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Lymphatic Targeting of Tenofovir; Intracellular Pharmacokinetics and Viral Dynamics

Lymphatic Targeting of Tenofovir; Intracellular Pharmacokinetics and Viral Dynamics. Arnold Fridland, Ph.D, William Lee, Ph.D. Gilead Sciences, Inc. Tenofovir and Tenofovir DF (Viread). Tenofovir intracellular t 1/2 ~ 50h once daily dosing good resistance profile. Viread

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Lymphatic Targeting of Tenofovir; Intracellular Pharmacokinetics and Viral Dynamics

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  1. Lymphatic Targeting of Tenofovir; Intracellular Pharmacokinetics and Viral Dynamics Arnold Fridland, Ph.D, William Lee, Ph.D. Gilead Sciences, Inc.

  2. Tenofovir and Tenofovir DF (Viread) • Tenofovir • intracellular t 1/2 ~ 50h • once daily dosing • good resistance profile • Viread • human % F = 40 • Approved 11/01

  3. Human PK after IV infusion (1.0 mg/kg) of Tenofovir and PO (300 mg) Tenofovir DF (Viread) 1000 5000 IV PO 1000 F = 40% [Tenofovir] (ng/mL) 100 100 10 10 0 6 12 0 12 24 36 48 Time Post Dose (Hr) • No prodrug is observed in plasma following PO

  4. Viread – What’s Not to Like? • Good oral bioavailability > 40% • Excellent efficacy, Viread/3TC/EFV result in > 70% patient below 50 copies/mL of HIV RNA @ wk 144 • Safety comparable to placebo • Available as combination pill w/FTC • Leading selling NRTi

  5. Δ HIV RNA (day 7) vs Tenofovir Exposure After Tenofovir (iv) or Viread (po) in Patients • Prodrug leads to higher intracellular levels of TPP

  6. Objectives for 2nd GenerationTenofovir Prodrug • Increased tissue exposure/decreased renal excretion • Observable plasma levels of prodrug after p.o. • Increased stability in blood compartment • Preferential metabolism in lymphatic tissues

  7. In Vitro/In Vivo Criteria for Prodrug Selection • EC50 ag HIV-1 • MT-2 cell extracts • Plasma stability • PLCE • Dog PK • PBMC levels • Tissue homogenates “Mono phenyl isopropylalaninyl mono amidate - (R,S,S)” GS-7340

  8. Stereochemistry at Phosphorus Determines Metabolic Stability and Antiviral Activity

  9. In vitro Activity & Metabolic Stability (t1/2) of GS 7340

  10. Plasma PMPA GS-7340 GS-7161 min PBMC PMPA PMPAp 7161 PMPApp min HPLC Chromatograms after 1 hr Incubation of GS 7340 in Human Whole Blood

  11. Plasma and PBMC Profiles of GS 7340 and tenofovir after iv infusion (0.5 mg/kg) and po (4.8 mg/kg) in dogs FPBMC = 15% FPLASMA = 23 %

  12. Plasma and PBMC AUC0-24 After Tenofovir (s.c.) and Tenofovir Prodrugs (p.o.) in Dogs

  13. Distribution in Dogs After Administration of a Single Oral Dose of [14C]-Tenofovir DF or [14C]-GS-7340

  14. PK/PD Conclusions • GS-7340-02 produces rapid achievement of high concentrations of GS-7340 in the plasma • Rapid distribution/elimination • T1/2 ~ 20 - 40 minutes • Sustained plasma concentrations of tenofovir • Lower tenofovir Cmax concentrations • AUC ~ proportional to tenofovir dose • Prolonged plasma T1/2 relative to TDF, greater accumulation to steady-state (150 mg 7340-02  300 mg TDF) • Improved intracellular distribution of tenofovir to PBMCs • ~ 6 to 20-fold higher concentrations relative to TDF 300 mg • No correlations between plasma or PBMC tenofovir exposure and antiviral activity

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