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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. - PowerPoint PPT Presentation
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Making Pharmacological Sense of the Successes and Failures Among PrEP
Clinical Trials
Craig Hendrix, MDJohns Hopkins University
Disclosure
Gilead provided partial support of research study; managed by Johns Hopkins University.
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?
UNIFYING THEME?
Relating Event, Concentration, Time
Pharmacodynamicsevent v. concentration
Concentration
Eve
nt
Pharmacokineticsconcentration v. time
Con
cent
ratio
n
Time
Survival Analysisevent v. time
Eve
nt
Time
Eve
nt
PharmacokineticsSpatio-temporal Drug Movement
active drug active site
Distant Compartment PK Informative?
Oral
CD4+ CellsTFVTFVpp
4
CD4+ CellsTFVTFVpp
2
CD4+ CellsTFVTFVpp
6[Tissue CD4+ TFV-Diphosphate]
Pharmacokinetic – Pharmacodynamic Link
Lumen5
Tissue3
Blood1
Rel
ativ
e R
isk
Red
uctio
n
Oral, Rectal, VaginalDaily, Weekly, Coitally
Pharmacokinetics (PK) Pharmacodynamics (PD)
0 20 40 60 80 100 120 140
Concentration
0.0
0.5
1.0
Like
lihoo
d of
Ser
ocon
vers
ion
0 20 40 60 80 100 120 140
Concentration
0.0
0.5
1.0
Like
lihoo
d of
Ser
ocon
vers
ion
[PBMC TFV-Diphosphate]
Sero
conv
ersi
on
Doesn’t have to be site of action, it only has to be informative
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
Unadjusted Plasma Tenofovir (ng/mL)
0.1 1 10 100 1000
Rel
ativ
e R
isk
Red
uctio
n fo
r HIV
Infe
ctio
n
0.0
0.2
0.4
0.6
0.8
1.0
PrEP RCT Plasma v. EffectWhy no consistent pattern among RCTs?
PP T poPP 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
RCT HeterogeneityRoute 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
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 log10 RV>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
DayRT:VT TFV
PlasmaRT:VT TFV-DPHomogenate
RT:VT TFV-DPCD4 Cells
Median (IQR) Median (IQR) Median (IQR)
1 33.8 (6.8, 37.8) 123.7 (8.4, 155.4) 19.20 (9.60, 28.8)8 4.5 (0.9, 31.3) 1.7 (0.3, 2.8) 0.20 (0.17, 0.23)
15 0.3 (0.3, 0.3) 2.5 (2.5, 2.6) 0.15 (0.15, 0.15)
Louissaint, et al. AIDS Res Hum Retrovir 2013
Duration of protectionLocation/Cell-specific TFV-DP Half-life
Anatomic Location Moiety Units
Terminal
Half-life* Median (IQR)
Plasma TFV ng/mL 69 (55, 77)PBMC TFV-DP fmol/M 48 (38, 76)
Blood CD4+ Cells TFV-DP fmol/M 112 (100, 118)VT TFV ng/gm 47 (38, 53) VT TFV-DP fmol/gm 53 (45, 68) VT Total Cells TFV-DP fmol/M 66 (43, 202)VT CD4+ Cells TFV-DP fmol/M 139 (121, 167)CVL** TFV ng/mL 40 (38, 43)
CVL Cells TFV-DP fmol/M -CT TFV ng/gm 31 (24, 36) CT TFV-DP fmol/gm 34 (21, 40) CT Total Cells TFV-DP fmol/M 82 (43, 89)CT CD4+ Cells TFV-DP fmol/M 60 (52, 72)
Colon Brush TFV ng/mL 20 (20, 21) Louissaint, et al. AIDS Res Hum Retrovir 2013
Adjusted Plasma Tenofovir (ng/mL)
0.1 1 10 100 1000
Relative R
isk Reduction for H
IV Infection
0.0
0.2
0.4
0.6
0.8
1.0
PIP T poPIP T/E po
TDF2 T/E po
VOICE T po
iPrEX T/E po
VOICE T/E poFEM-PrEP T/E po
IDU T po
VOICE T gel
PrEP RCT Plasma v. EffectAdjusting to Tissue Frame of Reference
Adherence or PK Differences?Parameter Estimate CV%Emax 0.94 44EC50 43 44EC90 107 44Gamma 2.4 56
Hours
0 2 4 6 8
Ser
um T
FV n
g/m
L
15
20
30
50
75
150
200
300
10
100
Hours
0 2 4 6 8
Ser
um T
FV C
hang
e ng
/mL
0
100
200
300
400
B SitesA Sites
MTN-001 Adherence or PK Variation?
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
B SitesA Sites
No 1h sample
Unadjusted Adjusted
PLANNING FUTURE STUDIES?
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
Days0.0 0.3 0.5 0.8 1.0 4.0 6.0 8.0 10.0 12.0 14.0
TFV
-DP
(fm
ol/m
illio
n ce
lls)
0.1
1
10
100
1000
PBMC CD4iPrEx EC90
Periodic PrEP DosingHow many doses until EC90?
• 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
TDF 300
TDF 600
TDF 150
TDF 75
iPrEx EC90
PB
MC
TFV
-DP
(fm
ol/m
illio
n ce
lls)
From Daily to Episodic Dosing What are the dosing targets?
Daily Oral TDFPBMC EC90
Single rectal TFV7-day protectionColon CD4 EC90
Episodic Topical DosingSpatio-temporal Drug & HIV Movement
HIV well covered
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
Thank You