Abstract
Obtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition models. We estimated the pharmacokinetics from FIH studies for five mAbs using a two-compartment model, both separately and together, using a simple pool, a third hierarchical level of random effects for between mAb differences and non-human-primate half-lives as a predictor covariate for said differences. There was good agreement between compounds for the rapidly accessible central volume of 2.9 L (70 kg human), but clearances and peripheral volumes differed with terminal half-lives ranging from 15 to 28 days. The simple pool of human studies gave inter-individual variability estimates of 32% coefficient of variation (CV) for clearance and 33% CV for peripheral volume, larger than for separate fits (13–26% CV and 15–35% CV for clearance and volume respectively). Using third level hierarchical random effects gave inter-individual variability estimates close to those of separate fits (24% and 16% CV respectively). The between-mAb differences became predictable if non-human primate body weight scaled terminal half-life estimates were included as covariates on clearance and peripheral volume. In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70 kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs.
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References
Lu R, Hwang Y, Liu I. Lee CC, Tsai HZ, Li HJ, Wu HC (2020) Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27:1. https://doi.org/10.1186/s12929-019-0592-z
Oitate M, Masubuchi N, Ito T, Yabe Y, Karibe T, Aoki T, Murayama N, Kurihara A, Okudaira N, Izumi T (2011) Prediction of human pharmacokinetics of therapeutic monoclonal antibodies from simple allometry of monkey data. Drug Metab Pharmacokinet 26(4):423–430. https://doi.org/10.2133/dmpk.dmpk-11-rg-011
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S (2011) Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs 3(1):61–66. https://doi.org/10.4161/mabs.3.1.13799
Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu C-P, Stouch BJ, Hurh E, Gibbs MA (2011) Quantitative prediction of human pharmacokinetics for monoclonal antibodies. Retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet 50:131–142
Nakamura G, Ozeki K, Nagayasu M, Nambu T, Nemoto T, Hosoya KI (2020) Predicting method for the human plasma concentration-time profile of a monoclonal antibody from the half-life of non-human primates. Biol Pharm Bull 43(5):823–830. https://doi.org/10.1248/bpb.b19-01042
Sheiner LB, Rosenberg B, Marathe VV (1977) Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm 5(5):445–479. https://doi.org/10.1007/BF01061728
Duffull SB, Wright DF, Winter HR (2011) Interpreting population pharmacokinetic-pharmacodynamic analyses—a clinical viewpoint. Br J Clin Pharmacol 71(6):807–814. https://doi.org/10.1111/j.1365-2125.2010.03891.x
EFPIA MID3 Workgroup, Marshall SF, Burghaus R et al (2016) Good practices in model-informed drug discovery and development: practice, application, and documentation. CPT Pharmacometrics Syst Pharmacol 5(3):93–122. https://doi.org/10.1002/psp4.12049
Food, Administration D, USA. Population pharmacokinetics guidance for industry. (2019) https://www.fda.gov/media/128793/download. Accessed 25 Aug 2020
Davda JP, Dodds MG, Gibbs MA, Wisdom W, Gibbs JP (2014) A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design. mAbs 6:1094–1102
Fink M, Lowe PJ, Shivva V (2016) Improving priors for human mAb linear PK parameters by using half-lives from pre-clinical studies. Population Approach Group Europe, Lisboa 9-June-2016. https://www.page-meeting.org/pdf_assets/6536-Fink%20-%20mAb%20priors%20-%20Short.pdf. Accessed 22 Aug 2020
Shivva V, Lowe PJ, Fink M (2016) Improving priors for human mAb linear PK parameters by using half-lives from pre-clinical species. https://www.go-acop.org/assets/Legacy_ACOPs/ACoP7/Abstracts/t-75.pdf. Accessed 22 Aug 2020
Zhao J, Cao Y, Jusko WJ (2015) Across-species scaling of monoclonal antibody pharmacokinetics using a minimal PBPK model. Pharm Res 32:3269–3281
Li L, Gardner I, Dostalek M, Jamei M (2014) Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model. AAPS J 16:1097–1109
Elmeliegy M, Lowe P, Krzyzanski W (2014) Simplification of Complex Physiologically Based Pharmacokinetic Models of Monoclonal Antibodies. AAPS J 16:810–842
Peletier LA, Gabrielsson J (2012) Dynamics of target-mediated drug disposition: characteristic profiles and parameter identification. J Pharmacokinet Pharmacodyn 39:429–451
West GB, Brown JH, Enquist BJ (1997) A general model for the origin of allometric scaling laws in biology. Science 276:122–126
Savic RM, Karlsson MO (2009) Importance of shrinkage in empirical Bayes estimates for diagnostics: problems and solutions. AAPS J 11:558–569
Comets E, Brendel K, Mentre F (2010) Model evaluation in nonlinear mixed effect models, with applications to pharmacokinetics. J Soc Française Stat 151:106–128
Levitt DG (2003) The pharmacokinetics of the interstitial space in humans. BMC Clin Pharmacol 3:3
Sarin H (2010) Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J Angiogenesis Res 2:14
Fronton L, Pilari S, Huisinga W (2014) Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models. J Pharmacokinet Pharmacodyn 41:87–107
Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C, Nanami M, Sekimori Y, Nabuchi Y, Aso Y, Hattori K (2010) Reduced elimination of IgG antibodies by engineering the variable region. Prot Eng Des Select 23:385–392
Datta-Mannan A, Thangaraju A, Leung D, Tang Y, Witcher DR, Lu J, Wroblewski VJ (2015) Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics. mAbs 7:1084–1093
Robbie GJ, Criste R, Dall’Acqua WF, Jensen K, Patel NK, Losonsky GA, Griffin MP (2013) Fc modified motavizumab-YTE extended half-life human. Antimicrob Agents Chemother 57:6147–6153
Souders CA, Nelson SC, Wang Y, Crowley AR, Klempner MS, Thomas W (2015) A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life. mAbs 7:912–921
Acknowledgements
Vittal Shivva was supported with doctoral internship sponsored by Novartis Pharma AG, Basel, Switzerland. The authors gratefully acknowledge the support of Aurélie Gautier and the Pharmacometrics programming team for the preparation of datasets for the analysis.
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At the time the analyses were carried out VS, MF and PJL were employees of Novartis Pharma AG.
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Shivva, V., Fink, M. & Lowe, P.J. Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates. J Pharmacokinet Pharmacodyn 48, 295–303 (2021). https://doi.org/10.1007/s10928-020-09731-y
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DOI: https://doi.org/10.1007/s10928-020-09731-y