Safety, Tolerability, and Pharmacokinetics of High‐Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers
| العنوان: | Safety, Tolerability, and Pharmacokinetics of High‐Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers |
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| المؤلفون: | Amanda Roden, Nan Hu, Logan Brooks, Monica K Wetzel-Smith, Montserrat Carrasco-Triguero, Geoffrey A. Kerchner, Michael J. Dolton, Kathleen Blondeau, Jill Smith, Ariel Waitz, Anita Moein, Kaycee M Sink, Angelica Quartino, Aaron Chesterman, Kun Peng, Ajay Deshmukh, Susanne Ostrowitzki |
| المصدر: | Clinical Pharmacology & Therapeutics. 110:1337-1348 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, Adolescent, Erythema, Hyaluronoglucosaminidase, Antibodies, Monoclonal, Humanized, Infusions, Subcutaneous, Placebo, Infusion Site, Young Adult, Pharmacokinetics, Humans, Medicine, Pharmacology (medical), Adverse effect, Aged, Aged, 80 and over, Pharmacology, business.industry, Middle Aged, Healthy Volunteers, Recombinant Proteins, Bioavailability, Recombinant Human Hyaluronidase, Tolerability, Anesthesia, Drug Therapy, Combination, Female, medicine.symptom, business |
| الوصف: | Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aβ monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile. |
| تدمد: | 1532-6535 0009-9236 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::34b222931c1ce53bd4112e16a60b1ec2Test https://doi.org/10.1002/cpt.2385Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....34b222931c1ce53bd4112e16a60b1ec2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15326535 00099236 |
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