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

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
Pharmacodynamics
Pharmacokinetics
event v. time
event v. concentration
concentration v. time
Event
Event
Event
Concentration
Survival Analysis
Time
Concentration
Time
Pharmacokinetics
Spatio-temporal Drug Movement
active drug
active site
Distant Compartment PK Informative?
Pharmacokinetics (PK)
CD4+ Cells
TFVTFVpp
6
Tissue
3
1.0
Blood
1
CD4+ Cells
TFVTFVpp
4
CD4+ Cells
TFVTFVpp
2
Seroconversion
Lumen
5
Oral
LikelihoodRisk
of Seroconversion
Reduction
Relative
Oral, Rectal, Vaginal
Daily, Weekly, Coitally
Pharmacodynamics (PD)
0.5
0.0
120
100
80
60
20
0
[Tissue
CD4+40 TFV-Diphosphate]
140
Concentration
[PBMC TFV-Diphosphate]
Pharmacokinetic – Pharmacodynamic Link
Doesn’t have to be site of action, it only has to be informative
iPrEx PBMC v Effect
Evident 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
PrEP RCT Plasma v. Effect
Relative Risk Reduction for HIV Infection
Why no consistent pattern among RCTs?
1.0
0.8
PP T/E T/E po
PP T po
CDC T/E po
0.6
iPrEX MSM T/E po
0.4
CAPRISA 004 T gel
0.2
VOICE T gel
VOICE T/E po
VOICE T po
0.0
0.1
1
FEM-PrEP T/E po
10
100
Unadjusted Plasma Tenofovir (ng/mL)
1000
RCT Heterogeneity
Route of Dosing Differences


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

Hendrix, et al. PLOS One 2013
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
Day
1
RT:VT TFV
Plasma
RT:VT TFV-DP
Homogenate
RT:VT TFV-DP
CD4 Cells
Median (IQR)
Median (IQR)
Median (IQR)
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




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
Duration of protection
Location/Cell-specific TFV-DP Half-life
Anatomic
Location
Moiety
Units
Plasma
PBMC
Blood CD4+ Cells
VT
VT
VT Total Cells
VT CD4+ Cells
CVL**
CVL Cells
CT
CT
CT Total Cells
CT CD4+ Cells
Colon Brush
TFV
TFV-DP
TFV-DP
TFV
TFV-DP
TFV-DP
TFV-DP
TFV
TFV-DP
TFV
TFV-DP
TFV-DP
TFV-DP
TFV
ng/mL
fmol/M
fmol/M
Terminal
Half-life*
Median (IQR)
69
(55, 77)
48 (38, 76)
112 (100, 118)
ng/gm
47
(38, 53)
fmol/gm
53
(45, 68)
fmol/M
66
(43, 202)
fmol/M
139 (121, 167)
ng/mL
40
fmol/M
-
ng/gm
31
(24, 36)
fmol/gm
34
(21, 40)
fmol/M
82
(43, 89)
fmol/M
60
(52, 72)
ng/mL
20
(20, 21)
Louissaint, et al. AIDS Res Hum Retrovir 2013
(38, 43)
Relative Risk Reduction for HIV Infection
PrEP RCT Plasma v. Effect
Adjusting to Tissue Frame of Reference
1.0
CV%
Adherence
or PK Differences?
Parameter Estimate
Emax
0.94
EC50
43
EC90
107
Gamma
2.4
0.8
44
44
44
56
PIP T/E po
PIP T po
TDF2 T/E po
0.6
IDU T po
iPrEX T/E po
0.4
VOICE T gel
0.2
FEM-PrEP T/E po
0.0
VOICE T/E po
VOICE T po
0.1
1
10
100
Adjusted Plasma Tenofovir (ng/mL)
1000
MTN-001 Adherence or PK Variation?
Unadjusted
Adjusted
400
300
B Sites
A Sites
Serum TFV Change ng/mL
200
Serum TFV ng/mL
150
100
75
50
No 1h sample
30
300
200
100
B Sites
A Sites
20
15
0
10
0
2
4
Hours



6
8
0
2
4
6
8
Hours
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
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
Periodic PrEP Dosing
How many doses until EC90?
PBMC
CD4
iPrEx EC90
100
10
1
0.1
0.0
0.3
0.5
0.8
1.0 4.0
6.0
8.0
10.0
12.0
PBMC TFV-DP (fmol/million cells)
TFV-DP (fmol/million cells)
1000
TDF 600
TDF 300
iPrEx EC90
TDF 150
TDF 75
14.0
Days
• 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
From Daily to Episodic Dosing
What are the dosing targets?
Daily Oral TDF
PBMC EC90
Single rectal TFV
7-day protection
Colon CD4 EC90
Episodic Topical Dosing
Spatio-temporal Drug & HIV Movement
HIV well covered
Questions

Is there a unifying theme among
heterogeneous PrEP RCT outcomes?


How to incorporate PK/PD into





Yes. PK & adherence, but not only…
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