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

6. Pharmacokinetics Spatio-temporal Drug Movement active drug active site

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

8. iPrEx PBMC v Effect Evident Concentration-Response iPrEx EC 90 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. Effect Why no consistent pattern among RCTs? PP T po PP T/E T/E po CDC T/E po VOICE T po iPrEX MSM T/E po VOICE T/E po VOICE T gel FEM-PrEP T/E po CAPRISA 004 T gel

10. RCT Heterogeneity Route of Dosing Differences Hendrix, et al. PLOS One 2013  Vaginal tissue TFV-DP Vaginal 130x > Oral (topical tissue advantage)  Serum TFV Oral 56x >Vaginal (serum doesn’t reflect tissue)  Rectal gel dosing shows similar trends

11. RCT Heterogeneity Colon v. Vaginal Risk Protection  Single oral dose TDF, 6 women (self as own control)  Sample blood, rectum, vagina, luminal fluid x2 weeks  2.1 log 10 RV>VT TFV-DP homogenate c/w Patterson (2011)  1.3 log 10 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 Day RT:VT TFV Plasma RT:VT TFV-DP Homogenate RT:VT TFV-DP CD4 Cells Median (IQR) 133.8 (6.8, 37.8)123.7 (8.4, 155.4)19.20 (9.60, 28.8) 84.5 (0.9, 31.3)1.7 (0.3, 2.8)0.20 (0.17, 0.23) 150.3 (0.3, 0.3)2.5 (2.5, 2.6)0.15 (0.15, 0.15) Louissaint, et al. AIDS Res Hum Retrovir 2013

12. Duration of protection Location/Cell-specific TFV-DP Half-life Anatomic LocationMoiety Units Terminal Half-life* Median (IQR) PlasmaTFV ng/mL69(55,77) PBMCTFV-DP fmol/M48(38,76) Blood CD4+ CellsTFV-DP fmol/M112(100,118) VTTFV ng/gm47(38,53) VTTFV-DP fmol/gm53(45,68) VT Total CellsTFV-DP fmol/M66(43,202) VT CD4+ CellsTFV-DP fmol/M139(121,167) CVL**TFV ng/mL40(38,43) CVL CellsTFV-DP fmol/M- CTTFV ng/gm31(24,36) CTTFV-DP fmol/gm34(21,40) CT Total CellsTFV-DP fmol/M82(43,89) CT CD4+ CellsTFV-DP fmol/M60(52,72) Colon BrushTFV ng/mL20(20,21) Louissaint, et al. AIDS Res Hum Retrovir 2013

13. PIP T po PIP T/E po TDF2 T/E po VOICE T po iPrEX T/E po VOICE T/E po FEM-PrEP T/E po IDU T po VOICE T gel PrEP RCT Plasma v. Effect Adjusting to Tissue Frame of Reference Adherence or PK Differences? ParameterEstimateCV% Emax0.9444 EC504344 EC9010744 Gamma2.456

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

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 Dosing How many doses until EC 90 ? Most subjects still below iPrEx EC 90 after 3-7 days iPrEx EC 90 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 TDF 300 TDF 600 TDF 150 TDF 75 iPrEx EC 90 PBMC TFV-DP (fmol/million cells)

18. From Daily to Episodic Dosing What are the dosing targets? Daily Oral TDF PBMC EC 90 Single rectal TFV 7-day protection Colon CD4 EC 90

19. Episodic Topical Dosing Spatio-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