Transcript R-Maseratix

Darunavir/Cobicistat: una nuova
opzione terapeutica a dose fissa
R. Maserati
Pavia
1
2
Numero di compresse/ di somministrazioni
Potenza virologica
Effetti avversi
Durabilità
Una classe in evoluzione…………..
3
ARTEMIS: Viral load <50 copies/mL
to Week 96 (ITT-TLOVR)
Patients with VL <50 copies/mL (% [±SE])
100
DRV/r qd (N=343)
LPV/r qd or bid (N=346)
80
79%
71%
60
40
Estimated difference in response vs LPV/r for non-inferiority:
PP = 8.4% (95% CI 1.9;14.8) p<0.001
20
Estimated difference in response vs LPV/r for superiority:
ITT = 8.3% (95% CI 1.8;14.7) p=0.012
0
0
8
16
24
36
48
60
Time (weeks)
72
84
96
ARTEMIS: change in median lipid levels up to Week 96
DRV/r baseline
LPV/r baseline
DRV/r Week 96
LPV/r Week 96
Median concentration mg/dL
193
2.3 200
200
161
1.7 150
150
NCEP cut-off
182
156
158
123
100
105
105
50
106
0.6
0
0
Triglycerides
89
1.1 100
105
91
43 48 44
50
53
0
Total
cholesterol
LDL
calculated
HDL
Baraldi E, et al. IAS 2009. MOPEB034
Once-daily Regimens Are Preferred by
Patients: APPT-1 Study
Once daily
Twice daily as divided dose
100
n=504
Patients preferring (%)
90
93
80
84
70
69
60
62
50
40
30
38
59
41
31
20
16
10
7
0
>8 pills
8 pills
Moyle G. Int J STD AIDS 2003;14(Suppl.1):34–36
6 pills
4 pills
3 pills
Better adherence with once-daily antiretroviral Regimens
One-daily
Author [ref]
Year
Benson
2004
Boyle
2008
Eron
2004
Gallant
2006
Kubota
2006
Molina
2007
Parienti
2007
Porthsmouth
2005
Rode
2008
Ruane
2006
Sosa
2005
META-ANALYSIS:
Twice-daily
N/Mean/SD N/Mean/SD
294/90/18.3
205/87.1/31
19/94/18.3
244/90/11.7
411/94.3/15.8
115/99.8/11
27/95/6.2
22/96.1/3.6
310/90.8/20.7
18/85.4/9.1
119/93/18.3
146/90/17.2
95/77.1/31
19/92/17.2
243/87/14
195/92.9/15.7
75/92.6/9.4
25/93.3/8.3
21/95.8/3.1
296/83.8/20.7
13/84.4/12
117/93/17.2
-10
Weight
Association measure
(%)
with 95% CI
10.34%
4.53%
2.40%
12.91%
12.07%
11.53%
9.30%
13.50%
10.74%
4.34%
8.34%
100%
0
10
20
Mean difference in adherence rate (%)
Favours twice-daily Favours once-daily
Adapted from Parienti J-J et al Clin Infect Dis 2009; 48:484–488.
2.88 (0.98 to 4.78)
VF
AEs + DEATH
OWN DECIS.
%
2
1
3
4
settimane
8
Da dove si partiva…..
 PREZISTA (darunavir, DRV) approvato nel giugno 2006
 DRV  “PK boosting” con ritonavir
 Ritonavir (RTV) già usato a dosaggio aumentato (600 mg bid )
come PI. Da tempo viene impiegato per il suo effetto di „PK
boosting“ al dosaggio di 100 mg per compressa.
9
Cobicistat – una nuova opzione di „boosting“
10
Cobicistat – una nuova opzione di „boosting“
11
REZOLSTA = 1 Compressa di DRV/cobi
 Impiego più comodo di DRV !!
Invece di:
12
DDI: RTV vs. COBI
ARV Drugs Mechanisms That May Affect or
Enzymes That Metabolize or Are
by Drug
Be Affected by Oral Absorption
Induced or Inhibited by ARV Drugs
Class
of ARV Drugs
Increasing
Gastric pH
Cationic
Chelation
P-glycoprotein
CYP
CYP
CYP
Substrate Inhibitor Inducer
Other
Mechanisms
of Drug
Interactions
UGT1A1
Pharmacokinetic (PK) Enhancers (Boosters)
Ritonavir
(RTV)
Cobicistat
(COBI)
...
...
...
...
Substrate, 3A4, 2D6 3A4, 2D6 1A2,
inhibitor
(lesser 2C8,
extent) 2C9,
2C19
Inhibitor 3A4
3A4, 2D6
...
Inducer
...
...
...
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arvguidelines/367/overview - Table 17
13
DIVERSO EFFETTO SUGLI ENZIMI DEL CITOCROMO P 450 (CYP)
DA PARTE DI COBICISTAT (COBI) E RITONAVIR (RTV)
I NUMERI RAPPRESENTANO LE IC50 IN MICROMOLI/L. VALORI PIU’ BASSI
INDICANO UN MAGGIORE EFFETTO INIBITORIO
Nathan B, et al, 2013
14
Secrezione tubulare di creatinina
Proximal Tubule
ATP
Pgp
ATP
ATP
MRP2
MATE1
OCT2
ATP-Binding
Cassette
BCRP
H+
Creatinine
Dolutegravir
Blood
(Basolateral)
