In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

Abstract

Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCV(a)) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the alpha-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a approximately 13% increase of AUC for 1.

Evaluation of the Potency of Telaprevir and Its Metabolites as Inhibitors of Renal Organic Cation Transporters, a Potential Mechanism for the Elevation of Serum Creatinine

“…1), have been identified in human plasma. VRT-127394 is an enantiomer of telaprevir, and the ratio of telaprevir:VRT-127394 in a phosphate buffer (pH 7.4) was found to be approximately 60:40, 17) similar to that in human plasma. VRT-0922061 is the main metabolite found in HCV patients with maximum unbound concentrations of 2 µM after repeated oral administration of 750 mg telaprevir.…”

Deuterium in Drug Discovery and Development

“…Compound 9, a deuterated analog of telaprevir in which the hydrogen at the chiral center adjacent to the ketoamide moiety was replaced with deuterium, has been reported [41]. Compound 9, a deuterated analog of telaprevir in which the hydrogen at the chiral center adjacent to the ketoamide moiety was replaced with deuterium, has been reported [41].…”

The potency–insolubility conundrum in pharmaceuticals: Mechanism and solution for hepatitis C protease inhibitors

“…Analysis of the pharmacokinetics (assuming the measured effective solubility for the materials in simulated intestinal fluid at 37°C, and assuming permeability estimates scaled from Caco-2 measurements) with an ACAT (advanced compartmental absorption and transit) model reveals that the improved oral exposure is a direct consequence of the enhanced effective aqueous solubility of the 4-HBA co-crystal (see solid lines in Fig. 3e; detail in SI Appendix) [26]. In the model, all disposition parameters (e.g., clearance, two compartment kinetic parameters, and permeability) are all constrained to be the same between amorphous and co-crystalline telaprevir as described in Materials & methods.…”