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Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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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, MD Johns Hopkins University
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Page 1: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

Making Pharmacological Sense of the Successes and Failures Among PrEP

Clinical Trials

Craig Hendrix, MDJohns Hopkins University

Page 2: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

Disclosure

Gilead provided partial support of research study; managed by Johns Hopkins University.

Page 3: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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?

Page 4: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

UNIFYING THEME?

Page 5: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 6: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

PharmacokineticsSpatio-temporal Drug Movement

active drug active site

Page 7: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 8: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 9: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 10: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 11: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 12: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 13: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 14: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 15: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

PLANNING FUTURE STUDIES?

Page 16: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 17: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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)

Page 18: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

From Daily to Episodic Dosing What are the dosing targets?

Daily Oral TDFPBMC EC90

Single rectal TFV7-day protectionColon CD4 EC90

Page 19: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

Episodic Topical DosingSpatio-temporal Drug & HIV Movement

HIV well covered

Page 20: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

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

Page 21: Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials

Thank You


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