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Volume10, Issue 12 (Suppl) J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Page 69
conferenceseries.com
World Biomarkers & Pharma Biotech 2017
December 07-09, 2017
December 07-09, 2017 | Madrid, Spain
&
20th International Conference on
PHARMACEUTICAL BIOTECHNOLOGY
9th WORLD BIOMARKERS CONGRESS
JOINT EVENT ON
A Physiologically-based pharmacokinetic model adequately predicted the human pharmacokinetic
profiles of YH4808, a novel potassium-competitive acid blocker, to treat gastric acid related diseases
Hyun A Lee, Yuchae Jung, Yoomin Jeon, Siun Kim and Howard Lee
Seoul National University College of Medicine and Hospital, Korea
YH4808 is a highly potent, selective and reversible potassium-competitive acid blocker on H+/K+-ATPase under
development for the treatment of gastric acid related diseases. The objectives of this study were to develop a human PBPK
model optimized by human pharmacokinetic (PK) data, to predict the PK profiles of YH4808 using the PBPK model in various
settings and to mechanistically understand the main factor of clinically observed nonlinear PK of YH4808 by exploring various
drug-drug interactions (DDIs). A PBPK model was developed using SimCYP® based on the physicochemical properties,
preclinical in vitro and clinical data of YH4808 (Figure 1), which was further refined using human plasma concentrations
obtained froma single-dose ascending phase I clinical trial of YH4808.The absorption of YH4808was described by the advanced
dissolution, absorption and metabolismmodel. The Vmax and Km values for each CYP isozyme involved in the metabolism of
YH4808 were determined from the in vitro Ki values using a graphical method (GraphPad Prism7, GraphPad Software, Inc.,
USA). The DDI potential for YH4808 with other co-administered drugs was predicted using the PBPK model by calculating
the geometric mean ratio of the model-predicted and observed for the area under the concentration-time curve (AUC). The
PBPK model adequately predicted the observed concentrations of YH4808 after a single and repeated oral administration at
100 mg (Figure 1 (b), Figure 2 (a)). However, the simulated plasma concentration profiles after repeated oral administration at
200 and 400 mg were not in line with the observed concentrations, particularly toward the terminal phase, showing some sort
of non-linear accumulation (Figure 2 (b) & (c)). The PBPK model-based simulated AUC of YH4808 increased by 2.08-2.90
times when co-administered with phenacetin, mephenytoin and dextromethorphan, respectively, suggesting the metabolism
of YH4808 may involve CYP1A2, 2C19 and 2D6, which was confirmed by in vitro DDI studies. These metabolic pathways
can be saturated at a higher dose of YH4808 at >200 mg, resulting in a non-linear PK profile. A PBPK model adequately
predicted observed concentrations of YH4808 in humans after a single and repeated oral administration. The saturation of
liver metabolism by CYP1A2, 2C19 and 2D6 appears to be associated with the nonlinear PK characteristics of YH4808 after
multiple oral administration. The PBPK model can be used to predict the PK profiles of YH4808 in various clinical settings.
Recent Publications:
1. Lee H A, Lee S, Yim S V, Kim B H (2017) Bioequivalence of two formulations of pregabalin 150 mg capsules under
fasting conditions in healthy male subjects. International Journal of Clinical Pharmacology and Therapeutics. 55 (2):
171-176.
2. Lee HA, Leavens T L, Mason S E, Monteiro-Riviere NA, Riviere J E (2009) Comparison of quantumdot biodistribution
with a blood-flow-limited physiologically based pharmacokinetic model. Nano Letters. 9 (2): 794-9.
3. Lee H A, Imran M, Monteiro-Riviere N A, Colvin V L, Yu W W, Riviere J E (2007) Biodistribution of quantum dot
nanoparticles in perfused skin: evidence of coating dependency and periodicity in arterial extraction. Nano Letters.
7 (9): 2865-70.
Biography
Hyun A Lee is a PhD student at the Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University
in South Korea. She is also a trainee in clinical pharmacology at the Department of Clinical Pharmacology and Therapeutics, Seoul National University College
of Medicine and Hospital. She has graduated from North Carolina State University (NCSU) in the USA with a Master’s degree in Biomathematics (2010). Prior to
that, she went to the University of Alabama (2001-2004), where she received a Bachelor’s degree in Biology and Mathematics. After completing her undergraduate
course, she worked as a Research Scientist at the Center for Chemical Toxicology Research and Pharmacokinetics (CCTRP) in NCSU. Her research area is
physiologically based pharmacokinetic (PBPK) modeling and simulation to optimize new drug development. She has a lot of experience in PBPK modeling and
simulation with new drugs.
Hyun A Lee et al., J Proteomics Bioinform 2017, 10:12(Suppl)
DOI: 10.4172/0974-276X-C1-110