Cobicistat
Ritonavir
Cimetidine
Trimethoprim
Active Tubular Secretion
MATE2-K
Solute Carrier
OCTN1
OCTN2
Urine
(Apical)
Gallant JE, et al. JID 2013
16
Study TMC114IFD1001
► REZOLSTA vs PREZISTA/r
Open label, randomized, phase 1, three-way crossover trial
• 36 healthy HIV-negative volunteers
Inclusion Criteria
• ≥ 18 years
Treatment Phase – 6 weeks
Treatment A
DRV + ritonavir
800 + 100 mg QD
n = 32
Washout
10 days
≥ 7 days
Primary Objective
Treatment C
Treatment B
DRV/c –G003
800/150 mg QD
n = 33
10 days
Washout
≥ 7 days
DRV/c –G004
800/150 mg QD
n = 33
Follow-Up
10 days
7 days
Adapted from Kakuda et al. J Clin Pharmacol, 2014 March
To assess the relative oral bioavailability of the fixed-dose combinations of darunavir/cobicistat (G003; G004) compared with
the co-administration of darunavir and ritonavir as single agents under fed and steady-state conditions
Secondary endpoints:
Short-term safety and tolerability
1.
Kakuda et al. J Clin Pharmacol 2014
Study TMC114IFD1001
► REZOLSTA is bioequivalent to PREZISTA/r
9,000
DRV/r 800/100mg qd as single agents (n=32)
Plasma concentration of
DRV (ng/mL) (mean ± SD)
8,000
DRV/COBI 800/150mg qd as FDC (G003) (n=33)
7,000
DRV/COBI 800/150mg qd as FDC (G004) (n=33)
6,000
5,000
4,000
3,000
2,000
1,000
0
0
3
6
9
12
Time (hours)
15
18
1.
21
24
Kakuda TN et al. 13th IWCPHT. Abstract O_20
2. Kakuda et al. J Clin Pharmacol 2014
18
Multiple-dose pharmacokinetics and statistical analyses of DRV
800mg with COBI 150mg (FDC) versus RTV 100mg
DRV
pharmacokinetics
(mean ± SD)
DRV/r 800/100mg qd,
(n=32)
DRV/COBI
DRV/COBI
800/150mg qd 800/150mg qd as
as FDC (G003)
FDC (G004)
(n=33)
(n=33)
C0h, ng/mL
2,015 ± 852.3
1,504 ± 1,114
1,478 ± 933.8
C24h, ng/mL
1,928 ± 717.9
1,493 ± 924.2
1,566 ± 885.1
Cmin, ng/mL
1,506 ± 630.1
1,146 ± 783.3
1,224 ± 680.6
Cmax, ng/mL
6,997 ± 1508
6,615 ± 1299
6,917 ± 1394
78,090 ± 20,640
74,080 ± 19780
76,490 ± 20900
AUC24h, ng•h/mL
LS means (90% CI)
C0h, ng/mL
0.65 (0.55-0.076)
0.68 (0.57-0.80)
Cmin, ng/mL
0.69 (0.60–0.81)
0.74 (0.63–0.86)
Cmax, ng/mL
0.97 (0.92–1.01)
1.00 (0.96–1.04)
AUC24h, ng•h/mL
0.97 (0.92–1.02)
0.99 (0.94–1.04)
SD=standard deviation; LS = least squares
•
•
The parameters Cmax and AUC24h were within the limits of bioequivalence between DRV + r and both FDCs of DRV/c.
Darunavir C0h and Cmin with the FDCs were lower as with darunavir co-administered with low-dose ritonavir
Study TMC114IFD1001
► REZOLSTA is bioequivalent to PREZISTA/r
Ratio of LS means (90% CI)
G004 AUC24h
AUC24h
G003 AUC24h
G004 Cmax
Cmax
G003 Cmax
0.5
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
1.
1.5
Kakuda TN et al. 13th IWCPHT. Abstract O_20
20
2. Kakuda et al. J Clin Pharmacol 2014
Study TMC114IFD1001: Conclusions
 Both DRV/COBI fixed-dose combination formulations
achieved comparable values for Cmax and AUC24h
 DRV Cmin and C0h were lower when combined with COBI than
with RTV:
– This is not considered clinically relevant
 No apparent relationship between DRV pharmacokinetics and
antiviral activity/safety (based on ARTEMIS and ODIN data)
Kakuda TN, et al. „Pharmacokinetics of Darunavir in Fixed-Dose Combination with Cobicistat Compared with Coadministration of Darunavir and
Ritonavir as Single Agents in Healthy Volunteers” J Clin Pharmacol, 2014 March
21
TMC114IFD1003
DRV/COBI – bioequivalence (BE) study
► FDC versus single agents
DRV/COBI
DRV + COBI
DRV/COBI
Food effect
DRV + COBI
BE Fasted
BE Fed
 Study design of phase 1, open-label, randomized, 3-panel,
cross-over study (NCT01619527)
DRV/COBI fasted
DRV/COBI high fat
1. Kakuda TN, et al. Antivir Ther 2014
22
Con CIBO
A DIGIUNO
Conclusions

