Impact of Concomitant Medication Burden on Tolerability of Disease-targeted Therapy and Survival in Interstitial Lung Disease

Rationale: Multimorbidity is common and leads to substantial concomitant medication burden in patients with interstitial lung disease (ILD), which may affect tolerability of ILD-targeted medications and health outcomes. Objectives: To determine the associations of concomitant medication burden with tolerability of ILD-targeted medications and survival in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. Methods: Patients with IPF receiving nintedanib or pirfenidone and patients with non-IPF ILD receiving azathioprine or mycophenolate were identified from two Australian and Canadian registries. Baseline concomitant medication burden was evaluated using three measures: medication count, polypharmacy (<= 5 medications), and the medication regimen complexity index (MRCI). Medication intolerance and discontinuation were evaluated at 6 months and 1 year after initiation of ILD-targeted medications, respectively. Cox regression models and likelihood ratio tests were used to determine the prognostic significance of medication burden on transplant-free survival. Results: In 645 treated patients with IPF, 43% experienced adverse reactions leading to intolerance (defined as dose reduction, temporary dose interruption, or permanent drug discontinuation) of antifibrotic medications within 6 months of initiation, with high baseline concomitant medication burden being consistently associated with intolerance (medication count: P = 0.005; polypharmacy: P = 0.006; MRCI: P = 0.004). This association was not observed for immunosuppressive medications in 1,255 treated patients with non-IPF ILD, who also had a lower intolerance (18%). Baseline concomitant medication burden was not independently associated with permanent discontinuation of antifibrotic (29%) and immunosuppressive medications (20%) at 1 year. The MRCI was the only measure of concomitant medication burden associated with transplant-free survival in both cohorts (P < 0.01 for both), which improved prognostication beyond common clinical factors and the ILDGAP index (P < 0.001 for both). Conclusions: Concomitant medication burden is associated with intolerance of antifibrotic medications in patients with IPF. Medication regimen complexity is superior to simpler evaluation of concomitant medication burden for predicting prognosis in ILD.