Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials Craig Hendrix, MD Johns Hopkins University.
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Making Pharmacological Sense of the Successes and Failures Among PrEP
Clinical Trials
Craig Hendrix, MD
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?
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
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
Re
lativ
e R
isk
Re
duct
ion
for
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
Re
lative
Risk R
ed
uction fo
r HIV
Infectio
n
0.0
0.2
0.4
0.6
0.8
1.0
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. 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
TF
V n
g/m
L
15
20
30
50
75
150
200
300
10
100
Hours
0 2 4 6 8
Se
rum
TF
V C
ha
ng
e n
g/m
L
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
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
Days
0.0 0.3 0.5 0.8 1.0 4.0 6.0 8.0 10.0 12.0 14.0
TF
V-D
P (
fmol
/mill
ion
cells
)
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
TF
V-D
P (
fmol
/mill
ion
cells
)
From Daily to Episodic Dosing What are the dosing targets?
Daily Oral TDFPBMC EC90
Single rectal TFV7-day protectionColon CD4 EC90
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
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