What is the Time to Protection in Women taking Oral TDF/FTC?

Peter Anderson, University of ColoradoMackenzie Cottrell, University of North Carolina Chapel Hill

Craig Hendrix, Johns Hopkins University

Background

• No study directly assessed time to clinical protection • Rational assumptions & models required

• Time to Protection ≠ Time to Steady-state• Anatomic compartment pharmacokinetics varies• Protective doses vary with anatomic HIV risk• Site of PrEP action not settled

• 3 Investigator Perspectives

Time0 20 40 60 80 100 120

Conc

entra

tion

0

2

4

6

8

10

12

14

Quasi-Steady-stateIN = OUT

Cmax,ss

Css

Cmin,ss

Cmax,1

Concentration – Time Principles

Ln D

rug

Con

cent

ratio

n

Time

• Repeat dosing gradually raises peaks (Cmax) & troughs (Cmin)• Steady-state occurs when peaks and troughs no longer change• Time to Steady-state varies w/ half-life (t1/2), independent of dose• Time to Protection determined by dose, frequency, PK

Time0 20 40 60 80 100 120

Conc

entra

tion

0

2

4

6

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10

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14

Cmax,ss

Css

Cmax,1

Cmax,ss

Css

Compare 2 Regimens, 2 Infection Sites

Ln C

once

ntra

tion

Time

FGT ProtectiveConcentration

GI ProtectiveConcentration

Time to GI Protection

Time to FGT Protection

1 t½50%

2 t½ 75%

3 t½ 87%

4 t½ 94%

5 t½ 97%

Ln C

TFVD

Por

Ln

(CTF

VDP/

CdA

TP)

PBM

C, M

ucos

al C

ell,

CD

4+

Time toSteady-State

(% Increments)

(Ignore numbers, order of time and direction of magnitude very roughly true)

• More frequent dosing, higher concentration, same time to Steady-state• Time to Steady-State may (FGT) or may not (GI) equal Time to Protection• Time to Protection varies with risk site & regimen

Linking Effect & Target Concentration

Oral

CD4+ CellsTFVTFVpp

4

CD4+ CellsTFVTFVpp

2

CD4+ CellsTFVTFVpp

6[Tissue CD4+ TFV-Diphosphate]

Pharmacokinetic – Pharmacodynamic Link

Lumen5

Tissue3

Blood1

Rela

tive

Risk

Red

uctio

n

Oral, Rectal, VaginalDaily, Weekly, Coitally

Pharmacokinetics (PK)Attaining the Target

Pharmacodynamics (PD)Defining the Target

0 20 40 60 80 100 120 140Concentration

0.0

0.5

1.0

Lik

elih

ood o

f S

ero

conve

rsio

n

0 20 40 60 80 100 120 140Concentration

0.0

0.5

1.0

Lik

elih

ood o

f S

ero

conve

rsio

n

[Drug Concentration]Se

roco

nver

sion

Doesn’t have to be active drug @ site of action, it only has to be informative

Site of Action?

Parameter Estimate CV%Emax 0.94 44EC50 43 44EC90 107 44Gamma 2.4 56

Tissue-Adjusted

Hendrix, Cell 2013

Tissue-Adjusted Plasma Tenofovir (ng/mL)

Unadjusted

Unadjusted Plasma Tenofovir (ng/mL)

• When evaluating both oral & topical dosing, …• Plasma concentration doesn’t explain variation well.• Tissue PK & susceptibility corrections explains far more variation.

Protective Concentration Targets?

Within Study: iPrEx

Parameter Estimate CV%Emax 0.94 44EC50 43 44EC90 107 44Gamma 2.4 56

Among Studies

Controlling for covariatesIC90 16 fmol/106 PBMC

Anderson, et al., Sci Trans Med 2012 Hendrix, Cell 2013

Tissue-Adjusted Plasma Tenofovir (ng/mL)

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

Time to Protection?

