ADM Kashuba, PharmD, Eshelman School of Pharmacy, UNC Chapel Hill

Transcription

1 ADM Kashuba, PharmD, Eshelman School of Pharmacy, UNC Chapel Hill

2

3 Stroma Is there an ARV target conc n to abort HIV infection in the stroma? Fauci A. WAC 2010

4 Monkey Plasma Concentration Relative to Human Exposure Lower 3X 100X A Dose-Response Relationship in HIV Prevention Preclinical Macaque Data: Systemic Administration SC or PO TFV ± FTC; Multiple Routes of Viral Challenge Rectal Challenge TFV Rectal 22mg/kg/d Challenge PO TFV Subbarao 22 + FTC 2006 Rectal 20mg/kg/d Challenge PO Garcia TFV Lerma 10mg/kg/d 2010 PO Van Rompay 2006 Vaginal Challenge TFV 30mg/kg/d Rectal Challenge SC TFV Otten 22 + FTC 2000 Oral 20mg/kg/d Challenge SC Garcia TFV Lerma 30 mg/kg/d 2008 Oral Challenge SC Van TFV Rompay 30 mg/kg/d 2001 IV Challenge SC Van TFV Rompay 30 mg/kg/d 1998 SC Tsai 1995 Limitation: lack of data on clinical scaling Oral Challenge TFV 10mg/kg/d Oral Challenge PO Van TFV Rompay.04 mg/kg/d 2006 Oral Challenge PO Van TFV Rompay.02 mg/kg/d 2002 PO Van Rompay 2006 No Protection Partial Protection Is there a concentration-response relationship? Full Protection

5 Heterogeneous Tissue Distribution.A Lesson From Antibiotics EFV in NHP Colorectal tissue Thompson et al. AAC 2015 Tissue drug distribution is nonhomogeneous and tissue specific. Representative PET images of human subjects following the administration of 18F-trovafloxacin are shown. Muller AAC 2004

6 Variable Antiretroviral Exposure at Mucosal Surfaces Female Genital Tract, Colorectal Tissue Exposure Relative to Blood FEMALE GENITAL TRACT COLORECTAL 1000 CCR5 Receptor Antagonists Integrase Inhibitors Nonnucleoside RT Inhibitors Nucleoside(tide) RT Inhibitors Protease Inhibitors 100 RAL (150) Matrix:Blood Plasma Ratio MRV (27) MRV (4) tissue/fluid = BP RAL (2) DTG (0.17) DTG (0.06) ETR (1.3) EFV (0.6) DLV (0.2) ETR (8) FTC/ 3TC (4) ZDV (2) NVP (0.8) TFV (1) DDI (0.21) ABC (0.08) D4T (0.05) TFV (46) FTC (2.6) RTV (13) DRV (2.7) IDV (2) APV (0.5) RTV (0.3) ATV (0.18) LPV (0.08) 0.01 SQV (ND)

7 Cheminformatics Approach with 58 Drugs/13 Classes in the FGT High FGT penetration if: high volume of distribution high MRP1 substrate probability low MRP4 substrate probability lower protein binding (?) Model predicted penetration of rilpivirine and dolutegravir Thompson et al. AIDS Res Hum Retro 2014 Hu et al. JCR 2015

8

9 TFV Gel > 1,000ng/mL 500fmol TFVdp/mg EC50 ~700fmol/mg Abdool-Karim et al, Lancet 2011 Nicol et al, J AIDS 2015

10 Maher et al. Biomet Opt Express 2015 May 8;6(6):

11

12 SYSTEMIC SYSTEMIC TOPICAL Stroma Fauci A. WAC 2010

13 FTCtp (fmol/g) Female Genital Tract AUC0-14d (fmol*d*g -1 ) >50-fold lower Rectal Time (hr)

14 Shattock Nat Rev Microbiol 2003

15 m=1 Yang et al. PLoS One. 2014; 9(10): e

16 Modeling Population Pharmacokinetics Steady State Mucosal Tissue Metabolite Concentrations Lower FGT Tissue Rectal Tissue FTCtp 1000 TFVdp 9 Ctrough (nmolar) TFVdp Ctrough (nmolar) FTCtp First 10 Daily Doses First 10 Daily Doses Cottrell ML et al. J Infect Dis Feb 24 [Epub ahead of print]. Yang K. American Conference on Pharmacometrics 5, Abstract. Las Vegas NV October 12-15, 2014.

17 Reversion of TFVdp RT Inhibition With High datp/tfvdp Ratios In Vitro Rectal Tissue Contains Significantly Less datp and dctp than Vaginal or Cervical Tissue datp TFV activity datp Concentration (nmolar) datp * * A dctp Concentration (nmolar) * dctp * B * Garcia-Lerma et al J Virol Cervical Tissue Vaginal Tissue Rectal Tissue Cervical Tissue Vaginal Tissue Rectal Tissue Cottrell et al JID, 2016

18 Modeling Population Pharmacokinetics Simulated Mucosal Tissue Molar Ratios Molar TFVdp:dATP Ratio Colorectal Female GT TFVdp:dATP FGT Tissue Rectal Tissue Trough SS Ratio FGT = Rectal = 17 Molar FTCtp:dCTP Ratio FTCtp:dCTP Female GT Colorectal Trough SS Ratio FGT = 1.8 Rectal = 1.8 FGT Tissue Rectal Tissue First 10 Daily Doses First 10 Daily Doses Yang K

19 Combination Data FTCtp:dCTP PKPD TFVdp:dATP PKPD Cottrell et al JID, 2016

20 iprex, FemPrEP, VOICE SS=3 doses SS= 9 doses Cottrell et al JID, 2016

21 Ipergay Cottrell et al JID, 2016

22 POOR MODEST Modeling to Explain Clinical Trials Outcomes iprex: 44 (15-63)% Efficacy FemPrEP: 6 (-52-41)% Efficacy (2-3) GOOD (4+) 40-60% Taking 2+ Doses Truvada Visit Week Anderson PL, et al. Sci Transl Med. 2012; 12:4(151) Corneli AL et al. J Acquir Immune Defic Syndr. 2014; 66(3):

23

24 One consistent marker of PrEP efficacy has not yet been defined

25

26 U01 AI P30 AI U19 AI S10 RR P01 MH R01 AI GSK/Viiv Abbott Gilead Tibotec Merck K23 AI T32 GM K23 HD R37 DK R56 AI K23 AI FHI360 CAPRISA FACTS USAID NC State