Population pharmacokinetics of azathioprine active metabolite in patients with inflammatory bowel disease and dosage regimens optimisation.
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 × 108 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.
['Lin|Rongfang|R|https://orcid.org/0000-0002-4810-0428', 'Lin|Weiwei|W|', 'Wang|Changlian|C|', 'Dong|Jiashan|J|', 'Zheng|Weiwei|W|', 'Zeng|Dayong|D|', 'Liu|Yiwei|Y|', 'Lin|Cuihong|C|', 'Jiao|Zheng|Z|', 'Huang|Pinfang|P|']
D000293:Adolescent D000328:Adult D001379:Azathioprine D005260:Female D005838:Genotype D006150:Guanine Nucleotides D006801:Humans D015212:Inflammatory Bowel Diseases D008297:Male D008780:Methyltransferases D008875:Middle Aged D008954:Models, Biological D020641:Polymorphism, Single Nucleotide D011755:Pyrophosphatases D013873:Thionucleotides D055815:Young Adult
population pharmacokinetics azathioprine inflammatory bowel disease TPMT individualised dosing