1. 1 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

2. 2 Outline: Valganciclovir Pharmacokinetics Background Studies and Analyses Conducted Summary of Study Results Conclusions

3. 3 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

4. 4 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

5. 5 VALGAN Use in Maintenance Therapy: Studies and Analyses Conducted Exposure-Response (PK/PD) Analysis (GANS 2226) Applicant concluded that AUC avg was the best predictor of time to first photographic progression Pharmacokinetic comparisons of GCV delivery systems

6. 6 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

7. 7 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

8. 8 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

9. 9 Ganciclovir Plasma Concentration- Time Profiles in HIV+/CMV+ Patients

10. 10 Ganciclovir Plasma Concentration- Time Profiles in HIV+/CMV+ Patients

11. 11 Ganciclovir Plasma Concentration- Time Profiles in HIV+/CMV+ Patients

12. 12 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

13. 13 Acknowledgements Valganciclovir Review Team Sue-Chih Lee, Ph.D., Pharmacometrics Reviewer