1618. The Pharmacokinetic Interactions of HCV Protease Inhibitor TMC435 With Antiretroviral Agents in Healthy Volunteers
Session: Poster Abstract Session: Novel Antimicrobial Agents
Saturday, October 20, 2012
Room: SDCC Poster Hall F-H
Posters
  • 233TIBGRA120020 TMC435 Poster_v8final.pdf (1.5 MB)
  • Background:

    TMC435 is an investigational, once daily (QD), oral hepatitis C virus (HCV) NS3/4A protease inhibitor currently in Phase III clinical development for the treatment of chronic HCV infection. A Phase III study, TMC435-TiDP16-C212, is ongoing to evaluate the safety, tolerability, efficacy and pharmacokinetics of TMC435 in chronic HCV-infected subjects co-infected with HIV-1. 

    Methods:

    Three Phase I studies were conducted in healthy subjects to investigate pharmacokinetic (PK) interactions between TMC435 and the antiretroviral (ARV) agents rilpivirine (RPV) or tenofovir disoproxil fumarate (TDF) in study TMC435‑TiDP16-C123, efavirenz (EFV) or raltegravir (RAL) in study TMC435‑TiDP16-C114, and darunavir/ritonavir (DRV/r) in study TMC435-TiDP16-C115.

    Results:

    No clinically relevant interactions were observed between TMC435 (150mg QD) and TDF, RPV and RAL. Co-administration with EFV, a CYP3A4 inducer, resulted in a significant decrease (71%) in exposure to TMC435 (150mg QD) (Table).  After the combined intake of TMC435 (50 mg QD) and DRV/r, the exposure of TMC435 was 2.6-fold higher compared to TMC435 (150 mg QD) alone. The observed interaction is consistent with the potent CYP3A4 inhibition by ritonavir. 

     

    LS means ratio (90% CI)

    ARV

    TMC435 AUCtau

    TMC435 Cmin

    ARV AUCtau

    ARV Cmin

    TMC435‑TiDP16‑C123

    RPV

    1.06 

    (0.94 - 1.19)

    0.96 

    (0.83 - 1.11)

    1.12 

    (1.05 - 1.19)

    1.25 

    (1.16 - 1.35)

    TDFa

    0.86 

    (0.76 - 0.98)

    0.93 

    (0.78 - 1.11)

    1.18 

    (1.13 - 1.24)

    1.24 

    (1.15 - 1.33)

    TMC435‑TiDP16‑C114

    EFV

    0.29 

    (0.26 - 0.33)

    0.09

    (0.08 - 0.12)

    0.90 

    (0.85 - 0.95)

    0.87

    (0.81 - 0.93)

    RAL

    0.89 

    (0.81 - 0.98)

    0.86 

    (0.75 - 0.98)

    1.08 

    (0.85 - 1.38)

    1.14 

    (0.97 - 1.36)

    TMC435‑TiDP16‑C115

    DRV/r

    2.59 

    (2.15 - 3.11)

    4.58 

    (3.54 - 5.92)

    1.18b

    (1.11 - 1.25)

    1.31b

    (1.13 - 1.52)

    aPK parameters are for tenofovir; bDRV data; LS, least squared; CI, confidence interval

    Conclusion:

    Dose adjustments are not required when RPV, TDF or RAL are co-administered with TMC435. If efficacy and safety of these combinations are confirmed, they may provide convenient once-daily treatment options for HIV/HCV co-infected patients. Co-administration of TMC435 and EFV or DRV/r should be avoided due to the observed decrease in TMC435 exposure in the presence of EFV and increase in TMC435 exposure in the presence of DRV/r.

    Sivi Ouwerkerk-Mahadevan1, Vanitha Sekar, PhD2, Alexandru Simion1, Monika Peeters1 and Maria Beumont-Mauviel, MD1, (1)Janssen Research & Development, Beerse, Belgium, (2)Janssen Research & Development, Titusville, NJ

    Disclosures:

    S. Ouwerkerk-Mahadevan, Janssen Research & Development: Employee and Shareholder, Salary

    V. Sekar, Janssen Research & Development: Employee and Shareholder, Salary

    A. Simion, Janssen Research & Development: Independent Contractor, Salary

    M. Peeters, Janssen Research & Development: Employee and Shareholder, Salary

    M. Beumont-Mauviel, Janssen Research & Development: Employee and Shareholder, Salary

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