Phase II dose selection for a hypothetical novel Direct Thrombin Inhibitor (DTI): an integrated approach using experimental and literature data.
H. Kramer1, A. Zandvliet1, R. Berg2, HJ Streefkerk4, P. Grobara3, P Peeters2, T Kerbusch1
1) P3 Pharmacokinetics, Pharmacodynamics and Pharmacometrics, 2 Early Clinical Research and Experimental Medicin, 3)Global Statistics, 4)peviously associated with Schering Plough coworker, 1,2,3) Schering-Plough
Background: Phase II dose selection includes in general many uncertainties after first healthy volunteers trials, e.g efficacy, safety, dose regimen, number of doses. However, integrating available knowledge with new experimental data, improves dose selection and decision making. DTI's inhibit thrombin from clotting in the bloodstream and reduce the risk of venous-thrombo-embolism (VTE). The DTI's Dabigatran (DAB) and Ximelagatran (XIM) have been developed (ref 1-6) for this indication. Clinically efficacious and sub-efficacious dose were described and publicly available. Also pharmacokinetics (PK) and biomarker concentration relationships have been described, especially for the Ecarin Clotting Time (ECT) which specifically reflects the mechanism of action of DTI's.
Objectives: By integrating the available competitor literature data with experimental data of a hypothetical novel DTI, selecting an active and safe dose range for a Proof of Concept (POC) trial,
Methods: For a hypothetical new DTI, PK and ECT-concentration data were generated. The assumed typical values for a 2 compartment model for the hypothetical DTI were CL/F=600 L/h, V1=200 L, V2=600 L, Q12=60 L/h, Ka=0.75 h and the in vitro ECT potency at 60 s*L/mg. To link the available PK and ECT data of the new DTI to the competitor data an integrated target value was needed. To define such a target value it was assumed that Exposure (AUC) to a DTI with a certain ECT response relates to efficacy. Under this assumption the ECT data were used to calculate the Area-under-ECT-time curve (AUE), being the integrated target value. This was calculated as AUCx*potencyxr=AUEx. The target AUE range was based on sub-efficacious (SEff) and efficacious (Eff) doses of DAB and XIM from phase II clinical trials (ref 1-6).
AUCs for DAB and XIM were determined based on published pop-PK data. For DAB and XIM ECT curves were determined in vitro. The linear relationships were described with the difference in slope as a relative potency measure. The target AUE's at the SEff and Eff were calculated by multiplying the AUC with the relative potency value.
The PK of a hypothetical novel DTI was simulated by a pop-PK model, using NONMEM, and PD (AUE) was scaled by the in vitro relative potency relationship. This implies that the PK was multiplied with the relative potency resulting in an AUE at a certain dose resulting in a linear AUE-Dose relationship. This relationship was then used to identify SEff and Eff for the novel DTI.
Results: Integrating experimental and literature data for DAB and XIm resulted in the following parameters:
DTI | SEff (mg) | Eff (mg) | ECT potency (s*L/mg) | CL/F (L/h) | AUC SEff (mg h/L) | AUC Eff (mg h/L) | AUE (s*h) SEff | AUE (s*h) Eff |
DAB | 100 | 150 | 84 | 103 | 0.98 | 1.45 | 82 | 122 |
XIM | 24 | 48 | 56 | 27.3 | 0.88 | 1.76 | 49 | 99 |
The integrated target value AUE to meet for the hypothetical DTI ranged between 49 and 122 s*h to achieve sub-efficacy or efficacy in a phase II PoC trial
As the slope of the linear relationship (AUE-Dose) was 0.1 it was estimated that for this DTI the dose-range for the POC trial would be 175-293 mg for SEff and 353 to 435 mg for Eff.
Conclusions: Experimental and literature data from a novel hypothetical Direct Thrombin Inhibitor and two existing competitors were successfully pooled in an integrated analysis. This approach allowed the selection of a dose range of 200-400 mg, which is anticipated effective in a POC trial patient population.
References:
[1] Troconiz, IF et al. 2007, J Clin Phamacol, 47(3), 371-382
[2] Cullberg-M et al. 2005.Clin Pharmacol Ther, 77(4), 279-290
[3] Eriksson, B et al. 2003, Thromb Haemost, 89(2), 288-296
[4] Eriksson, B et al. 2002, Lancet, 360(9344) 1441-1447
[5] Eriksson-B et al. 2005, J Throm Haemost, 3(1), 103-111
[6] Eriksson-B et al. 2007, J Throm Haemost, 5(11) 2178-2185
