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
8
10
12
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
0
10
20
30
40
50
60
70
80
90
100
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
io
0
10
20
30
40
50
60
70
80
90
100
First 10 Daily Doses
1 2 3 4 5 6 7 8 9 10 11
% P
opul
atio
n Ac
hiev
ing
EC90
Rat
io
0
10
20
30
40
50
60
70
80
90
100
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
opul
atio
n Ac
hiev
ing
EC90
Rat
io
0
10
20
30
40
50
60
70
80
90
100
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
atio
n Ac
hiev
ing
EC90
Rat
io
0
10
20
30
40
50
60
70
80
90
100
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