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

Megan Eb Clowse, Frauke Förger, Caroline Hwang, John Thorp, Radboud Jem Dolhain, Astrid van Tubergen, Laura Shaughnessy, Jeff Simpson, Marie Teil, Nathalie Toublanc, Maggie Wang, Thomas W Hale, Megan Eb Clowse, Frauke Förger, Caroline Hwang, John Thorp, Radboud Jem Dolhain, Astrid van Tubergen, Laura Shaughnessy, Jeff Simpson, Marie Teil, Nathalie Toublanc, Maggie Wang, Thomas W Hale

Abstract

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--free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding.

Trial registration number: NCT02154425; Results.

Keywords: Anti-tnf; Autoimmune Diseases; Rheumatoid Arthritis; Spondyloarthritis.

Conflict of interest statement

Competing interests: MEBC has received research support from Janssen and Pfizer and is a consultant for UCB Pharma; FF has received research grants from UCB Pharma and is a consultant for and/or has received speakers’ fees from Mepha, Roche and UCB Pharma; CH has received research support from AbbVie and UCB Pharma and is a consultant for Janssen; JT has received research grants from UCB Pharma and is a consultant for Genentech/Roche and UCB Pharma; RJEMD has received unrestricted research grants from UCB Pharma; AvT has received research grants and/or clinical trial support from AbbVie, Celgene, Janssen Cilag, MSD, Novartis, Pfizer and UCB Pharma, has received speakers’ bureau from Janssen Cilag, MSD and Pfizer and is a consultant for and/or has served on advisory boards for AbbVie, Janssen Cilag, Novartis and Pfizer; LS, JS, MT, NT and MW are employees of UCB Pharma; TWH is a consultant for UCB Pharma.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
CRADLE study design. CZP, certolizumab pegol; Q2W, every 2 weeks; Q4W, every 4 weeks.

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