Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy

ABSTRACT: The primary objective of this work was to determine the optimal time for administration of an erythropoietin (Epo) dose to maximize the erythropoietic effect using a simulation study based on a young sheep pharmacodynamic model. The dosing optimization was accomplished by extending a Hb production pharmacodynamic model, which evaluates the complex dynamic changes in the Epo recepto

Phase 1 Evaluation of Elezanumab (Anti–Repulsive Guidance Molecule A Monoclonal Antibody) in Healthy and Multiple Sclerosis Participants

ObjectiveThis study was undertaken to describe the safety, tolerability, pharmacokinetics, and immunogenicity of elezanumab (ABT-555), a fully human monoclonal antibody (mAb) directed against repulsive guidance molecule A (RGMa), in healthy and multiple sclerosis (MS) study participants.MethodsThe single-center, first-in-human, single ascending dose (SAD) study evaluated elezanumab (50-1,600mg intravenous [IV] and 150mg subcutaneous) in 47 healthy men and women. The multicenter multiple ascending dose (MAD; NCT02601885) study evaluated elezanumab (150mg, 600mg, and 1,800mg) in 20 adult men and women with MS, receiving either maintenance or no immunomodulatory treatment.ResultsNo pattern of study drug-related adverse events was identified for either the SAD or MAD elezanumab regimens. Across both studies, the Tmax occurred within 4 hours of elezanumab IV infusion, and the harmonic mean of t1/2 ranged between 18.6 and 67.7 days. Following multiple dosing, elezanumab Cmax , area under the curve, and Ctrough increased dose-proportionally and resulted in dose-dependent increases in elezanumab cerebrospinal fluid (CSF) concentrations. Elezanumab CSF penetration was 0.1% to 0.4% across both studies, with CSF levels of free RGMa decreased by >40%. Changes in CSF interleukin-10 (IL-10) and free RGMa demonstrated dose/exposure-dependence.InterpretationThe elezanumab pharmacokinetic profile supports monthly, or bimonthly, administration of up to 1,800mg with the option of a loading dose of 3,600mg. Elezanumab partitioning into CSF is within the range expected for mAbs. Reduced CSF levels of free RGMa demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1,800mg IV. Exposure-associated increases in CSF IL-10, an anti-inflammatory cytokine with neuroprotective/neurorestorative properties, support potential pathway modulation in MS participants. ANN NEUROL 2023;93:285-296

Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy

The primary objective of this work was to determine the optimal time for administration of an erythropoietin (Epo) dose to maximize the erythropoietic effect using a simulation study based on a young sheep pharmacodynamic model. The dosing optimization was accomplished by extending a Hb production pharmacodynamic model, which evaluates the complex dynamic changes in the Epo receptor (EpoR) pool from the changes in Epo clearance. Fourteen healthy 2-month-old sheep were phlebotomized to Hb levels of 3 to 4 g/dl. Epo clearance was evaluated longitudinally in each animal by administering tracer doses of 125I-recombinant human Epo multiple times during the experiment. Kinetic parameters were estimated by simultaneously fitting to Hb data and Epo clearance data. The phlebotomy caused a rapid temporary increase in the endogenous Epo plasma level. The Hb began to increase after the increased in the Epo level with a lag time of 1.13 ± 0.79 days. The average correlation coefficients for the fit of the model to the Hb and clearance data were 0.953 ± 0.018 and 0.876 ± 0.077, respectively. A simulation study was done in each sheep with fixed individual estimated model parameters to determine the optimal time to administer a 100 U/kg intravenous bolus Epo dose. The optimal dose administration time was 11.4 ± 6.2 days after phlebotomy. This study suggests that the Hb produced from Epo administration can be optimized by considering the dynamic changes in the EpoR pool

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

Abstract Background Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile