Sherri A Smith,
Relay Therapeutics, USA
Title: Pharmacokinetic and pharmacodynamic considerations for drugs binding to alpha-1-acid glycoprotein
Biography
Biography: Sherri A Smith,
Abstract
Abstract
According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action. Albumin, the most abundant plasma protein (~50 mg/mL), and alpha-1-acid glycoprotein (AAG, ~1 mg/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.