The determination of the efficiency of first time-in-human study designs

Abstract

The goal of this study was to evaluate the comparative efficiency of non-oncology FTIH study designs with emphasis on drug-related adverse event (AE) characterization. Nine study designs were chosen for investigation. Pharmacokinetic (PK) data were simulated assuming a one compartment model with first order input and elimination (i.e. Ka = 1 hr−1, V/F = 17.5 L/hr, CL/F = 50 L, intersubject variability = 45%, residual variability =15%), and dose proportionality. AEs were simulated assuming that they were exposure (AUC) related. The study designs were evaluated on the basis of the quality of PK parameter estimates, the resulting safety profile, the duration of the trial, and the assumed budget required to perform that design. An efficiency-cost metric (ECM) was proposed and used to evaluate design efficiency that took into account the complexity of the designs. All designs provided similar PK parameter estimates and supported the underlying assumption of dose proportionality. The nine designs considered fell into 3 tiers based on the ECM. The top tier of designs described the AE profile equally well. The worst design in the bottom tier severely underestimated the AE profile in the safety scenarios considered. A methodology for evaluating prospective FTIH study design was developed, and has applicability for other FTIH designs. Clinical Pharmacology & Therapeutics (2004) 75, P88–P88; doi: 10.1016/j.clpt.2003.11.337