Distribution Half-Life
Distribution half-life, \(T_{dist, compartment}\), is the half-life of distribution between the central circulation into a compartment of interest, such as the peripheral, disease, or tox compartments. Distribution half-life can be defined for any soluble species that transports between compartments, including ligands, soluble receptors, and drugs.
For ADCs, \(T_{dist,PL}\), refers to the half-life of distribution of the unbound payload between the cell to the interstitial space.
Distribution Half-Life in Assess
Distribution half-life of drug between the central and peripheral compartment can be defined by the drug pharmacokinetics. Since antibody-based biotherapeutics often display consistent PK behavior, typical values can be used. When PK data is available, \(T_{dist}\) can be fit to the data. When parameters from a standard 2-compartment PK model parameters are available, \(T_{dist}\) can be defined by the equation:
Where \(k_{12}\) is the transport rate constant governing the transport of the drug from the central compartment into the compartment of interest, and \(k_{21}\) is the transport out of the compartment of interest and into the central compartment.
\(T_{dist}\) of a drug between central and disease or tox compartments depends on the tissue being described. As in the case of \(P_{dist}\), it may be defined from analysis of PBPK models or from measurements of plasma and tissue drug concentrations after systemic administration. It is difficult to find experimental data that is sampled with enough time resolution to define \(T_{dist}\) well.
\(T_{dist}\) of soluble receptors and ligands can depend on the molecular weight of the protein. It is often difficult to find direct data to parameterize, so common assumptions are often used.
In all cases, scanning over a standard range of values can determine the importance of the parameter.
Typical Values
\(T_{dist, peripheral}\) for antibodies in cyno and human are defined based on literature reported PK
| Species | \(T_{dist,peripheral}\) (hr) | Reference |
|---|---|---|
| Cyno | 11 | Betts et al. 2018; Singh et al. 2015; Deng et al. 2011 |
| Human | 35 | Dirks and Meibohm 2010; Betts et al. 2018; Davada et. al.; Singh et al. 2015 |
For highly perfused organs or diseased tissues, the half-life of distribution is generally assumed to be fast, 1-5 hours. For instance, for bone marrow, the spleen, the liver, or well vascularized tumors.
For less perfused organs or those with selective transport mechanisms, the half-life of distribution is assumed to be similar to \(T_{dist, peripheral}\).
The half-life of distribution for other soluble proteins (ligands, soluble receptors) are generally assumed to be fast (~ 1hr) unless specific data is available. Frequently, model results will be insensitive to this parameter.
References
- Betts, Alison, Anne Keunecke, Tamara J. van Steeg, Piet H. van der Graaf, Lindsay B. Avery, Hannah Jones, and Jan Berkhout. 2018. "Linear Pharmacokinetic Parameters for Monoclonal Antibodies Are Similar within a Species and across Different Pharmacological Targets: A Comparison between Human, Cynomolgus Monkey and hFcRn Tg32 Transgenic Mouse Using a Population-Modeling Approach." mAbs 10 (5): 751–64.
- Davda, Jasmine P., Michael G. Dodds, Megan A. Gibbs, Wendy Wisdom, and John Gibbs. 2014. "A Model-Based Meta-Analysis of Monoclonal Antibody Pharmacokinetics to Guide Optimal First-in-Human Study Design." mAbs 6 (4): 1094–1102.
- Deng, Rong, Suhasini Iyer, Frank Peter Theil, Deborah L. Mortensen, Paul J. Fielder, and Saileta Prabhu. 2011. "Projecting Human Pharmacokinetics of Therapeutic Antibodies from Nonclinical Data: What Have We Learned?" mAbs 3 (1): 61–66.
- Dirks, Nathanael L., and Bernd Meibohm. 2010. "Population Pharmacokinetics of Therapeutic Monoclonal Antibodies." Clinical Pharmacokinetics 49 (10): 633–59.
- Singh, Aman P., Wojciech Krzyzanski, Steven W. Martin, Gregory Weber, Alison Betts, Alaa Ahmad, Anson Abraham, Anup Zutshi, John Lin, and Pratap Singh. 2015. "Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition." The AAPS Journal 17 (2): 389–99..