Antidrug Antibodies Common, Significantly Impact Biologic Efficacy

Antidrug antibodies (ADAs) are commonly found in healthy subjects after a single intravenous dose of infliximab and result in faster clearance of infliximab, shorter elimination time, and lower serum infliximab levels, according to a study published in the September 2017 issue of Drugs in R&D by Eli D. Ehrenpreis, MD.

ADAs to infliximab developed in 37% of healthy subjects, and clearance of infliximab is more rapid, elimination half-lives shorter, and trough levels decreased in subjects with ADAs. The study is the first to detail the pharmacokinetic (PK) effects of ADAs following a single dose of intravenous infliximab in a group of healthy subjects, and it shows that development of ADAs has the profound effect of increasing drug clearance following the first dose of biologic therapy.

The study obtained data from a single-blind, parallel-group, single-dose study of healthy subjects in 3 treatment groups: SB2 (an infliximab biosimilar), European Union-sourced Remicade (EU-IFX), and US-sourced Remicade (US-IFX). In the study, 159 subjects received 5 mg per kg of intravenous SB2, EU-IFX, or US-IFX for 120 minutes on study day 1, and were followed for 10 weeks for safety, PK, and immunogenicity measurements. Intravenous hydrocortisone, oral acetaminophen, and oral loratadine were given prior to the infusion.

Serum infliximab levels were measured at 1, 2, 3, 6, 12, 24, 48, and 72 hours and at 5, 7, 14, 21, 28, 42, 56, and 70 days after administration. Samples were collected to monitor ADA and neutralizing antibodies (Nabs) at pre-dose and 28 and 70 days after dosing. Data from the first 10 subjects randomized to each treatment arm constituted the group of 30 subjects examined in the study.

• At 70 days after dosing, 37% of subjects developed ADAs; 13% of the total number of subjects had Nabs.
• No ADAs were detected at baseline or at 28 days after dosing.
• ADAs were detected in 4 subjects after SB2, 1 subject after EU-IFX, and 6 subjects after US-IFX. Of these, Nabs occurred in 1 subject after SB2, no subjects after EU-IFX, and 3 subjects after US-IFX.
• Infliximab clearance was markedly increased in subjects with ADAs compared with those without ADAs.

The study demonstrates that the presence of ADAs in this population profoundly increases infliximab clearance. “This finding has implications related to the administration of both infliximab and other biologic therapies,” the author concludes. “Since the development of infliximab ADAs probably begins at the time of the first injection and evolves during its presence in circulation, it is likely that an even higher rate of ADA formation is prevented by premedication with intravenous hydrocortisone.”

Further clinical studies will be required to interpret the significance of rapid ADA development to biologic therapy, and strategies for early intervention to prevent this occurrence may be warranted.