Hinder, Markus and Sinha, Vikram-1 (2025) Letter to the editor of the Brit J Clin Pharmacol on Heuberger et al. 2025. Letter to the editor of the Brit J Clin Pharmacol, 91 (2). p. 2767. ISSN DOI: 10.1002/bcp.70154

Abstract

No abstract as this is a letter. This is the entire letter:

Dear editor,
Heuberger and colleagues [1] need to be commended for their effort to systematize approaches to sentinel dosing in early phase clinical pharmacology trials. To not only consider first-in-human studies for these questions but also reflecting on situations where early clinical trials move into not yet investigated exposures or duration of exposures expands the concept of sentinel dosing and is a very important thought overall. Bonate et al. on behalf of the ACCP Public Policy Committee have recently advocated for a risk-based approach for decisions on sentinel dosing [2]. Based on the two most recent misadventures (TGN1412 and BIA10-2474) and their learnings, we feel there are two important additional considerations: A) a novel mode of action with antagonistic properties has a more predictable pre-defined maximum effect than an agonist and the potential risk to trial participants may therefore be easier to assess. B) the likelihood of unique human metabolites (as discussed for BIA10-2474) which are not seen under single dose conditions and accumulate eliciting toxicities under multiple dosing conditions is an important aspect to take into account. We therefore believe that these two aspects which are not explicitly mentioned in [1] should be considered when assessing the overall risk and included in the framework in assessing the need for sentinel dosing in early clinical trials.

Item Type:	Article
Date Deposited:	20 Jan 2026 00:46
Last Modified:	20 Jan 2026 00:46
URI:	https://oak.novartis.com/id/eprint/57627