Can First-Time-In-Human Trials Replace Thorough QT Studies?
Anne Chain (1), Francesco Bellanti (1), Meindert Danhof (1), Oscar Della Pasqua (1, 2)
(1) Division of Pharmacology, Leiden University, Leiden, The Netherlands; (2) GlaxoSmithKline, London, United Kingdom
Objectives: The aim of the present study was to investigate if the first-time-in-human (FTIH) trials can be modified and optimised to achieve the same information from thorough QT (TQT) studies.
Methods: Four different FTIH trial designs were simulated and analyzed using hypothetical drugs that have negative and positive QT/QTc prolongation. First is the traditional dose escalation study simulated and analyzed according to a standard protocol used a control. Second is the same standard study, however, prior information of a positive control compound were used on the parameter estimates during analysis. Third is the traditional study with the addition dose of moxifloxacin where only PD measurements are sampled and historical PK information is used. The last scenario is also with the additional dose of moxifloxacin; however both PK and PD observations are simulated.
Simulations of the FTIH trials are entirely performed in R2.12 for cohorts of 12 and 18 subjects using traditional sampling scheme. The QT-interval prolongation effects of the hypothetical compound were simulated to be 2, 5, or 10 ms. Information on moxifloxacin is derived from a meta-analysis of four different clinical studies where it was used as a positive control. Modeling and simulation efforts were done in NONMEM VI. The analysis of all the simulated trials was performed in WinBUGS v 1.4.3 where the probabilities of a QT/QTc interval prolongation compared .
Results: All four scenarios performed were able to adequately capture the drug-induced QT-interval prolongation with the probabilities correctly indicating the likelihood of a prolongation greater than 10 ms. Scenarios with moxifloxacin as positive control further supported the simulated analyses by providing the sensitivity of the studies.
Conclusions: Thorough QT studies are expensive trials that are required early during clinical drug development. Before true efficacy can be established, it is advantageous to find out the propensity the compound's ability to induce unwanted QT interval prolongation before embarking on further costly studies. By modifying the traditional FTIH studies, we are able to gain valuable safety information early in development which can aid with decision making.
 Krudys K., et al., PAGE 16 (2007) Abstr 1125 [www.page-meeting.org/?abstract=1125]