Minimal to no transfer of certolizumab pegol into breast milk: Results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study

Background Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. Methods CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. Results 19 CZP-Treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0-0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-Age infants. Conclusion When quantifiable, CZP concentrations were <3× LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc-Â-free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. Trial registration number NCT02154425; Results

Factors associated with preterm delivery among women with rheumatoid arthritis and juvenile idiopathic arthritis.

OBJECTIVE Pregnant women with inflammatory arthritis may be at increased risk for preterm delivery (PTD), yet it is unclear what drives this risk. This prospective cohort study of pregnant women with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), or healthier comparison women analyzed the independent effects of maternal disease activity, medication use, and comorbid pregnancy conditions on PTD risk. METHODS Women were enrolled before 19 weeks' completed gestation as part of the Organization of Teratology Information Specialists (OTIS) Autoimmune Disease in Pregnancy Project. Data on pregnancy events, medications, disease activity, and outcomes were obtained by maternal report and validated by medical records. Poisson regression with robust standard errors estimated risk ratios (RR), multivariable adjusted risk ratios (aRR) and 95% Confidence Intervals (CI). RESULTS A total of 657 women with RA, 170 with JIA, and 564 comparison women without autoimmune disease who delivered live-born infants from 2004-2017 were included for analysis. Both RA and JIA groups had an increased risk of PTD versus the comparison group (RR 2.09, 95% CI 1.50-2.91; and RR 1.81, 95% CI 1.14-2.89, respectively). Active RA at enrollment (aRR 1.58, 95% CI 1.10-2.27) and anytime during pregnancy (aRR 1.52, 95% CI 1.06-2.18) was associated with PTD. Corticosteroid use in every trimester was associated with an approximate 2 to 5-fold increased risk for PTD for both arthritis groups, independent of disease activity. CONCLUSION Women with RA and JIA are at increased risk for PTD. Maternal disease activity and corticosteroid use may contribute to some of this excess risk. This article is protected by copyright. All rights reserved