PMID- 38399334
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240227
IS  - 1999-4923 (Print)
IS  - 1999-4923 (Electronic)
IS  - 1999-4923 (Linking)
VI  - 16
IP  - 2
DP  - 2024 Feb 16
TI  - Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict CYP3A-Mediated 
      Drug Interaction between Saxagliptin and Nicardipine: Bridging Rat-to-Human 
      Extrapolation.
LID - 10.3390/pharmaceutics16020280 [doi]
LID - 280
AB  - The aim of this study was to predict the cytochrome P450 3A (CYP3A)-mediated 
      drug-drug interactions (DDIs) between saxagliptin and nicardipine using a 
      physiologically based pharmacokinetic (PBPK) model. Initially, in silico and in 
      vitro parameters were gathered from experiments or the literature to construct 
      PBPK models for each drug in rats. These models were integrated to predict the 
      DDIs between saxagliptin, metabolized via CYP3A2, and nicardipine, exhibiting 
      CYP3A inhibitory activity. The rat DDI PBPK model was completed by optimizing 
      parameters using experimental rat plasma concentrations after co-administration 
      of both drugs. Following co-administration in Sprague-Dawley rats, saxagliptin 
      plasma concentration significantly increased, resulting in a 2.60-fold rise in 
      AUC, accurately predicted by the rat PBPK model. Subsequently, the workflow of 
      the rat PBPK model was applied to humans, creating a model capable of predicting 
      DDIs between the two drugs in humans. Simulation from the human PBPK model 
      indicated that nicardipine co-administration in humans resulted in a nearly 
      unchanged AUC of saxagliptin, with an approximate 1.05-fold change, indicating no 
      clinically significant changes and revealing a lack of direct translation of 
      animal interaction results to humans. The animal-to-human PBPK model 
      extrapolation used in this study could enhance the reliability of predicting drug 
      interactions in clinical settings where DDI studies are challenging.
FAU - Lee, Jeong-Min
AU  - Lee JM
AD  - Department of Digital Anti-Aging Healthcare, Inje University, Gimhae 50834, 
      Republic of Korea.
FAU - Yoon, Jin-Ha
AU  - Yoon JH
AD  - College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
FAU - Maeng, Han-Joo
AU  - Maeng HJ
AD  - College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
FAU - Kim, Yu Chul
AU  - Kim YC
AUID- ORCID: 0000-0001-7280-9317
AD  - Department of Digital Anti-Aging Healthcare, Inje University, Gimhae 50834, 
      Republic of Korea.
AD  - Department of Pharmaceutical Engineering, Inje University, Gimhae 50834, Republic 
      of Korea.
LA  - eng
GR  - 2022R1F1A1069323/National Research Foundation of Korea/
PT  - Journal Article
DEP - 20240216
PL  - Switzerland
TA  - Pharmaceutics
JT  - Pharmaceutics
JID - 101534003
PMC - PMC10892660
OTO - NOTNLM
OT  - CYP3A4
OT  - PBPK modeling
OT  - drug-drug interaction
OT  - nicardipine
OT  - saxagliptin
COIS- The authors declare no conflicts of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2024/02/24 11:45
MHDA- 2024/02/24 11:46
PMCR- 2024/02/16
CRDT- 2024/02/24 01:18
PHST- 2024/01/03 00:00 [received]
PHST- 2024/02/09 00:00 [revised]
PHST- 2024/02/14 00:00 [accepted]
PHST- 2024/02/24 11:46 [medline]
PHST- 2024/02/24 11:45 [pubmed]
PHST- 2024/02/24 01:18 [entrez]
PHST- 2024/02/16 00:00 [pmc-release]
AID - pharmaceutics16020280 [pii]
AID - pharmaceutics-16-00280 [pii]
AID - 10.3390/pharmaceutics16020280 [doi]
PST - epublish
SO  - Pharmaceutics. 2024 Feb 16;16(2):280. doi: 10.3390/pharmaceutics16020280.