PMID- 33150655
OWN - NLM
STAT- MEDLINE
DCOM- 20211004
LR  - 20211004
IS  - 1742-7843 (Electronic)
IS  - 1742-7835 (Linking)
VI  - 128
IP  - 3
DP  - 2021 Mar
TI  - Population pharmacokinetics of azathioprine active metabolite in patients with 
      inflammatory bowel disease and dosage regimens optimisation.
PG  - 482-492
LID - 10.1111/bcpt.13530 [doi]
AB  - Azathioprine is a first-line drug used to maintain the remission of inflammatory 
      bowel disease (IBD). As a prodrug, azathioprine is metabolised to produce active 
      6-thioguanine nucleotides (6-TGN). There are large individual variations in the 
      pharmacokinetics/pharmacodynamics of 6-TGN in patients with IBD. Here, we aimed 
      to develop a model to quantitatively investigate factors that affect 6-TGN 
      pharmacokinetics to formulate a dosage guideline for azathioprine. Data were 
      collected prospectively from 100 adult patients with IBD who were receiving 
      azathioprine. Patients were genotyped for two single-nucleotide polymorphisms 
      (TPMT*3C c.719A > G and NUDT15 c.415C > T). Using high-performance liquid 
      chromatography, we measured 156 steady-state trough concentrations of 6-TGN 
      within the range 0.09 to 1.16 mg/L (ie 133-1733 pmol per 8 x 10(8) RBC). The 
      covariates analysed included sex, age, body-weight, laboratory tests and 
      concomitant medications. A population pharmacokinetic model was established using 
      "non-linear mixed-effects modelling" software and the "first-order conditional 
      estimation method with interaction." Body-weight, TPMT*3C polymorphisms and 
      co-therapy with mesalazine were found to be important factors influencing the 
      clearance of 6-TGN. A dosage guideline for azathioprine was developed based on 
      the PPK model that enables individualised azathioprine dosing in adult patients 
      with different body-weights, TPMT*3C genotypes and co-administration with 
      mesalazine.
CI  - (c) 2020 Nordic Association for the Publication of BCPT (former Nordic 
      Pharmacological Society).
FAU - Lin, Rongfang
AU  - Lin R
AUID- ORCID: 0000-0002-4810-0428
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Lin, Weiwei
AU  - Lin W
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Wang, Changlian
AU  - Wang C
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Dong, Jiashan
AU  - Dong J
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Zheng, Weiwei
AU  - Zheng W
AD  - Department of Gastroenterology, The First Affiliated Hospital, Fujian Medical 
      University, Fuzhou, China.
FAU - Zeng, Dayong
AU  - Zeng D
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Liu, Yiwei
AU  - Liu Y
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Lin, Cuihong
AU  - Lin C
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
FAU - Jiao, Zheng
AU  - Jiao Z
AD  - Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, 
      Shanghai, China.
FAU - Huang, Pinfang
AU  - Huang P
AD  - Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, 
      Fuzhou, China.
LA  - eng
GR  - 2017-ZQN-40/Young and Middle-aged Backbone Personnel Training Project of Fujian 
      Province Health and Family Planning Commission, China/
GR  - 2017-CX-31/Fujian medical innovation project/
GR  - 2018-ZQN-53/Scientific Research Talents Training Project of Fujian Province 
      Health and Family Planning, China/
PT  - Journal Article
DEP - 20201121
PL  - England
TA  - Basic Clin Pharmacol Toxicol
JT  - Basic & clinical pharmacology & toxicology
JID - 101208422
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (TPMT protein, human)
RN  - EC 2.6.1.- (NUDT15 protein, human)
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Azathioprine/*administration & dosage/metabolism
MH  - Female
MH  - Genotype
MH  - Guanine Nucleotides/*pharmacokinetics
MH  - Humans
MH  - Inflammatory Bowel Diseases/*drug therapy
MH  - Male
MH  - Methyltransferases/genetics
MH  - Middle Aged
MH  - Models, Biological
MH  - Polymorphism, Single Nucleotide
MH  - Pyrophosphatases/genetics
MH  - Thionucleotides/*pharmacokinetics
MH  - Young Adult
OTO - NOTNLM
OT  - TPMT
OT  - azathioprine
OT  - individualised dosing
OT  - inflammatory bowel disease
OT  - population pharmacokinetics
EDAT- 2020/11/06 06:00
MHDA- 2021/10/05 06:00
CRDT- 2020/11/05 06:12
PHST- 2020/07/23 00:00 [received]
PHST- 2020/10/12 00:00 [revised]
PHST- 2020/11/02 00:00 [accepted]
PHST- 2020/11/06 06:00 [pubmed]
PHST- 2021/10/05 06:00 [medline]
PHST- 2020/11/05 06:12 [entrez]
AID - 10.1111/bcpt.13530 [doi]
PST - ppublish
SO  - Basic Clin Pharmacol Toxicol. 2021 Mar;128(3):482-492. doi: 10.1111/bcpt.13530. 
      Epub 2020 Nov 21.