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Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials. Craig Hendrix, MD Johns Hopkins University. Disclosure. Gilead provided partial support of research study; managed by Johns Hopkins University. . Questions .

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Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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  1. Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials Craig Hendrix, MD Johns Hopkins University

  2. Disclosure • Gilead provided partial support of research study; managed by Johns Hopkins University.

  3. Questions • Is there a unifying theme among heterogeneous PrEP RCT outcomes? • How to incorporate PK/PD into • Periodic or Episodic TFV-based PrEP? • PrEP trials of new products? • What is needed for the future?

  4. Unifying theme?

  5. Relating Event, Concentration, Time Survival Analysis event v. time Pharmacokinetics concentration v. time Pharmacodynamics event v. concentration Event Concentration Event Event Time Time Concentration

  6. PharmacokineticsSpatio-temporal Drug Movement active drug active site

  7. Distant Compartment PK Informative? Pharmacokinetics (PK) Pharmacodynamics (PD) Oral Oral, Rectal, Vaginal Daily, Weekly, Coitally Lumen 5 Tissue 3 Blood 1 Relative Risk Reduction Seroconversion CD4+ Cells TFVTFVpp 6 CD4+ Cells TFVTFVpp 4 CD4+ Cells TFVTFVpp 2 [Tissue CD4+ TFV-Diphosphate] [PBMC TFV-Diphosphate] Pharmacokinetic – Pharmacodynamic Link Doesn’t have to be site of action, it only has to be informative

  8. iPrEx PBMC v EffectEvident Concentration-Response • iPrEx EC90 16 fmol/M cells (3-28 95% CI), c/w mITT TFV>LLOQ • Colored panels, adherence benchmarks (STRAND DOT IQRs) • Anderson, et al. Sci Trans Med 2012

  9. PrEP RCT Plasma v. EffectWhy no consistent pattern among RCTs? PP T/E T/E po PP T po CDC T/E po iPrEX MSM T/E po CAPRISA 004 T gel VOICE T gel FEM-PrEP T/E po VOICE T/E po VOICE T po

  10. RCT HeterogeneityRoute of Dosing Differences • Vaginal tissue TFV-DP Vaginal 130x >Oral(topical tissue advantage) • Serum TFV Oral56x >Vaginal(serum doesn’t reflect tissue) • Rectal gel dosing shows similar trends Hendrix, et al. PLOS One 2013

  11. RCT HeterogeneityColon v. Vaginal Risk Protection • Single oral dose TDF, 6 women (self as own control) • Sample blood, rectum, vagina, luminal fluid x2 weeks • 2.1 log10RV>VT TFV-DP homogenate c/w Patterson (2011) • 1.3 log10 RV>VT TFV-DP extracted CD4+ cell • RT:VT ratio varies with drug moiety & sample type • Rectal “advantage” depends on dosing rate • colon homogenate and CD4 cell half-life < vaginal tissue Louissaint, et al. AIDS Res Hum Retrovir 2013

  12. Duration of protectionLocation/Cell-specific TFV-DP Half-life Louissaint, et al. AIDS Res Hum Retrovir 2013

  13. PrEP RCT Plasma v. EffectAdjusting to Tissue Frame of Reference Adherence or PK Differences? PIP T/E po PIP T po TDF2 T/E po IDU T po iPrEX T/E po VOICE T gel FEM-PrEP T/E po VOICE T/E po VOICE T po

  14. MTN-001 Adherence or PK Variation? Unadjusted Adjusted • Pre-dose concentration (2o adherence, PK) 5:1 ratio • After observed dose, pattern identical (2o PK only) • Pop PK with adherence term confirms no PK difference No 1h sample B Sites A Sites

  15. Planning future studies?

  16. iPrEx PK/PD What are concentration targets? • iPrEx 16 fmol/M cells (3-28 95% CI) • Colored panels adherence benchmarks (STRAND DOT IQRs) • Anderson, et al. Sci Trans Med 2012

  17. Periodic PrEP DosingHow many doses until EC90? TDF 600 TDF 300 PBMC TFV-DP (fmol/million cells) iPrEx EC90 TDF 150 TDF 75 • Most subjects still below iPrEx EC90 after 3-7 days • iPrEx EC90 may not be applicable • Method Conversion from 16 viable PBMC to 24-48 fresh lysed PBM) • Louissaint ARHR 2013; Anderson Sci Transl Med 2012; Chaturvedula 2013

  18. From Daily to Episodic Dosing What are the dosing targets? Daily Oral TDF PBMC EC90 Single rectal TFV 7-day protection Colon CD4 EC90

  19. Episodic Topical DosingSpatio-temporal Drug & HIV Movement HIV well covered

  20. Questions • Is there a unifying theme among heterogeneous PrEP RCT outcomes? • Yes. PK & adherence, but not only… • How to incorporate PK/PD into • Periodic or Episodic TFV-based PrEP? • PrEP trials of new products? • Bridging several studies to estimate/plan • Best to confirm with prospective trial • What is needed for the future? • Mechanistic thinking, not simply empirical • PD surrogates, allometric scaling • Clinical trial simulation

  21. Thank You

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