O. Stepanov(1), M. Learoyd(1), L. Clegg(2), U. Wählby Hamrén(3), I. Pouliquen(1)
AstraZeneca UK Limited
Introduction:
Due to the coronavirus disease 2019 (COVID-19) pandemic and the rise of drug-resistant bacteria, the rapid development of neutralizing monoclonal antibodies (mAbs) for the prevention and passive immunization of infectious diseases (ID) is urgently needed. Our study aims to investigate and compare the pharmacokinetic profiles of different YTE-modified mAbs [1-2] across indications and species. We will also demonstrate the practical utility of the established model, particularly in guiding and accelerating new drug development and in determining initial human dosing.
Objectives:
- To investigate and compare the pharmacokinetic profiles of various mAbs featuring YTE-modification across diverse ID indications and species.
- To illustrate the utility of an established model for AZD7442 in guiding the development of new mAbs and determining the first in human dose.
Method:
Nonlinear mixed-effects modeling was performed with NONMEM [3], using the “Stochastic Approximation Expectation Maximization” (SAEM) method. Data were log-transformed prior to modeling. Perl-Speaks-NONMEM [4] was also used for facilitation of NONMEM tasks, such as covariate testing. R [5] was used for graphical analysis, model diagnostics, and simulations.
Results:
Pharmacokinetic profiles showed remarkable similarity between AZD7442 and nirsevimab in cynomolgus monkey studies and in adult clinical studies. In particular, both drugs had comparable half-lives, indicating consistent elimination rate constants across species.
Using the robust population pharmacokinetic model developed for AZD7442, we successfully describe the paediatric data for nirsevimab. Although initially developed for adults, the model skillfully integrated parameters derived from the age-maturation functions observed in nirsevimab paediatric studies, underscoring its adaptability and predictive power in diverse populations.
Confirming the consistency across indications, our investigation revealed that the pharmacokinetic properties of a new mAb were consistent with those of AZD7442. This finding not only underscores the reliability and reproducibility of AZD7442 ‘s pharmacokinetic properties, but also suggests potential class-wide pharmacokinetic behaviour. As a result, we used the AZD7442 population pharmacokinetic model to inform dose selection decisions for Phase 1 trials of a novel drug in a different ID, thereby streamlining early phase development efforts and mitigating the risks associated with suboptimal dosing strategies.
Conclusion:
Our approach enables the prediction of concentrations in both adults and children prior to Phase 1 results. This advance facilitates the selection of first-in-human doses. In addition, our model supports early initiation of paediatric study plans (PSP) and paediatric investigation plans (PIP). With a high probability of predicting population pharmacokinetics, our methodology facilitates the optimisation of clinical trials and reduces the need for extensive pharmacokinetic sampling, thereby increasing efficiency and cost-effectiveness.
Author information: 1 Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; 2 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, USA; 3 Clinical Pharmacology & Quantitative Pharmacology, R&D, AstraZeneca, Gothenburg, Sweden
References:
[1] Loo YM, McTamney PM, Arends RH, Abram ME, Aksyuk AA, Diallo S, Flores DJ, Kelly EJ, Ren K, Roque R, Rosenthal K, Streicher K, Tuffy KM, Bond NJ, Cornwell O, Bouquet J, Cheng LI, Dunyak J, Huang Y, Rosenbaum AI, Pilla Reddy V, Andersen H, Carnahan RH, Crowe JE Jr, Kuehne AI, Herbert AS, Dye JM, Bright H, Kallewaard NL, Pangalos MN, Esser MT. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci Transl Med. 2022 Mar 9;14(635):eabl8124. doi: 10.1126/scitranslmed.abl8124. Epub 2022 Mar 9. PMID: 35076282; PMCID: PMC8939769.
[2]Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J, Moldt B, Khan A, Svabek C, McAuliffe JM, Wrapp D, Patel NK, Cook KE, Richter BWM, Ryan PC, Yuan AQ, Suzich JA. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci Transl Med. 2017 May 3;9(388):eaaj1928. doi: 10.1126/scitranslmed.aaj1928. PMID: 28469033.
[3] version 7.4.4; ICON Development Solutions, Ellicott City, MD, USA
[4] PsN; Department of Pharmacy, Uppsala University, Uppsala, Sweden, version 4.8.1
[5] R Core Team, Vienna, Austria, version 4.0.4
Reference: PAGE 32 (2024) Abstr 11135 [www.page-meeting.org/?abstract=11135]
Poster: Drug/Disease Modelling - Infection