Population Pharmacokinetics and Pharmacodynamics of Benralizumab in Healthy Volunteers and Patients With Asthma

Wang, B; Li, Yan; Yao, Zhenling; Roskos, L

doi:10.1002/psp4.12160

Cited by 35 publications

(26 citation statements)

References 28 publications

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“…When benralizumab PK exposure was stratified by weight groups, no clear differences were observed between devices. Consistent with a previous PK modeling study (19), benralizumab PK exposure was greater for volunteers in the lowest weight group compared with those in the other weight groups. Benralizumab was well-tolerated with low prevalence of ADAs, consistent with previous studies (15)(16)(17).…”

Section: Discussionsupporting

confidence: 89%

“…AMES was a multicenter, randomized, open-label, parallel group, Phase I study performed at two sites in Berlin, Germany, and London, United Kingdom. The study included a screening period of 28 days; a single treatment period during which volunteers received benralizumab at the study center on Day 1 and returned for follow up on Days 2,4,5,6,8,15,19,and 43; and an end-of-treatment visit on Day 57.…”

Section: Methodsmentioning

confidence: 99%

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Comparison of autoinjector with accessorized prefilled syringe for benralizumab pharmacokinetic exposure: AMES trial results

Martin

Fuhr²,

Forte

et al. 2019

Journal of Asthma

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Objective: We compared the pharmacokinetic exposure following a single subcutaneous dose of benralizumab 30 mg using either autoinjectors (AI) or accessorized prefilled syringes (APFS). APFS and AI functionality and reliability for at-home benralizumab delivery have been demonstrated in the GREGALE and GRECO studies, respectively. Methods: In the open-label AMES study (NCT02968914), 180 healthy adult men and women were randomized to one of two device (AI or APFS) and three injection site (upper arm, abdomen, or thigh) combinations. Randomization was stratified by weight (<70 kg, 70-84.9 kg, and !85 kg). Blood eosinophil counts were measured on Days 1, 8, 29, and 57. Results: Benralizumab pharmacokinetic exposure was similar between AI and APFS. Geometric mean ratios (AI/APFS) (90% CI) were 92.8% (87.4-98.6) and 94.5% (88.2-101.2) for two area under the concentration-time curve measurements (AUC last and AUC inf). Benralizumab exposure was approximately 15-30% greater for thigh vs. abdomen or upper arm administration. Exposure was slightly greater for APFS vs. AI regardless of injection site or weight class. These differences were unlikely to be clinically relevant, as eosinophil depletion was achieved consistently with both devices at all injection sites. No device malfunctions were reported. No new or unexpected safety findings were observed. Conclusion: Benralizumab pharmacokinetic exposure was similar between AI and APFS, with consistent blood eosinophil count depletion observed with both devices. These results support benralizumab administration with either AI or APFS, providing patients and physicians increased choice, flexibility, and convenience for potential at-home delivery.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Comparison of autoinjector with accessorized prefilled syringe for benralizumab pharmacokinetic exposure: AMES trial results

Martin

Fuhr²,

Forte

et al. 2019

Journal of Asthma

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“…Benralizumab PK data were initially fitted using a two-compartment model with first-order absorption from the subcutaneous dosing site and first-order elimination from the central compartment, based on a previous population PK analysis of data from early phase studies [ 10 ]. The model was parameterized using bioavailability ( F 1 ) fraction, an apparent absorption rate constant ( k a ), systemic CL, central volume of distribution ( V c ), intercompartmental CL ( Q ), and peripheral volume of distribution ( V p ) (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Pharmacokinetic (PK) and blood eosinophil count data from early stage clinical studies were modeled to facilitate selection of optimal dose levels and dosing schedule of benralizumab for a phase IIb proof-of-concept study for adult patients with severe asthma [ 9 , 10 ]. Subsequently, two dosing regimens of benralizumab 30 mg (every 4 weeks, or every 4 weeks for the first three doses followed by every 8 weeks) were selected for the following phase III trials: SIROCCO [ 11 ] and CALIMA [ 12 ], which evaluated the effect of benralizumab on the rate of annual asthma exacerbation; ZONDA [ 13 ], an oral corticosteroid (OCS) reduction study; and BISE [ 14 ], a pulmonary function study.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma

