(M1330-11-64) Prediction Accuracy of Allometrically Scaled VLX-1005 Pharmacokinetics

Purpose: To compare allometrically scaled pharmacokinetic (PK) parameters and metrics of VLX-1005, a novel inhibitor of 12-lipoxygenase for the treatment of heparin induced thrombocytopenia, to human pharmacokinetic data generated from the first-in-human study VLX-1005-001.

Methods: Animal Studies: VLX-1005 was administered intravenously to mice, rats, monkeys, and dogs to generate plasma concentration data for compartmental modeling and allometric scaling. Human Studies: Seven cohorts of healthy volunteers (6 active / 2 placebo) were randomized to receive a single one-hour infusion of VLX-1005 at doses of 10, 30, 100, 200, 400 and 600 mg after a one-hour or 600 mg after a four-hour infusion. Four cohorts (8 active / 2 placebo) were randomized to receive multiple doses of 100 mg, 200 mg, and 400 mg after a one-hour or 400 mg after a four-hour infusion once daily for 5 days. Plasma samples were collected over 36 hours after single doses and over 120 hours after multiple doses. Bioanalysis: Plasma samples from all species were analyzed for VLX-1005 with LC/MS/MS methods. Pharmacokinetic Modeling: PK parameters for VLX-1005 were calculated by fitting a 2-compartment IV infusion model to the data from the non-clinical species and humans. The model was parameterized using the clearances (CL, CLD2) and volumes of distribution (V1, V2). Allometric Scaling: A power model equation of the form y=x^a was used to fit parameters describing the clearances and volumes of distribution to the body weight from non-clinical species. Human PK parameters were then predicted from the fitted equation and compared to observed human PK parameters from study VLX-1005-001.

Results: A 2-compartment model was consistent with the plasma concentration-time data from all non-clinical species and humans. Both CLs and Vs exhibited reasonable allometric relationships with body weight, and the allometric exponents were within the expected ranges seen for most drugs. As shown in the table below, with the exception of CL, for which the predicted value was overestimated leading to a slight underestimation of t½, the predicted values were consistent with the observed values.

Conclusion: A two-compartment IV infusion model was consistent with the VLX-1005 concentration-time data after IV administration to non-clinical species and humans. Allometric scaling provided a reasonable prediction of intercompartmental clearance and both volumes of distribution in humans, with clearance overestimated and t½ slightly underestimated.

Acknowledgements: William Kramer is a paid consultant to Veralox Therapeutics.


Figure 1. Allometric relationship between individual animal clearance (CL) and body weight after IV administration of VLX-1005 to mice, rats, monkeys and dogs.


Figure 2. Allometric relationship between individual animal central compartment volume (V1) and body weight after IV administration of VLX-1005 to mice, rats, monkeys and dogs.


Table 1. Comparison of Scaled and Observed PK Parameters in Humans.