Department Name
An exploration of adherence measures
to detect recent changes in Truvada ®
dosing patterns
Daijha JC Anderson, PharmD, Heather MA Prince, PA-C, Amanda Poliseno,
BS, Kristen Moody, PharmD, Ashley Saunders, PharmD candidate, Craig
Sykes, MS, Amanda P Schauer, BS, Brian Van Horne, BS, Katie Mollan, MS,
PhD candidate, Angel D Davalos, PhD candidate, Michael G Hudgens, PhD,
and Angela DM Kashuba, BScPhm, PharmD, DABCP, FCP
University of North Carolina Chapel Hill
Disclosures – Daijha JC Anderson
2Department Name
No conflicts of interests
Relations possible relevant to this
meeting:
None
Sponsoring & Research grants NIH Grant #: R01 AI 122319
CFAR grant #: P30 AI50410
Consultation fees: None
Stock shareholder: None
Other support: Pharmaceutical Product Development
(PPD) sponsored Drug Development
and Clinical Research fellowship
3Department Name
• Adherence to Truvada® and valid measures of
adherence are crucial for the success of PrEP.
• Measured concentrations in various blood
sample matrices have been used as objective
measures of adherence.1
Background
1.) Fonner, VA et al. AIDS . 2016 Jul31; 30(12):1973–83.2.) Patterson, KB et al. Sci Transl Med. 2011 Dec 7;3(112):112re4
3.) Brooks KM and Anderson PL. Clin Pharmacol Ther. 2018 Dec;104(6):1056-1059
TFVdp FTCtp
PBMCs 6 days 1.6 days
RBCs 17 days 1.5 days
TFV FTC
Plasma 17 hours 10 hours
1-2 months3
TFVdp in RBC1-2 weeks3
TFVdp in PBMCs1-7 days2
Parent drugs in plasma
Half-lives
Adherence Over Time
UNC ENLIGHTEN study: (Establishing Novel Antiretroviral Imaging for Hair To End Nonadherence)
4
Secondary Objective1. Assess the ability of blood matrices to discriminate changes in
Truvada® dosing patterns within one month. Mitra
Primary Objective
1. Assess dose-proportionality of tenofovir/emtricitabine (TDF/FTC)
maraviroc (MVC), and dolutegravir (DTG) in hair compared to:
a) Plasma
b) Peripheral Blood Mononuclear Cells (PBMCs)
c) Upper Layer Packed Cells (ULPCs)
d) Dried Blood Spots (DBS)
e) Whole blood microsamplers (Mitra)
NCT03218592
Methods: Study Allocation Scheme
5
Single Dose
on Day 0Daily Dosing
Dose
Proportionality
Single-center, open-label, 3-arm, directly observed therapy, triple phase study
Study Site: UNC Clinical & Translational Research Center (CTRC) Chapel Hill, NC
0
(n=4)
Doses/Week
1
(n=4)
3
(n=4)
Phase 1:
28 days
Phase 2:
28 days
Phase 3:
28 days
Days 3, 7, 14, 21, 28:
Hair Samples, Plasma, PBMC, ULPC, DBS, Mitra
and Adverse Event Monitoring
NCT03218592
Tenofovir/
emtricitabine
(n=12)
Methods: Data Analysis
6
• TFV and FTC (measured in the plasma), and TFVdp and FTCtp (measured in cells)
by LC-MS/MS.
1.) Patterson, KB et al. Sci Transl Med. 2011 Dec 7;3(112):112re4
2.) Cottrell, ML et al. J Infect Dis. 2016 Jul 1;214(1):55-64
3.) Adams, JL et al. J Acquir Immune Defic Syndr. 2013 Mar 1;62(3):260-6
LLOQPlasma
(ng/mL)1
PBMC
(ng/mL lysate)2
ULPC
(fmol/mL)3
DBS
(fmol/3mm punch)4
Mitra
(fmol/sample tip)5
TFV/TFVdp1.0 0.02
10,000100 300
FTC/FTCtp 5,000
- All BLQ values imputed as 0.5 * LLOQ
4.) Schauer, AP et al. J Pharm Biomed Anal. 2018 Feb 5;149:40-45
5.) Schauer, AP et al. Mass Spectrometry:Applications to the Clinical Lab
2019. Atlanta, GA. Abstract 296390. Poster MP067
• Concentrations reported as median (25th-75th percentile).
• Pearson correlations were used to described the dose-concentration response
relationship within each blood matrix (SigmaPlot®, v13.0).
• Dose-concentration effect was then evaluated using a tobit linear mixed effects model
predicting concentrations based on the number of doses per week (SAS/STAT®, v15.1).
