C. Lin,1 R. Menon,1 W. Liu,1 S. Mensing,2 T. Podsadecki,1 N. Shulman,1 B. DaSilva-Tillmann,1 W. Awni,1 S. Dutta1; 1Abbvie, North Chicago, IL, 2Abbvie, Ludwigshafen, Germany
BACKGROUND: Safety and efficacy of the combination regimen of ABT-450/r (NS3 protease inhibitor identified by AbbVie and Enanta, coadministered with ritonavir), ombitasvir (NS5A inhibitor) and dasabuvir (NS5B polymerase inhibitor) ± ribavirin (RBV) have been evaluated in phase III trials in HCV genotype 1 infected subjects. This analysis characterizes the relationships between exposures and clinical safety (adverse events [AEs] and laboratory abnormalities [LAs]) in these studies (N=2346).
METHODS: Relationships between AE/LA response variables (ALT, total bilirubin, hemoglobin, rash) and drug exposures (steady-state AUC from pharmacokinetic (PK) analyses) were evaluated by logistic regression analyses. A forward selection method was used to select PK variables (AUC of each drug) and covariates (demographics, baseline values of AEs/LAs, etc.).
RESULTS: No significant associations were found between ombitasvir, dasabuvir or ritonavir exposures and safety variables. After adjusting for other covariates, risk of rash (by company MedDRA query) was higher when RBV was in the regimen, but was not related to RBV exposures. Grade ≥ 3 ALT (5x ULN) post-baseline values occurred in 0.91% overall with increased risk with higher ABT-450 exposures. Grade ≥ 3 (3x ULN) total bilirubin values occurred in 4.0% overall with increased risk in subjects with higher RBV and ABT-450 exposures. Grade ≥2 anemia (Hemoglobin ≤ 10 gm/dL) occurred in 5.2% subjects with RBV in the regimen and risk increased with increasing RBV AUCs.
CONCLUSION: While ABT-450 and RBV exposures showed associations with AEs/LAs, the relationships were shallow. Given the low incidence of adverse events across phase III studies, increases in ABT-450 exposure of up to two-fold are not predicted to increase AEs/LAs meaningfully (by ≤2%).