Wang

Chia

et al. 2019

Clin Pharmacokinet

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Introduction Benralizumab, an interleukin-5 receptor alpha–directed cytolytic anti-eosinophil monoclonal antibody, was recently approved as add-on maintenance treatment for patients aged 12 years and older with uncontrolled asthma with eosinophilic inflammation. Methods Pharmacokinetic (PK) data from nine clinical trials for patients with asthma were pooled and analyzed to further characterize the PK of benralizumab and evaluate demographic covariate effects. Results Population modeling results demonstrated that the PK of benralizumab were dose-proportional across a wide dosage range and were adequately described by a two-compartment model with first-order absorption from the subcutaneous dosing site and a first-order elimination pathway from the central compartment. Following subcutaneous administration, the absorption half-life of benralizumab was 3.54 days, and the absolute bioavailability was 58.9%. Estimated clearance (CL; 0.291 L/day), central volume of distribution (V c ; 3.13 L), and peripheral volume of distribution (V p ; 2.52 L) were typical for therapeutic immunoglobulins. Elimination half-life was approximately 15.5 days for patients with asthma. Age, sex, race, liver function, renal function, baseline blood eosinophil count, anatomic injection site, and commonly used small-molecule drugs had no clinically relevant impact on benralizumab CL. Only body weight and antidrug antibodies (ADAs) were identified as relevant PK covariates. Power parameters (exponent) of body weight on CL, V c , and V p were 0.807, 0.803, and 0.528, respectively, and the presence of ADAs increased benralizumab CL by 124%. Conclusions Over 5–20 weeks, the PK of benralizumab were dose-proportional across a dosage range of 0.03–3 mg/kg intravenously and 2–200 mg subcutaneously administered every 4 weeks or every 8 weeks (first three doses every 4 weeks). Body weight and ADA status were identified as relevant PK covariates. Baseline eosinophil count, hepatic and renal functions, anatomical subcutaneous injection site, and commonly used small-molecule drugs had no impact on the PK of benralizumab.

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“…Ternant et al quantified the influence of ADA on IFX PK and reported a 2.7-fold increase in clearance and a 34% decrease in elimination half-life in inflammatory bowel disease patients [275]. ADA is a clinically significant covariate for clearance of number of mAbs like golimumab [276,277], ustekinumab [278,279], anti-IL1β mab [280], daclizumab [281], amatuximab [282], atezolizumab [283] and benralizumab [284] (Table 4). For most of the above cited therapeutic mAbs, the patients developed ADA 12 weeks after initiation of therapy, in line with the known somatic hypermutation kinetics of IgGs [269].…”

Section: Anti-drug Antibodiesmentioning

confidence: 99%

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Thomas

Balthasar

2019

Antibodies

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Monoclonal antibodies (mAbs) are currently the largest and most dominant class of therapeutic proteins. Inter-individual variability has been observed for several mAbs; however, an understanding of the underlying mechanisms and factors contributing to inter-subject differences in mAb disposition is still lacking. In this review, we analyze the mechanisms of antibody disposition and the putative mechanistic determinants of inter-individual variability. Results from in vitro, preclinical, and clinical studies were reviewed evaluate the role of the neonatal Fc receptor and Fc gamma receptors (expression and polymorphism), target properties (expression, shedding, turnover, internalization, heterogeneity, polymorphism), and the influence of anti-drug antibodies. Particular attention is given to the influence of co-administered drugs and disease, and to the physiological relevance of covariates identified by population pharmacokinetic modeling, as determinants of variability in mAb pharmacokinetics.

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Population Pharmacokinetics and Pharmacodynamics of Benralizumab in Healthy Volunteers and Patients With Asthma

Cited by 35 publications

References 28 publications

Comparison of autoinjector with accessorized prefilled syringe for benralizumab pharmacokinetic exposure: AMES trial results

Comparison of autoinjector with accessorized prefilled syringe for benralizumab pharmacokinetic exposure: AMES trial results

Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

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