– Target β estimate > 1.0
Results: Selecting Steady State Conditions
7
TFV/TFVdp Concentrations
after 28 days of Daily Dosing
FTC/FTCtp Concentrations
after 28 days of Daily Dosing
Assumed Css
Sampling Days
TFV and FTC TFVdp FTCtp
3 + 7 28 14 + 21 + 28
PlasmaPlasma
DBSDBS
PBMC
PBMC
MitraMitra
ULPC
ULPC
TFV in Plasma (t1/2 = 17 hrs)
Results: Plasma and PBMCs
8TFV = tenofovir FTC = emtricitabine
TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate
TFVdp in PBMC (t1/2 = 6 days)
TFV in Plasma
Phase 3Phase 2
7 doses/week (n=12)
3 doses/week (n=4)
1 dose/week (n=4)
0 doses/week (n=4)
7 doses/week (n=12)
3 doses/week (n=4)
1 dose/week (n=4)
0 doses/week (n=4)
Phase 3Phase 2
TFVdp in PBMC
TFV in Plasma (t1/2 = 17 hrs)
Results: Plasma and PBMCs
9TFV = tenofovir FTC = emtricitabine
TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate
FTC in Plasma (t1/2 = 10 hrs)
TFVdp in PBMC (t1/2 = 6 days) FTCtp in PBMC (t1/2 = 1.6 days)
β = 0.81 [95%CI: 0.64-0.98]
r = 0.85
β = 1.37 [95%CI: 1.25-1.48]
r = 0.95
β = 1.53 [95%CI: 1.20-1.86]
r = 0.92
β = 1.17 [95%CI: 1.07-1.28]
r = 0.95
Target β estimate > 1.0
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Results: DBS
TFV = tenofovir FTC = emtricitabine
TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate
DBS = Dried Blood Spot
TFVdp in DBS (t1/2 = 17 days) FTCtp in DBS (t1/2 = 1.5 days)
β = 0.36 [95%CI: 0.25-0.46]
r = 0.72β = 0.92 [95%CI: 0.72-1.13]
r = 0.77
Target β estimate > 1.0
11
Results: ULPC and Mitra
TFV = tenofovir FTC = emtricitabine
TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate
ULPC = Upper Layer Packed Cells
Mitra = whole blood microsampler
TFVdp in ULPC (t1/2 = 17 days) FTCtp in ULPC (t1/2 = 1.5 days)
TFVdp in Mitra (t1/2 = 17 hrs) FTCtp in Mitra (t1/2 = 1.5 days)
β = 0.44 [95%CI: 0.35-0.52]
r = 0.84
β = 0.83 [95%CI: 0.71-0.94]
r = 0.89
β = 0.42 [95%CI: 0.25-0.59]
r = 0.63
β = 0.33 [95%CI: 0.17-0.49]
r = 0.62
Target β estimate > 1.0
Limitations
• Secondary endpoint was not powered as for our primary endpoints.
• Values were imputed for 0 doses/week for log transformation of data.
• Despite the use of the tobit linear mixed effects model because of left censoring due to
BLQ values, data were still non-linear in some matrices.
12
Conclusions
Intermediate half-lives TFVdp and FTCtp in PBMCs are best in detecting changes in
dosing patterns over one month.
If using DBS, FTCtp concentrations can be used for recent dosing. In this analysis:
- Concentrations < 300 fmol/3mm punch = taking < 7 doses/week
- Concentrations < 140 fmol/3mm punch = taking < 3 doses/week
13
TFV/TFVdp
β Estimate [95% CI]
TFV/TFVdp
Pearson’s r
FTC/FTCtp β
Estimate [95% CI]
FTC/FTCtp
Pearson’s r
PBMC 1.17 [1.07-1.28] 0.95 1.37 [1.25-1.48] 0.95
ULPC 0.42 [0.25-0.59] 0.63 0.83 [0.71-0.94] 0.89
DBS 0.36 [0.25-0.46] 0.72 0.92 [0.72-1.13] 0.77
Mitra 0.33 [0.17-0.49] 0.62 0.44 [0.35-0.52] 0.84
Acknowledgements:
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Future Directions
• Exploring measuring both TFV and FTC concentrations, along with measuring
metabolite concentrations, in one DBS sample.
Sponsors:R01 AI122319; Division of AIDS, NIAID, US National Institutes of Health
P30 AI50410: UNC Center for AIDS Research, NIAID, US National Institutes of Health
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ENLIGHTEN Study Team
15Department Name
QUESTIONS?