Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials Craig Hendrix, MD Johns Hopkins University.

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

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

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

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

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

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