Pharmacokinetic Information Submitted to Support Valganciclovir Use in Maintenance Therapy for CMV R...
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Pharmacokinetic Information Submitted to Support Valganciclovir Use in Maintenance Therapy for CMV Retinitis. Robert O. Kumi, Ph.D. Reviewer, Pharmacokinetics Food and Drug Administration, Office of Clinical Pharmacology and Biopharmaceutics, Division of Pharmaceutical Evaluation III.

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Robert o kumi ph d reviewer pharmacokinetics

Pharmacokinetic Information Submitted to Support Valganciclovir Use in Maintenance Therapy for CMV Retinitis

Robert O. Kumi, Ph.D.

Reviewer, Pharmacokinetics

Food and Drug Administration, Office of Clinical Pharmacology and Biopharmaceutics, Division of Pharmaceutical Evaluation III


Outline valganciclovir pharmacokinetics

Outline: Valganciclovir Pharmacokinetics

  • Background

  • Studies and Analyses Conducted

  • Summary of Study Results

  • Conclusions


Ganciclovir delivery systems

Ganciclovir Delivery Systems

  • Intravenous and oral ganciclovir formulations available for maintenance therapy

    • Oral capsule has poor bioavailability (F):F < 10 % in the presence of food

  • Valganciclovir hydrochloride NDA under review


Valganciclovir prodrug of ganciclovir

Valganciclovir- Prodrug of Ganciclovir

  • VALGAN is rapidly and extensively converted to GCV and valine

  • Following VALGAN administration, GCV bioavailability in presence of food is approximately 60 %

  • Low Systemic Availability of VALGAN: VALGAN Exposure < 5 % of GCV Exposure


Valgan use in maintenance therapy studies and analyses conducted

VALGAN Use in Maintenance Therapy: Studies and Analyses Conducted

  • Exposure-Response (PK/PD) Analysis (GANS 2226)

    Applicant concluded that AUCavg was the best predictor of time to first photographic progression

  • Pharmacokinetic comparisons of GCV delivery systems


Ganciclovir pk pd analysis

Ganciclovir PK/PD Analysis

  • Objective

    • to determine if any GCV PK parameter (s) predict response (time to first photographic progression) during maintenance therapy

  • Methodology

    • three oral GCV dose regimens and one IV GCV dose regimen

    • PK parameter estimates obtained using population approach

    • Population PK parameter estimates were used to evaluate PK/PD relationship


Limitations of gcv pk pd analysis

Limitations of GCV PK/PD Analysis

  • Errors in PK parameter estimates anticipated due to insufficient dosing time records

  • Accuracy of individual parameter estimates unknown, because of the sampling scheme used

  • Population pharmacokinetic analysis results could not be used for further PK/PD analysis


Pharmacokinetic comparisons alternative to pk pd analysis

Pharmacokinetic Comparisons: Alternative to PK/PD Analysis

Plasma concentration-time profile comparisons

  • three ganciclovir delivery systems at recommended and proposed doses

  • IV GCV, VALGAN, and Oral GCV


Ganciclovir plasma concentration time profiles in hiv cmv patients

Ganciclovir Plasma Concentration-Time Profiles in HIV+/CMV+ Patients


Ganciclovir plasma concentration time profiles in hiv cmv patients1

Ganciclovir Plasma Concentration-Time Profiles in HIV+/CMV+ Patients


Ganciclovir plasma concentration time profiles in hiv cmv patients2

Ganciclovir Plasma Concentration-Time Profiles in HIV+/CMV+ Patients


Conclusions

Conclusions

  • GCV Plasma concentration-time profile comparisons of VALGAN to two approved GCV regimens support the use of VALGAN for CMV retinitis maintenance therapy

  • PK/PD model is not needed to support VALGAN use during maintenance therapy


Acknowledgements

Acknowledgements

  • Valganciclovir Review Team

  • Sue-Chih Lee, Ph.D., Pharmacometrics Reviewer


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