Benralizumab is a humanized, afucosylated, anti‐interleukin‐5 receptor α, immunoglobulin G (IgG) 1 κ monoclonal antibody. We developed a population pharmacokinetic (PK)/pharmacodynamic (PD) model for benralizumab by analyzing PK and blood eosinophil count data from two healthy volunteer studies (N = 48) and four studies in patients with asthma (N = 152). Benralizumab PK was dose‐proportional and adequately described by a two‐compartment model with first‐order elimination from the central compartment and first‐order absorption from the subcutaneous dosing site. The estimated systemic clearance and volume of distribution were typical for human IgG. Body weight and high‐titer antidrug antibodies were identified as relevant covariates influencing the PK of benralizumab. Depletion of blood eosinophil counts was depicted by a modified transit model in which benralizumab induced depletion of eosinophils in each age compartment. Stochastic simulations supported an every‐8‐week dosing schedule of benralizumab for a phase IIb study in patients with uncontrolled asthma.

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BackgroundThe CD40/CD40L pathway is involved in the T-cell-dependent activation of B cells, which subsequently produce autoantibodies and inflammatory mediators that contribute to autoimmune disease pathology. MEDI4920 is an engineered fusion protein and antagonist of CD40L that lacks the fragment crystallisable (Fc) domain thought to be involved in thromboembolic events (TEs) previously reported with anti-CD40L agents containing an Fc domain.ObjectivesThe primary objective of this Phase I, randomised, double-blind, placebo-controlled, single-ascending dose study was to evaluate the safety and tolerability of MEDI4920 in healthy subjects. Secondary objectives were to characterize T-cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) neoantigen, pharmacokinetics (PK), and anti-drug antibodies (ADAs) to MEDI4920.MethodsFifty-six healthy adult male subjects, aged 19–49 years, received a single intravenous dose of either MEDI4920 (3, 10, 30, 100, 300, 1000 or 3000 mg) or placebo. TDAR inhibition was analysed by measuring serum concentrations of IgG and IgM antibodies to KLH over time. A dose−response model was generated for TDAR inhibition. Blood samples were collected to evaluate PK, total soluble CD40L (sCD40L) and ADA concentrations.ResultsNo deaths, TEs, severe or serious hypersensitivity reactions or infections or infusion-related reactions were observed in the study. One serious adverse event (fractured tibia) was reported in the placebo arm. MEDI4920 showed inhibition of the TDAR IgG response after the second administration of KLH on Day 15 at higher doses (≥300 mg; Figure 1A). An Emax model adequately characterised the TDAR dose−response at Day 43 (p<0.001; ED50=491 mg), with the 3000 mg dose showing 86% inhibition of the TDAR (95% CI: 68–94%; Figure 1B). MEDI4920 exhibited linear PK. MEDI4920 produced a dose-dependent increase in total sCD40L concentrations. A high ADA incidence (90%) was observed in dose cohorts ≤100 mg; however, ADA incidence (29%) and ADA titres decreased with ≥300 mg doses of MEDI4920. ADA-high subjects had reduced MEDI4920 and total sCD40L concentrations compared with ADA-negative subjects or those with low ADA titres. ADA incidence did not correlate with any clinical events.ConclusionsMEDI4920 demonstrated an acceptable safety and tolerability profile, and dose-dependent inhibition of TDAR. The dose-dependent increase in total sCD40L concentrations indicates binding of MEDI4920 to sCD40L and target engagement. The decreases in ADA incidence and ADA titres correlate with increasing MEDI4920 dose, consistent with the immunosuppressive mechanism of action of this molecule. These results support further exploration of MEDI4920 administration in subjects with autoimmune diseases where the CD40/CD40L pathway is activated.AcknowledgementsFunded by MedImmune. Medical writing support: D. Trivedi, MedImmune LLC, Gaithersburg, MD, USA. Technical editing support: R. Plant, QXV Comms, an Ashfield company, which was funded by MedImmune.Disclosure of InterestM. Albulescu Shareho...

Background/Aims ABX‐IL8 is a fully human IgG2 monoclonal antibody generated using transgenic XenoMouse® technology that binds to human interleukin‐8 with high affinity and specificity, and has been evaluated in various inflammatory diseases. The objective of this investigation was to develop a population PK model for ABX‐IL8 in psoriasis patients. Methods In this analysis, 878 PK observations from 81 psoriasis patients were pooled from 2 clinical trials and analyzed simultaneously using NONMEM. One study was a single‐dose, cohort dose‐escalation study with intensive PK sampling. The other was a multiple‐dose study in which ABX‐IL8 was administered intravenously once every 3 weeks for 12 weeks with sparse PK sampling. Weight‐adjusted dosing was used in both studies. Results The PK of ABX‐IL8 was adequately described by a 2‐compartment model with first‐order elimination. The estimated population mean (±SE) clearance (CL) was 0.260±0.010 L/d with an interindividual variability (IIV) of 28% CV. The estimated central (Vc) and peripheral (Vp) volumes of distribution were 4.14±0.14 L (IIV 24%) and 1.68±0.22 L (IIV 20%), respectively. From the covariate analysis, sex and age had no impact on the PK of ABX‐IL8. Body weight was a minor contributor to PK variability. Conclusions The PK of ABX‐IL8 in psoriasis patients was consistent with that of endogenous IgG antibodies, and was adequately described by the developed population model. Simulations support fixed dosing of ABX‐IL8. Clinical Pharmacology & Therapeutics (2005) 77, P91–P91; doi: