1. Nancy Sheehan
Québec Antiretroviral Therapeutic Drug Monitoring Program,
McGill University Health Centre, Pharmacy Department, 1001
boulevard Décarie, Montréal (Québec) H4A 3J1, Canada
@: nancy.sheehan@umontreal.ca
BACKGROUND
 StribildTM (elvitegravir (EVG)/ cobicistat (cobi)/
emtricitabine/ tenofovir disoproxil fumarate) is
indicated for the treatment of antiretroviral (ARV)-
naïve HIV-infected patients;
 An off-label ARV regimen of darunavir (DRV) and
Stribild is of interest for patients with resistance who
require a low pill burden and/or a ritonavir (rtv)
sparing regimen;
 Lower trough concentrations (Ctau) of darunavir
have been documented when administered with EVG
and/or cobi.
STUDY OBJECTIVES
To present the DRV concentrations and virologic
response of treatment-experienced HIV-1-infected
subjects receiving DRV 800 mg and Stribild once
daily.
RESULTS
DISCUSSION / CONCLUSIONS
Poster 50
16th International Workshop on
Clinical Pharmacology of HIV and
Hepatitis Therapy
Washington DC, USA
26-28 May 2015
ACKNOWLEDGMENTS
CONTACT INFORMATION
Low darunavir concentrations in patients receiving StribildTM (elvitegravir / cobicistat /
emtricitabine / tenofovir disoproxil fumarate) and darunavir once daily
Ricard F1,2, Wong A1,2, Lebouché B1,3, Therrien R4, Lachance MJ5, Munoz M6,7, Thibeault D8, Sheehan NL1,2,9
1Chronic Viral Illness Service, McGill University Health Centre (MUHC), Montréal, Canada; 2Pharmacy Department, MUHC, Montréal, Canada; 3Department of Family Medicine,
McGill University, Montréal, Canada; 4Unité hospitalière de recherche, d’enseignement et de soins sur le SIDA (UHRESS), Hôpital Hôtel-Dieu, Centre hospitalier de l’Université de
Montréal (CHUM), Montréal, Canada; 5Pharmacy Department, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada; 6UHRESS, Hôpital Notre-Dame, CHUM, Montréal,
Canada; 7Clinique Médicale L’Actuel, Montréal, Canada; 8Biochemistry Department, MUHC, Montréal, Canada; 9Faculty of Pharmacy, Université de Montréal, Montréal, Canada
METHODS
Retrospective case series
Inclusion criteria
All patients who had DRV therapeutic drug monitoring
(TDM) done at least once while on Stribild.
Pharmacokinetic sampling and analysis
DRV concentrations were measured by a validated
LC-MS/MS assay. Limit of quantification for DRV for
the assay was 0.01 mg/L;
For samples collected > 10 hours post-dose: DRV
Ctau was extrapolated using mean DRV elimination
half-life (7.57h with DRV 800mg/ EVG 150mg/ cobi
150mg daily);
Patients with no DRV resistance-associated
mutations (RAM): Ctau target 0,17 mg/L (3 x protein
adjusted wild-type IC50 of 0.055 mg/L);
Patients with DRV-RAMs: genotypic inhibitory
quotient (GIQ) target 2.15 mg/L/mutation;
GIQ mutations included were those used in the GIQ
study by Bonora et al (9th HIV PK Workshop, 2008):
11I, 32I, 33F, 47V, 50V, 54L/M, 73S, 76V, 84V and
89V.
Statistical analysis
Descriptive statistics using medians and interquartile
ratios.
 No apparent DRV PK/PD relationship in patients without DRV-RAMs in 48 week studies.
Low DRV concentrations, however, may possibly influence durability of virologic response.
 Considering 3 / 8 subjects with viral blips, it would be preferable to consider another
treatment option until more clinical data is available; if this regimen is prescribed, closer
follow-up of viral load is indicated.
 Further analyses are required to investigate the cause of low DRV exposure. Some
hypotheses are:
Induction of cobi metabolism by DRV and EVG decreasing cobi exposure and related
CYP3A4 inhibition at the end of the dosing interval;
Similar intestinal CYP3A4 inhibition with cobi compared to rtv (similar Cmax) but lower
hepatic CYP3A4 inhibition with cobi over a 24 hour period compared to rtv.
We sincerely thank the patients. We are grateful to Gilead
Sciences Canada for an unrestricted research grant. This
study was also supported in part by the FRQS AIDS and
Infectious Diseases Network.
DRV 800/cobi vs
DRV/rtv daily1:
DRV Ctau  30.6%
DRV 800/EVG/cobi vs
DRV800/cobi daily2
DRV Ctau  21%
EVG Ctau  52%
 A total of 8 subjects were identified
 Experienced population
 Past virologic failure PIs 88%
 Median # ARV regimens in past 9
 1 subject with 1 (33F) DRV RAM
7 (88%) subjects had VL < 40 copies/mL at
the last time of TDM
3 patients had virologic blips
100% adherence reported by subjects
Median DRV Ctau 0.273 mg/L (IQR: 0.164-
0.501)
80% lower than historical median of 1.36
mg/L with DRV/RTV daily
In 2 patients DRV Ctau ↓ 25 and 83%,
respectively, compared to DRV/rtv
 52.6% DRV concentrations were
subtherapeutic
↑ DRV 1200 mg provided little improvement
1. Kakuda et al, 13th HIV PK Workshop, 2012;
2. Ramanathan et al, 13th HIV PK Workshop, 2012