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Pharmacokinetic-pharmacodynamic (PK-PD) analyses of TMC435 in treatment-naïve hepatitis C (HCV)-infected patients in the OPERA-1 study
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Reported by Jules Levin
EASL Apr 14-18 2010 Vienna Austria
V. Sekar1, P. Vis2, O. Lenz2, P. Meyvisch2, M. Peeters2, G. De Smedt2
1Tibotec Inc, USA; 2Tibotec BVBA, Belgium
AUTHOR CONCLUSIONS
In treatment-naive HCV-infected patients, following 28 days of treatment with TMC435 in combination with P/R, a dose-proportional increase in TMC435 exposure was observed from 25 to 75mg QD, with a more than dose-proportional increase in TMC435 exposure observed from 75 to 200mg QD.
There was no clear PK-PD relationship between TMC435 exposure and antiviral activity with TMC435 doses of 75mg QD or higher.
A trend towards mild increases in serum bilirubin and ALP was observed with higher TMC435 exposure, with increases mainly observed at the 200mg dose.
However, no clear PK-PD relationship was observed for other liver parameters.
The PK-PD findings reported here support the TMC435 75 and 150mg QD doses selected for further evaluation in treatment-naive patients as part of the ongoing
Phase IIb trial, PILLAR.
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Table 1. Patient demographics and baseline characteristics of patients included in Cohorts 1 and 2 of OPERA-1.
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a For 1 subject in the placebo group of Cohort 1 the HCV subtype (NS5B) was unknown
ALT, alanine aminotransferase; HCV, hepatitis C virus; RNA, ribonucleic acid
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Table 2. Pharmacokinetic proGle of TMC435 in treatment-naive patients in Cohorts 1 and 2 of OPERA-1 who received 7 days of TMC435 monotherapy followed by 21 days of triple therapy (TMC435+P/R) (A) or 28 days of triple therapy (TCM435+P/R) (B).
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AUC24h, area under the concentration-time curve from time of administration up to 24 hours; C0h, pre-dose plasma concentration; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; P, pegylated interferon alfa-2a; QD, once daily; R, ribavirin; tmax, time to reach the maximum plasma concentration
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Figure 2. Change in log10 plasma HCV RNA from baseline to Day 28 as a function of TMC435 exposure (deGned as AUC24h).
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Table 3. Simulated ratios of the medians of TMC435 pharmacokinetic parameters
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Figure 3. Change from baseline to Day 28 in (A) total, (B) direct and (C) indirect bilirubin; (D) alkaline phosphotase (ALP); (E) aspartate aminotransferase (AST) and (F) alanine aminotransferase (ALT) levels as a function of TMC435 exposure (defned as AUC24h).
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Lines represent the LOESS spline !tted to the data
AUC24h, area under the concentration-time curve from time of administration up to 24 hours; C, cohort; DB, direct bilirubin; IB, indirect bilirubin; PA, panel A; PB, panel B; TB, total bilirubin
References
1. Lin TI et al. Antimicrob Agents Chemother 2009; 53: 1377-1385.
2. Reesink HW et al. Gastroenterology 2010; 138: 913-921.
3. Reesink HW et al. Poster presented at the 60th American Association for the Study of Liver Diseases (AASLD) meeting, Boston, MA, USA, 30 October-3 November, 2009.
4. Marcellin P et al. Poster presented at the 44th Annual Meeting of European Association for the Study of the Liver (EASL), Copenhagen, Denmark, 22-26 April, 2009.
5. Manns M et al. Presented at the 44th Annual Meeting of European Association for the Study of the Liver (EASL), Copenhagen, Denmark, 22-26 April, 2009.
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