Azathioprine Safety and Pharmacokinetics in Pregnant Women with Rheumatic Disease and their Infants

About This Grant

ABSTRACT Pregnant women with systemic lupus and other rheumatic diseases often receive treatment with azathioprine (AZA) to control maternal inflammatory disease and optimize maternal and child outcomes. Although AZA has been the standard of care in pregnancy for over a decade, systematic evaluations of its dosing and safety for mothers and infants has not been completed. Recent data suggest pregnant patients taking AZA can develop drug-induced hepatotoxicity including intrahepatic cholestasis of pregnancy (ICP). The hallmark of ICP is elevated bile acids, which cross the placenta and can result in stillbirth, preterm birth, and other infant harms. As a result, the FDA published a safety alert warning clinicians about the occurrence of ICP in pregnant patients receiving AZA and other thiopurines. In our clinic, we observed several pregnant women on AZA who developed high AZA metabolite (6-MMPN) levels with concurrent elevated bile acids that subsequently resolved on dose reduction or discontinuation; suggestive of altered AZA metabolism and pharmacokinetics in pregnancy. Based on this observation, coupled with our expertise in studying pharmacokinetics (PK) in pregnancy and our track record of conducting prospective studies of pregnant women with rheumatic disease, we developed this proposal to characterize the safety and optimal dosing of AZA in pregnancy. In AIM 1, we will enroll 75 pregnant women prescribed AZA for systemic lupus, other autoimmune diseases, or stable organ transplants into a prospective, observational, PK study to determine the impact of pregnancy physiology on AZA metabolite levels and the need for dose adjustments. Next, we will longitudinally measure bile acids in these 75 pregnant patients along with an additional 125 pregnant women with autoimmune diseases or organ transplant not receiving AZA as a comparator cohort to relate AZA exposure with the development of ICP (AIM 2). Lastly, in AIM 3, we will evaluate infant safety over 1 year by measuring AZA metabolite levels, fetal blood counts and chemistries including bile acids, and neurocognitive outcomes. Upon completion of this study, we will tangibly change clinical practice by 1) establishing the relationship between AZA exposure with ICP and long-term outcomes; 2) determining a safe dose of AZA during pregnancy; and 3) evaluating the utility of measuring bile acids and AZA metabolite levels to identify at-risk pregnancies in whom early intervention may improve maternal and child outcomes.