• Daily dosing consistently in iPrEx target range, but only after one week• Empiric data, not modeled data; only possible results are integer weeks

• Most subjects TFV-DP < iPrEx EC90 with single or double dose• iPrEx EC90 likely not be relevant for vaginal protection • PBMC data may not be relevant for colon & cervicovaginal tissue

Hendrix ARHR 2015; Louissaint ARHR 2013; Anderson Sci Transl Med 2012

Days0 7 14 21 28 35 42 49

TFV-

DP

fmol

/M c

ells

PBM

C

0

10

20

30

40

50

60

70

801 tab weekly1 tab 2x/week2 tabs 2x/week1 tab daily

Single Dose (14C-TDF Study)Multiple Dose/Regimen (HPTN 066)

iPrE

x IC

90

Days

0.0 0.3 0.5 0.8 1.0 4.0 6.0 8.0 10.0 12.0 14.0

TFV-

DP

(fmol

/milli

on c

ells

)

0.1

1

10

100

1000

PBMC CD4iPrEx EC90

Cell type specific PK?

Louissaint, et al. ARHR 2013; Anderson, et al. Sci Transl Med 2012

• 6 healthy women• Single oral dose

• TDF• 14C-TDF microdose

• Sample • Blood plasma, PBMC

q4 x 24h• rectum, vagina,

luminal fluid, blood D1, 8, 15

• Assays• TFV• TFV-DP

Anatomic PK Variation?

• CD4+ TFV-DP t1/2 & Tss FGT > PBMC > Colon• CD4+ TFV-DP t1/2 & Tss > Unfract. cells for PBMC & FGT; colon similar• 1.3 – 2.1 log10 RT>VT TFV-DP CD4+ & tissue homogenate, respectively• TFV, TFV-DP homog. Rectal/Vaginal ratios c/w Patterson

Louissaint, et al. AIDS Res Hum Retrovir 2013; Patterson, et al. STM 2011

RT:VT TFVHomogenate

RT:VT TFV-DPHomogenate

RT:VT TFV-DPCD4 Cells

24 hrs 33.8 (6.8, 37.8) 123.7 (8.4, 155.4) 19.20 (9.60, 28.8)

MatrixCD4+ Cells Unfractionated Cells

t1/2 (hrs) Tss 90% (days) t1/2 (hrs) Tss 90% (days)PBMC 112 (100, 118) 16.3 (14.6, 17.2) 48 (38, 76) 7.0 (5.5, 11.1)Colon 60 ( 52, 72) 8.8 ( 7.6, 10.5) 82 (43, 89) 12.0 (6.3, 13.0)FGT 139 (121, 167) 20.3 (17.6, 24.4) 66 (43, 202) 9.6 (6.3, 29.5)

Summary• FGT protection requires 6-7 doses per week•∴ Time to Protection must nearly equal Tss (Steady-state)

• CD4+ cell most relevant cell even if site uncertain• CD4+ TFV-DP t1/2

• FGT 139 hrs• PBMC 112 hrs• Colon 60 hrs

•∴ Time to Protection• FGT 20 days • PBMC 16 days • Colon 9 days

Peter AndersonUniversity of Colorado

Cell-Prep: intracellular TFV-DP and FTC-TP

• Goal: Determine accumulation kinetics in PBMC, rectal mononuclear cells, cervical brush cells.

40 volunteers (13 female)

• Multiple PBMC at each visit• One visit with one rectal sample• One visit with one cervical sample

PBMC ~SS 7 days

Chen. PLoS ONE 11(11): e0165505. doi:10.1371/journal.

fmol

/106

PBM

C

Day

7

Day

7washout washoutDaily dosing Daily dosing

Tenofovir-diphosphate Emtricitabine-triphosphate

Rectal mononuclear cells

Seifert. ARHR. 2016 Oct/Nov;32(10-11):981-991.

Cervical brush cells, viable and total

• N=13

Dumond/Kashuba: First dose vs SS

Dumond. AIDS. 2007 Sep 12;21(14):1899-907.

