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Volume 08
Clinical Pharmacology & Biopharmaceutics
ISSN: 2167-065X
Pharmacology 2019
World Heart Congress 2019
August 19-20, 2019
JOINT EVENT
conferenceseries
.com
August 19-20, 2019 Vienna, Austria
&
7
th
World Heart Congress
24
th
World Congress on
Pharmacology
Pharmacokinetic and Pharmacodynamic considerations for drugs binding to alpha-1-acid glycoprotein
Sherri A Smith
Relay Therapeutics, USA
A
ccording to the free drug hypothesis only the unbound drug is available to act at physiological sites of action.
Albumin, the most abundant plasma protein (~50mg/mL), and alpha-1-acid glycoprotein (AAG, ~1mg/mL) are
both involved with drug binding and distribution. While albumin levels are similar across species, marked species,
age, and disease state differences in AAG expression, homology and drug binding affinity have been reported. Drug
binding to plasma proteins can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/
PD), safety margin predictions, and relationships from preclinical species to human as well as adults to neonates
(Smith and Waters, 2019). The impact of AAG binding on PK has been reported for multiple drug/candidate
molecules including pinometostat (Smith et al., 2016), vismodegib (Gianetti et al., 2011), imatinib (Widmer et al.,
2006), and UCN-01(Fuse et al., 1998). Obtaining accurate fraction unbound (fu) values, especially for highly bound
drugs, is critical to PK and safety predictions (Di et al., 2017). The role of plasticizers used in blood collection bags
has recently been reported to contribute to inaccurate overestimation of fu for drugs that preferentially bind to AAG
(Butler et al., 2015, Ingram et al., 2019). Experimental considerations as well as recommendations for understanding
the potential impact of AAG on PK through drug discovery and early development will be reviewed.
Recent Publications:
1.
Smith S and Waters N (2019) Pharmacokinetic and pharmacodynamic considerations for drugs binding to
alpha-1-acid glycoprotein. Pharm Res 36(2):30,
doi.org/10.1007/s11095-018-2551-x.2.
Smith S, Gagnon S, Waters N. (2016) Mechanistic investigations into the species differences in pinometostat
clearance: impact of binding to alpha-1-acid glycoprotein and permeability-limited hepatic uptake.
Xenobiotica, 47(3)185-93, doi: 10.3109/00498254.2016.1173265.
3.
Gianetti A, Wong H, Dijkgraaf G, Dueber E, Ortwine D, Bravo B et al. (2011) Identification, characterization,
and implications of species-dependent plasma protein binding of the oral hedgehog pathway inhibitor
vismodegib (GDC-0449). J Med Chem, 54(8):2592-601, doi: 10.1021/jm1008924.
4.
Widmer N, Descosterd L, Csajka C, Leyvraz S, Duchosal M, Rosselet A, et al. (2006) Population
pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol, 62(1):97-112, doi:
10.1111/j.1365-2125.2006.02719.x.
5.
Fuse F, Tanni H, KurataN, Kobayashi H, Shimada Y, Tamura T, et al. (1998) Unpredicted clinical pharmacology
of UCN-01 caused by specific binding to human alpha 1-acid glycoprotein. Cancer Res, 58(15):3248-53.
6.
Di L, Breen C, Chambers R, Eckley S, Frick R, Ghosh A. et al. (2017) Industry perspective on contemporary
protein-binding methodologies: considerations for regulatory drug-drug interaction and related guidelines
on highly bound drugs. J Pharm Sci, 106(12):3442-52, doi: 10.1016/j.xphs.2017.09.005.
7.
Butler P, Frost K, Barnes K, Smith S, Rioux N, Waters N (2015) Impact of blood collection method on human
plasma protein binding for compounds binding preferentially to α-1-acid glycoprotein. Drug Metab Rev, doi:
10.1080/03602532.2016.1191843.
8.
Ingram N, Dishinger C, Wood J, Hutzler JM, Smith S, Huskin N (2019) Effect of the Plasticizer DEHP in
Blood Collection Bags on Human Plasma Fraction Unbound Determination for Alpha-1-Acid Glycoprotein
(AAG) Binding Drugs. AAPS J 16;21(1):5, doi: 10.1208/s12248-018-0276-8.
Sherri A Smith, Clin Pharmacol Biopharm, Volume 08