Physiologically-Based Pharmacokinetic Modeling of Anti-Tumor Necrosis Factor Agents for Inflammatory Bowel Disease Patients to Predict the Withdrawal Time in Pregnancy and Vaccine Time in Infants.

Anti-tumor necrosis factor (anti-TNF) agents are widely applied for patients with inflammatory bowel disease (IBD); however, the timing of the last dosing for IBD pregnancy and time to elimination in anti-TNF agent-exposed infants is controversial. This study aimed to determine the optimal timing for the last dosing of anti-TNF agents (infliximab, adalimumab, and golimumab) in pregnant women with IBD, as well as to investigate the recommended vaccine schedules for infants exposed to these drugs. A physiologically-based pharmacokinetic (PBPK) model of anti-TNF agents was built for adults and extrapolated to pregnant patients, fetuses, and infants. The PBPK models successfully predicted and verified the pharmacokinetics (PKs) of infliximab, adalimumab, and golimumab in pregnancy, fetuses, and infants. The predicted PK data were within two-fold of the observed data. The simulated results were used as timing advice. According to the dose of administration, the suggested timing of the last dosing for infliximab, adalimumab, and golimumab is successfully provided based on PBPK predictions. PBPK models indicated that, for infants, the advocated timing of vaccination is 12, 8, and 5 months after birth for infliximab, adalimumab, and golimumab, respectively. Our study illustrated that PBPK models can provide a valuable tool to predict the PKs of large macromolecules in pregnant women, fetuses, and infants, ultimately informing drug-treatment decisions for pregnancy and vaccination regimens for infants.

Importance of NUDT15 c.415C>T phenotype in treatment of inflammatory bowel disease with azathioprine and occurrence of severe myelosuppression: A case report.

Azathioprine is one of the main drugs in the treatment of inflammatory bowel disease (IBD). It has been widely used in the remission and maintenance treatment of IBD. Some patients may experience some degree of myelosuppression, but very few patients experience severe myelosuppression. Here, we report a 20-year-old male Asian patient with severe myelosuppression due to azathioprine treatment of IBD. In this case, the azathioprine-related genotyping test showed that homozygous wild-type TPMT*3 but a c.415C>T homozygous mutation was found in NUDT15. Our report strengthens the association between genetic polymorphisms of azathioprine-metabolizing enzymes and severe myelosuppression. Therefore, we recommend routine NUDT15 c.415C>T phenotype testing prior to long-term azathioprine treatment to avoid severe myelosuppression.