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Drug Exposure and Correlates of Oral and Topical ARV Protection

Drug Exposure and Correlates of Oral and Topical ARV Protection. Microbicides and PrEP : Back to Basics Wednesday July 25, 2012 ADM Kashuba. Drug Exposure Predicts Efficacy SC or PO tenofovir±emtricitabine Multiple Routes of Viral Challenge. Vaginal Challenge TFV 30mg/kg/d SC Otten 2000.

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Drug Exposure and Correlates of Oral and Topical ARV Protection

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  1. Drug Exposure and Correlates of Oral and Topical ARV Protection Microbicides and PrEP: Back to Basics Wednesday July 25, 2012 ADM Kashuba

  2. Drug Exposure Predicts Efficacy SC or PO tenofovir±emtricitabineMultiple Routes of Viral Challenge Vaginal Challenge TFV 30mg/kg/d SC Otten 2000 Rectal Challenge TFV 22 + FTC 20mg/kg/d SC Garcia Lerma 2008 Oral Challenge TFV 30 mg/kg/d SC Van Rompay 2001 100X Oral Challenge TFV 30 mg/kg/d SC Van Rompay 1998 IV Challenge TFV 30 mg/kg/d SC Tsai 1995 Monkey Plasma Concentration Relative to Human Exposure Rectal Challenge TFV 22mg/kg/d PO Subbarao 2006 Rectal Challenge TFV 22 + FTC 20mg/kg/d PO Garcia Lerma 2010 3X Rectal Challenge TFV 10mg/kg/d PO Van Rompay 2006 Oral Challenge TFV 10mg/kg/d PO Van Rompay 2006 Oral Challenge TFV .04 mg/kg/d PO Van Rompay 2002 “Lower” Oral Challenge TFV .02 mg/kg/d PO Van Rompay 2006 No Protection Partial Protection Full Protection

  3. Adherence Predicts EfficacyDrugs only Work If They Are Used: HPTN 052 Immediate Arm Delayed Arm (not on ART) Delayed Arm (on ART) 90% Cohen et al. MOAXO102, 6th IAS Conference, Rome, Italy, 2011

  4. Efficacy with Modest Adherence to TDF/FTC in MSM (iPrEx) ??? Anderson, Liu et al. CROI 2012

  5. Infection with (Seemingly) Good Adherence (Partners PrEP) >40ng/mL TFV Plasma Concentration (ng/mL) 0 3 6 9 12 15 18 21 24 27 30 Visit Months ??? Donnell et al. CROI 2012

  6. The Relationship Between Pharmacokinetics (drug exposure) & Pharmacodynamics (drug target) Can Alter The Importance of Adherence Q Week Concentration Q Day Minimum Effective Concentration Days The Principles of PrEP

  7. TDF vs TFV 1% Gel in WomenConcentrations Differ With Formulation TFV 1% Gel Vaginal Lumen Placebo gel TFV Gel ≤ 1,000ng/mL 100-1000x TDF Tablet Vaginal Lumen TFV Gel > 1,000ng/mL Abdool-Karim et al, Lancet 2011 Schwartz et al PloS One, 2011; Dumond et al AIDS 2008

  8. TDF vs TFV 1% Gel in Women Do different formulations act differently? Are target concentrations different for topical versus systemic delivery? TFV 1% Gel Lumen, Tissue, Regional Lymph Nodes Plasma MUSCULARIS TDF 300mg Chuchuen et al M2011

  9. TDF/FTC and Colorectal TissueARV Concentrations Differ Compared to Cervicovaginal Tissue TFV Rectal Tissue Implications for Efficacious Dosing Depending on Surface to be Protected At 24h: Colorectal TFV-DP ~200 fmol/mg Vaginal TFV-DP ~1 fmol/mg FTC Vaginal Tissue FTC Rectal Tissue TFV Vaginal Tissue Patterson et al SciTransl Med, 2011

  10. TDF vs TFV 1% Gel in Colorectal Tissue Concentrations Less Divergent With Different Formulations? ORAL DOSE TOPICAL DOSE 30min 30min 24h Patterson et al 2011 30min Anton et al CROI 2011

  11. An Intricate Relationship Exists Between Pharmacokinetics, Pharmacodynamics, and Adherence in PrEP Oral TDF/FTC Dosing for Colorectal Protection Topical TFV Dosing for Cervicovaginal Protection Less than Daily Adherence May Provide Protection (≤ 2x/wk; BAT24) Concentration Minimum Effective Concentration Oral TDF Dosing for Cervicovaginal Protection Requires high daily (eg>80%) adherence Days To be determined: Effect of inflammation & other physiologic factors on PK-PD-Adherence Relationship; Relationship Between Drug Exposure and MEC for New Drugs in Vaginal Rings, LAIs, etc

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