Abstract
The volume of distribution at steady state (Vss) of therapeutic proteins is usually assessed by non-compartmental or compartmental pharmacokinetic (PK) analysis wherein errors may arise due to the elimination of therapeutic proteins from peripheral tissues that are not in rapid equilibrium with the sampling compartment (usually blood). Here we explored another potential source of error in the estimation of Vss that is linked to the heterogeneity of therapeutic proteins which may consist of components (e.g. glycosylation variants) with different elimination rates. PK simulations were performed with such hypothetical binary protein mixtures where elimination was assumed to be exclusively from the central compartment. The simulations demonstrated that binary mixtures containing a rapid-elimination component can give rise to pronounced bi-phasic concentration–time profiles. Apparent Vss observed with both non-compartmental and 2-compartmental PK analysis, increased with increasing fraction as well as with increasing elimination rate k 10 of the rapid-elimination component. Simulation results were complemented by PK analysis of an in vivo study in cynomolgus monkeys with different lots of lenercept, a tumor necrosis factor receptor-immunoglobulin G1 fusion protein, with different heterogeneities. The comparative Vss data for the three lenercept lots with different amounts of rapidly cleared components were consistent with the outcome of our simulations. Both lots with a higher fraction of rapidly cleared components had a statistically significant higher Vss as compared to the reference lot. Overall our study demonstrates that Vss of a therapeutic protein may be overestimated in proteins with differently eliminated components.
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References
Straughn AB (2006) Limitations of noncompartmental pharmacokinetic analysis of biotech drugs. In: Meibohm B (ed) Pharmacokinetics and pharmacodynamics of biotech drugs: principles and case studies in drug development. Wiley-VCH, Weinheim
Mordenti J, Rescigno A (1992) Estimation of permeance time, exit time, dilution factor, and steady-state volume of distribution. Pharm Res 9:17–25
Tang L, Persky AM, Hochhaus G, Meibohm B (2004) Pharmacokinetic aspects of biotechnology products. J Pharm Sci 93:2184–2204
Lobo ED, Hansen RJ, Balthasar JP (2004) Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 93:2645–2668
Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Nature 84:548–558
Yates JWT, Arundel PA (2008) On the volume of distribution at steady state and its relationship with two-compartmental models. J Pharm Sci 97:111–122
Richter W, Loetscher H, Schreitmueller T (2005) Pharmacokinetic simulations on a potential error in the volume of distribution estimation of therapeutic proteins composed of differently cleared components. AAPS J 7(S1):T2048
Jones AJS, Papac DI, Chin EH, Keck R, Baughman SA, Lin YS, Kneer J, Battersby JE (2007) Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkey. Glycobiology 17:529–540
Keck R, Nayak N, Lerner L, Raju S, Ma S, Schreitmueller T, Chaow S, Moorhouse K, Kotts C, Jones A (2008) Characterization of a complex glycoprotein whose variable metabolic clearance in humans is dependent on terminal N-acetylglucosamine content. Biologicals 36:49–60
Richter WF, Gallati H, Schiller C-D (1999) Animal pharmacokinetics of the tumor necrosis factor receptor-immunoglobulin fusion lenercept and their extrapolation to humans. Drug Metab Disp 27:21–25
Gabrielsson J, Weiner D (2006) Pharmacokinetic & pharmacodynamic data analysis: concepts and applications, 4th edn. Swedish Pharmaceutical Press, Stockholm, pp 65–69
McFarlane AS (1956) Labelling of plasma proteins with radioactive iodine. Biochem J 62:135–143
Cohen S, Holloway RC, Matthews C, McFarlane AS (1956) Distribution and elimination of 1311I- and 14C-labelled plasma proteins in the rabbit. Biochem J 62:143–154
Ariens EJ (1984) Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol 26:663–668
Ariens EJ (1988) Stereoselectivity, a natural aspect of molecular biology: a blind spot in clinical pharmacology and pharmacokinetics. Eur J Drug Metab Pharmacokinet 13:307–308
Drayer DE (1986) Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clin Pharmacol Ther 40:125–133
Huang L, Biolsi S, Bales KR, Kuchibhotla U (2006) Impact of variable domain glycosylation on antibody clearance. An LC/MS characterization. Anal Biochem 349:197–207
Millward TA, Heitzmann M, Bill K, Längle U, Schumacher P, Forrer K (2008) Effect of constant and variable domain glycosylation on the pharmacokinetics of therapeutic antibodies in mice. Biologicals 36:41–47
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Richter, W.F., Grimm, H.P. & Theil, FP. Potential errors in the volume of distribution estimation of therapeutic proteins composed of differently cleared components. J Pharmacokinet Pharmacodyn 38, 581–593 (2011). https://doi.org/10.1007/s10928-011-9209-1
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DOI: https://doi.org/10.1007/s10928-011-9209-1