Clinical Pharmacology Manager Pfizer, United States
Disclosure(s):
Huili Chen: No financial relationships to disclose
Objectives: This study aims to re-examine previous evaluations of body size-based dosing approaches by Wang et al [1] and Zhang et al [2] using a larger dataset including FDA-approved monoclonal antibodies (mAbs), fusion proteins (FPs), bispecifics (bsAbs), antibody drug conjugates (ADCs), peptides, and oligonucleotides. This work will: (1) evaluate the body size effect on CL (α) across modalities, (2) examine the impact of α on approved dosing approach, (3) investigate dosing approach justification for the approved dosing approach, and (4) assess changes of dosing approach in first-in-human (FIH) trials. Our objective is to provide updated recommendations on the use of body size-based versus FIH trials, Phase 2/3 trials, and approval.
Methods: FDA approved therapeutic proteins and oligonucleotides (TPOs) prior to September 2024 were reviewed and compiled from publicly available sources [3-10]. Key information gathered include dosing approach used in the FIH trial, approved dosing approach, details of the PopPK model (e.g. model structure for body size covariate and α value), and justification of approved dosing approach when α did not explain the dosing approach. Entries were excluded for biosimilars, duplicates between sources, combination drug products, non-systemic routes of administration, radiopharmaceuticals, if the covariate analysis on body size was not available or not conducted, if no PopPK model based only on adult subjects (≥18 years old) was available, or if the PopPK model did not include linear clearance as a parameter.
Results: A total of 143 TPOs were included in the dataset, including 79 mAbs, 7 FPs, 11 bsAbs, 12 ADCs, 6 oligonucleotides, and 28 peptides. Results showed that 57% non-ADC large molecules had an α < 0.7, and fixed dosing was the most common approved approach (62%). For 27 molecules with α > 0.7, fixed dosing was approved due to lack of clinically meaningful body size-related exposure differences. The α value and dose justification supported fixed dosing for 84% of non-ADC large molecules. The percentage of drugs approved with fixed dosing increased after the publication of Wang et al [1] and Zhang et al [2]. The approved dosing approach was the same as the dosing approach in the FIH for 72% (96/134) of TPOs when FIH information was available.
Conclusions: These findings confirm Wang et al's [1] and Zhang et al's [2] previous conclusions, continuing to support their recommendations. For FIH trials, fixed dosing is recommended as the starting dosing approach. Once sufficient PK data becomes available, the effect of body size on CL should be evaluated. If α < 0.5, fixed dosing is recommended as it results in lower IIV compared to body size-based dosing. In the range of 0.5 ≤ α ≤ 0.7, although body size may outperform fixed dosing in reducing IIV, this difference is unlikely to be clinically significant. Therefore, fixed dosing is recommended, unless the safety data suggest otherwise. If α > 0.7, body size-based dosing is recommended, particularly if exposure differences at extreme body sizes are clinically meaningful, though fixed dosing may still be used when the therapeutic window is wide.
Citations: [1] Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009 Sep;49(9):1012-24. doi: 10.1177/0091270009337512. Epub 2009 Jul 20. PMID: 19620385. [2] Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012 Jan;52(1):18-28. doi: 10.1177/0091270010388648. Epub 2011 Jan 13. PMID: 21233304. [3] U.S. Food and Drug Administration. Purple Book: Database of FDA-Licensed Biological Products. Silver Spring (MD): FDA; 2024. Available from: https://purplebooksearch.fda.gov/ [4] Wang L, Wang N, Zhang W, Cheng X, Yan Z, Shao G, Wang X, Wang R, Fu C. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022 Feb 14;7(1):48. doi: 10.1038/s41392-022-00904-4. PMID: 35165272; PMCID: PMC8844085. [5] Al Musaimi O, Al Shaer D, Albericio F, de la Torre BG. 2020 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2021 Feb 11;14(2):145. doi: 10.3390/ph14020145. PMID: 33670364; PMCID: PMC7918236. [6] Al Shaer D, Al Musaimi O, Albericio F, de la Torre BG. 2021 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2022 Feb 13;15(2):222. doi: 10.3390/ph15020222. PMID: 35215334; PMCID: PMC8876803. [7] Al Musaimi O, Al Shaer D, Albericio F, de la Torre BG. 2022 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2023 Feb 22;16(3):336. doi: 10.3390/ph16030336. PMID: 36986436; PMCID: PMC10056021. [8] Al Shaer D, Al Musaimi O, Albericio F, de la Torre BG. 2023 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2024 Feb 13;17(2):243. doi: 10.3390/ph17020243. PMID: 38399458; PMCID: PMC10893093. [9] U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. Silver Spring (MD): FDA; Available from: https://www.accessdata.fda.gov/scripts/cder/daf/ [10] National Library of Medicine (US). ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), National Institutes of Health; Available from: https://clinicaltrials.gov/
Keywords: body size effect on clearance, body size based dosing approach, large molecule therapeutics
