Physiologically-based Pharmacokinetic Modeling of Natalizumab for Multiple Sclerosis Patients to Predict the Withdrawal Time in Pregnancy and Vaccine Time in Infants.

Natalizumab (NAT) is a monoclonal antibody that targets integrin α4 (anti-ITGA-4), approved by the FDA for treating multiple sclerosis (MS). However, the optimal timing of the final dose during pregnancy and the postponement of vaccinations for infants remains open to discussion. This study aimed to analyze variations in plasma concentrations of NAT in pregnant women and infants using a physiologically based pharmacokinetic (PBPK) model. Additionally, it provided informed guidelines on drug cessation timing and vaccination schedules. A PBPK model was developed and validated by comparison with drug concentrations in clinical data. The results showed that most observed values were within 0.5 to 2 times the predicted values, indicating that the model successfully predicted the concentration-time profiles of NAT in pregnant women, fetuses, and infants. The findings revealed that plasma NAT concentration in pregnant women was lower than that in the general population, and the drug clearance time in infants was influenced by age and physiological changes. The simulation suggested extending the dosing interval for pregnant women to eight weeks, and withdrawing the drug within 5.5 weeks before delivery. Furthermore, the model predicted that live vaccine administration should be delayed for infants up to eight months after birth. This study provides a theoretical basis for the safe use of NAT during pregnancy and helps to establish more rational clinical dosing regimens. By utilizing precise pharmacokinetic modeling, clinicians can better evaluate the risks and benefits of NAT treatment in pregnant women and infants, ultimately enhancing the safety and efficacy of the therapy.