WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.
While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.
“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”
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The transmission potential, however, has always been assumed to be low. “It’s a protein that would largely be degraded in the gastrointestinal tract of the baby, so there would be low bioavailability. But also CZP has no Fc portion, so it is not pulled across the intestinal lumina by the neonatal Fc receptor.”
Despite those assumptions and the positive – although limited – data, UCB conducted a 4-week postmarketing study to fully determine transmission levels. The CRADLE study enrolled 17 women taking CZP while breastfeeding healthy, full-term infants. Breast milk samples were taken at days 0, 2, 4, 6, 8, 10, 12, and 14 across one dosing period (14 days for those taking 200 mg every 2 weeks; and 28 days for those taking 400 mg every 4 weeks).
In addition to being the first study to estimate the average daily infant dose, CRADLE used a specially created ELISA to measure the drug. “This was a very carefully thought-out measure designed to be 10 times more sensitive than any assay ever used to identify this drug,” Dr. Clowse said. “It had a very high specificity, having to attach to both the TNF portion and the PEG component.”
All the women had a healthy term infant who was exclusively breastfed. Mothers had to be in steady-state dosing with at least three prior doses before the first sample and could not have taken any other biologics within five half-lives of those medications.
The mean age of the 17 women in the analysis was 34 years. Rheumatoid arthritis was the most common diagnosis (7); other conditions were Crohn’s disease (5), psoriatic arthritis (3), and ankylosing spondylitis (2). The majority of the infants (13) were younger than 6 months at the time of the study.
Most of the women (13) had some measurable CZP in at least one sample, and four had measurable CZP in almost every sample. But of the entire 137 samples tested, 77 (56%) came back below the limit of quantification, which was less than 0.032 mcg/mL. Another 52 samples came back as less than twice the lower limit of quantification (less than 0.064 mcg/mL). Among these, though, most were less than 0.050 mcg/mL. Only eight samples approached the level of less than three times the lower limit of quantification (less than 0.096 mcg/mL); of these, the highest level was 0.076 mcg/mL.
There were some strong individual trends, Dr. Clowse noted. Only two women showed the highest levels: Out of seven samples, one had two such readings, and the other had five. In four women, all of the samples were below the lower limit of quantification. The rest of the women had mixed results, which tended to cluster in the middle of their treatment cycle and then go down.
The median maximum concentration in breast milk was 0.04285 mcg/mL, which translated to an average daily infant dose of 0.0035 mg/kg/day. This was an infant dose of 0.125% of the mother’s dose, Dr. Clowse said.
A 5-week safety study followed the breast milk sampling phase. During this time, nine infants had some sort of event. These were mild and not different from that normally seen in breastfed infants. Several events were paired with maternal events, Dr. Clowse said. Two pairs had upper respiratory tract infections, and one mother developed a Candida skin infection while her infant developed oral candidiasis.
UCB sponsored the CRADLE study. Dr. Clowse is a consultant for the company.
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