Evaluating Transfer of Certolizumab Pegol into Breast Milk: Results from CRADLE, a Prospective, Postmarketing, Multicenter Pharmacokinetics Study

Abstract

Introduction: Women with chronic inflammatory diseases face uncertainty regarding the safety of the use of biologics during breastfeeding. Currently, limited and non-validated data exist on potential transfer of anti-TNFs into breast milk. CRADLE was the first sponsored study designed to evaluate certolizumab pegol (CZP) concentrations ([C]) in breast milk, and to estimate the average daily infant dose. Methods: CRADLE (NCT02154425) was a safety and pharmacokinetic study of lactating mothers (≥6 weeks postpartum) receiving commercial CZP for an approved indication. Decision to treat with CZP and to breastfeed was made independently of study participation. At steady-state (≥3 CZP doses), breast milk samples were collected at days 0, 2, 4, 6, 8, 10, 12, 14 (±28) from each mother across 1 dosing period. A highly sensitive CZP-specific ELISA was developed (validated in milk; LLQ=0.032μg/mL, 10-fold lower than assay used in CZP PK studies1). CZP stability in milk was confirmed. Results: 18 CZP-treated mothers were screened and 17 entered the sampling period; 16 on CZP 200mg Q2W; 1 on CZP 400mg Q4W (5 CD; 12 RA/SpA; Table 1). Samples from 4/17 mothers had no measurable CZP in breast milk; 13/17 had quantifiable levels at any time point (highest [C]: 0.076μg/mL; Figure 1). Estimated average daily infant dose ranged 0-0.0104mg/kg/day; median relative infant dose (RID, calculated 2 post hoc by Dr Hale): 0.15%. The infants of mothers exposed to CZP had a safety profile consisting of events occurring in unexposed infants of similar age (Table 2).Figure 1Table 1: Baseline Characteristics of Mothers and InfantsTable 2: Summary of Adverse Events from the Safety Set during the CRADLE Study (from Screening to Safety Follow-Up)Conclusion: Using the highly sensitive assay, 56% of samples were below LLQ while remainder had maximum CZP [C] < 3 times LLQ ( < 1% of expected plasma [C] of a therapeutic dose 1) indicating minimal to no transfer of CZP from plasma to breast milk. RID was below 0.5% of maternal dose ( < 10% unlikely to be of concern to infant wellbeing2). Additionally, CZP absorption by infants via breast milk is unlikely due to its Fc-free molecular structure3 and low oral bioavailability. These findings imply that continuation of CZP treatment is compatible with breastfeeding. 1. Lacroix BD. Gastroenterol 2010;138:S163-4 2. Bennett PN. Drugs and Human Lactation. 1996 3. Israel EJ. Immunology 1997;92:69-74 Funding: UCB Pharma We are indebted to the mothers and their infants for their altruistic participation. We thank the nurses, investigator teams, Nicole Hurst (PPD) and acknowledge Amanda Golembesky and Gerry Parker, UCB Pharma.