IMPACT OF LOW-DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF DANOPREVIR

IMPACT OF LOW-DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF DANOPREVIR (RG7227; ITMN-191), A HIGHLY POTENT AND SELECTIVE INHIBITOR OF THE HCV NS3/4A PROTEASE - see attached full poster report



Reported by Jules Levin, EASL Apr 14-18 2010 Vienna Austria

Joshua Haznedar,1 Jennifer Fretland,2 Gilbert Leong,2 Steven Blotner,3 Todd Hill,4 Patrick Smith,1 and Jonathan Tran1. 1Roche, Clinical Pharmacology, South San Francisco, CA, USA; 2Roche Palo Alto LLC, Department of Drug Metabolism and Pharmacokinetics, Palo Alto, CA, USA; 3Hoffmann-La Roche Inc., Pharma Development Innovation Biomathematics, Nutley, NJ, USA; 4Hoffmann-La Roche Inc., Clinical Research and Exploratory Development Operations, Nutley, NJ, USA



Author Discussion

- CYP3A-mediated inhibition by low-dose RTV has been successfully utilised in the HIV treatment paradigm to simplify HIV protease inhibitor regimens.

- The main objective of this pilot PK study in healthy volunteers was to determine if low-dose RTV could ‘boost’ the PK of danoprevir. Low-dose RTV significantly enhances danoprevir C12h (representative of Cmin for a q12h dosing regimen), which appears to be the key parameter driving efficacy and prevention of resistance. Less of an effect was observed on AUC and Cmax, which are key parameters often attributed to safety.

- The effect of multiple doses of RTV 100 mg q12h x 10 days on danoprevir C12h is about 2-fold less than the effect of a single dose of RTV 100 mg. This is likely due to the mixed inhibition and induction effects of RTV on CYP enzymes.[4]

- Based on the PK results, a phase Ib study of RTV-boosted danoprevir in combination with standard of care in HCV-infected patients was conducted.[5] Low doses and dosing frequency of danoprevir (100 mg and 200 mg; q12h and q24h) were chosen for co-administration with RTV 100 mg to achieve lower danoprevir Cmax and AUC than unboosted high doses of danoprevir while maintaining optimal Cmin for efficacy.



Author Conclusions

- PK boosting of danoprevir by low-dose RTV appears feasible. Danoprevir dose and dosing frequency may be reduced when co-administered with low-dose RTV.

- The co-administration of danoprevir single dose and low-dose RTV was safe and well tolerated in healthy volunteers.
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