of Subcutaneous Injection Site and Concentration, and Patient Characteristics

Abstract 1863 Background:The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM); the recommended dose and schedule is 1.3 mg/m2 administered by intravenous (IV) injection on days 1, 4, 8, and 11 of 21-day cycles. Findings from the phase 3 randomized, non-inferiority, MMY-3021 study (Moreau et al, Lancet Oncol 2011) demonstrated that subcutaneous (SC) administration of bortezomib, using the same dose and schedule, was feasible, and resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus IV bortezomib in patients with relapsed MM. These findings built upon an earlier randomized phase 1 study (CAN-1004; Moreau et al, Haematologica 2008). Here we present a comprehensive analysis of the PK and PD of SC versus IV bortezomib and evaluate the impact of SC administration site/concentration and patient characteristics, using all available data from MMY-3021 and CAN-1004, and pooled analyses. Methods:Patients with relapsed MM after 1–3 (MMY-3021) or ≥1 (CAN-1004) prior therapies were randomized to receive up to eight (or 10 for patients with late evolving response in MMY-3021) 21-day cycles of SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11. The SC injection concentration was 1 mg/mL in CAN-1004, but 2.5 mg/mL in MMY-3021, to reduce the volume injected. SC injection sites were the thighs and abdomen, and were rotated for successive injections. In both studies, the IV injection concentration was 1 mg/mL. In MMY-3021, 17/18 SC and 14/14 IV patients enrolled to the PK/PD substudy at selected sites were assessable; in CAN-1004, 10/12 patients on each arm were included in the PK/PD analyses. Blood samples were collected pre-dosing and at multiple time points post-dose on day 11 of cycle 1 for PK/PD analyses. Results:PK analyses demonstrated that bortezomib systemic exposure was equivalent with SC versus IV administration in MMY-3021 (AUClast: 155 vs 151 ng.hr/mL, geometric mean ratio of 0.992 [90% CI: 80.18, 122.80]) and comparable in CAN-1004 (AUClast: 195 vs 241 ng.hr/mL), although as would be expected, Cmax was lower (MMY-3021, 20.4 vs 223 ng/mL, Figure; CAN-1004, 22.5 vs 162 ng/mL) and Tmax was longer (both studies, 30 vs 2 mins; Figure). PD parameters of proteasome inhibition were also similar with SC versus IV bortezomib (Emax: MMY-3021, 63.7 vs 69.3%; CAN-1004, 57.0 vs 68.8%; AUE72hr: MMY-3021, 1714 vs 1383 %.hr; CAN-1004, 1619 vs 1283 %.hr), although time to Emax was longer (MMY-3021, 120 vs 5 mins; CAN-1004, 120 vs 3 mins). Analyses of PK and PD parameters in MMY-3021 according to SC injection site showed no differences (Table). Comparison of SC bortezomib PK and PD parameters between MMY-3021 and CAN-1004 showed that SC injection concentration (2.5 vs 1 mg/mL) had no appreciable effect. Demographic covariates had no impact on bortezomib systemic exposure based on pooled bortezomib PK parameters following SC injection in the two studies. Full results from subgroup analyses will be presented. Conclusions:Data from these randomized studies of SC versus IV bortezomib in patients with relapsed MM demonstrate that SC administration results in equivalent bortezomib plasma exposure, albeit with a lower Cmax and longer Tmax, compared with IV administration, together with comparable PD effects. SC injection site and concentration of the injected solution did not affect bortezomib PK and PD parameters, and the demographic covariates did not appear to have an impact on the PK and PD of SC bortezomib. The non-inferior efficacy of SC versus IV bortezomib in relapsed or refractory MM demonstrated in MMY-3021, together with the equivalent total systemic exposures (AUC) via the SC and IV routes of administration, support the use of bortezomib via the SC route across the settings of clinical use in which the safety and efficacy of IV bortezomib has been established.Mean (SD) bortezomib PK/PD parameters by injection sitePK by injection siteCmax(ng/mL)Tmax(hr)*AUClast(ng.hr/mL)Thigh (N = 11)17.7 (8.40)0.50 (0.08–1.00)171 (62.1)Abdomen (N = 6)25.4 (8.08)0.38 (0.25–1.00)127 (33.3)PD by injection siteEmax(%)Tmax(hr)*AUE72hr(%.hr)Thigh (N = 11)59.1 (6.37)2.00 (0.50–10)1700 (484)Abdomen (N = 6)72.3 (12.1)3.00 (1.00–24)1741 (863)*Median (range). [Display omitted] Disclosures:Moreau:Janssen: Advisory board, Honoraria; Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria. Off Label Use: Bortezomib administered via subcutaneous injection. Hulin:Celgene: Honoraria; Janssen-Cilag: Honoraria. Leleu:Janssen: Insitutional grants and lecture fees. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Venkatakrishnan:Millennium Pharmaceuticals, Inc.: Employment. Skee:Janssen Research & Development: Employment. Feng:Janssen Research & Development: Employment. Girgis:Janssen Research & Development: Employment. Cakana:Janssen Research & Development: Employment. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Facon:Janssen: Advisory committee, Speakers Bureau.