Summary

• PBMC SS ~ day 7

• Rectal cells SS ~ day 5-7

• Cervical cells less conclusive. Under powered. Epithelial cells with low viability. Concentrations from days 1-7 overlapped with SS predictions.

Discussion points• Parent TFV/FTC appears rapidly in CVF. Despite limited data

in cervical epithelial cells, concentrations within first week overlapped with SS. Systemic drug reached SS at ~7 days.

• Relevance of male genital tract? We have no data in male genital tract tissue (eg foreskin)…possible PK similarities to female genital tract? Its relevant that we see high efficacy in MSM, presumably including insertive exposures.

• Relevance of PEP/animal models? Drug started within 36 hours after vaginal exposure effective in macaques (HIV-2). Event-driven oral dosing effective for vaginal exposures in macaques (SHIV).

PMID: 23226529, 25202923, 11000253

Mackenzie CottrellUNC Chapel Hill

Adherence Correlates with Clinical Trial Results

Adapted from Landovitz R. PrEP for HIV Prevention: What We Know and What We Still Need to Know for Implementation. CROI 2015.

Adherence Correlates with Clinical Trial Results

Clinical Trial

Detectable Drug Concentrations

Infected Cases

Uninfected Controls

Total

iPrEx2 of 33

6%17 of 35

49%19 of 68

28%

FEM-PrEPVOICE

iPrEx

Clinical Trial

Detectable Drug Concentrations

Infected Cases

Uninfected Controls

Total

iPrEx2 of 33

6%17 of 35

49%19 of 68

28%

FEM-PrEP4 of 2715%

19 of 7824%

28 of 12822%

VOICE N/A 29-30%

Adapted from Landovitz R. PrEP for HIV Prevention: What We Know and What We Still Need to Know for Implementation. CROI 2015.

Approach to Predicting PrEP Efficacy

1. Determine drug concentrations in HIV susceptible tissues of healthy volunteers

2. Build mathematical model to predict drug concentrations in these tissues

3. Determine efficacy target to protect human cells from HIV infection

4. Predict the percent of the population that would achieve efficacy target if taking daily or intermittent TDF±FTC for HIV PrEP

Selecting an Efficacy Target

New

HIV

DN

A

U

CG

U

C

A

HIV Enzyme

CG

Tem

plat

e fo

r HIV

DN

A

DNA Material

Drug Inhibition

Replication

Dose vs Response Relationship

Drug Concentration

1 10 100 1000 10000 100000

Per

cent

Inhi

bitio

n

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EC50→EC90→

EC99→

←Why a Ratio?

Why EC90?→

First 10 Daily Doses

1 2 3 4 5 6 7 8 9 10 11

% P

opul

atio

n Ac

hiev

ing

EC90

Rat

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First 10 Daily Doses

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Tenofovir-DFEmtricitabineTDF/FTC

Predicting Efficacy in the PopulationFirst 10 Daily Doses

96332 3

Rectal TissueLower FGT Tissue

Cottrell ML et al. J Infect Dis. 2016 Jul 1;214(1):55-64.

Doses/Week

% P

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EC90

Rat

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1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7Emtricitabine Tenofovir-DF TDF/FTC

Doses/Week

% P

opul

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hiev

ing

EC90

Rat

io

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1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7Emtricitabine Tenofovir-DF TDF/FTC

Predicting Efficacy in the Population Reduced Frequency Dosing

Lower FGT Tissue Rectal Tissue

65%

100%98% 100%

Cottrell ML et al. J Infect Dis. 2016 Jul 1;214(1):55-64.

Study Conclusions

1. TDF active metabolite exposure in lower GI tract was greater than in FGT tissues

2. Mathematical modeling predicted drug concentrations in mucosal tissues

3. The maximal proportion of the population achieved our efficacy target by the 3rd dose of Truvada® PrEP

4. 100% of the population achieved our efficacy target with daily versus 100% in lower GI tract and 65% in FGT with twice weekly Truvada®

5. Our model reasonably correlated with clinical trial results

Discussion