The darunavir/cobicistat FDC (formulation G006; 800/150mg) was bioequivalent to darunavir (800mg) and cobicistat
(150mg) administered as single agents, under fed and
fasted conditions.

A food effect was observed for darunavir, as Cmax, AUClast and
AUC∞ were all higher with a high-fat meal compared with fasted
conditions for the FDC these food effects with darunavir are
consistent with the food effect reported with darunavir/ritonavir,
where a 1.47-fold increase in AUClast was seen in volunteers
receiving a high-fat breakfast compared with fasting conditions15

The darunavir/cobicistat FDC should therefore be taken
with food.

Administration of a single dose of darunavir/cobicistat 800/150mg,
either as the FDC or as single agents, was generally well tolerated,
with no new safety issues identified.
GS-US-216-0130
GS-US-216-0130
Introduction
 This Phase IIIb trial evaluated the pharmacokinetics,
pharmacodynamics, efficacy, safety and tolerability of
darunavir and cobicistat, given with two fully active
NRTIs, in HIV-1-infected, treatment-naïve and treatmentexperienced patients with no darunavir RAMs (GS-US-2160130; NCT01440569)
GS-US-216-0130
Patients and study design
Phase IIIb, open-label, single-arm, 48-week, multicenter study
DRV/COBI
800/ 150 mg QD
Inclusion criteria
2 NRTIs
48 Weeks
•Adult patients with HIV-1 infection
•Viral plasma load >1000 copies/mL
•Patients were treatment-naïve or –experienced
(on stable antiretroviral regimen for ≥12 weeks)
•No DRV resistance-associated mutations1
Primary endpoint
•
Occurrence of any treatment-emergent grade 3 or grade 4 AE up to Week 24
Secondary endpoint
•
•
Occurrence of any treatment-emergent AE
Antiviral efficacy at Weeks 24 and 48
(VL <50 copies/mL by the FDA snapshot algorithm,missing=failure analysis)
GS-US-216-0130
Baseline demographics and characteristics
All patients (N=313)
Male, n (%)
Age, years, median (range)
Race, n (%)
White
Black or African heritage
Asian
Other
Exp (N=18)
Naives (N=295)
279 (89)
35 (18–72)
187 (60)
108 (35)
4 (1)
14 (4)
Median log10 VL, HIV-1 RNA copies/mL
(range)
VL >100,000 HIV-1 RNA copies/mL, n (%)
4.8 (2.6–7.0)
131 (42)
9 (50)
122 (41.9)
Median CD4+ count, cells/mm3 (range)
CD4+ count ≤200 cells/mm3, n (%)
361 (5–1473)
59 (19)
12 (66.7)
47 (16.0)
Treatment naïve, n (%)
295 (94)
Asymptomatic HIV infection, n (%)
251 (80)
Co-infection with HBV, n (%)
5 (2)
Co-infection with HCV, n (%)
8 (3)
Median eGFRcg, mL/min (range)
114 (67–321)
GS-US-216-0130
Efficacy

Virologic response defined as VL <50 copies/mL and evaluated by FDA
snapshot analysis
•
Week 24: 82%
(285/313; 95% CI: 78–87%)
•
Week 48: 81%
(253/313; 95% CI: 76–85%)
GS-US-216-0130
Efficacy

Virologic responses with
darunavir/cobicistat
800/150mg once daily
were similar to historic
data for
darunavir/ritonavir
800/100mg once daily
from ARTEMIS1 and ODIN2
ARTEMIS
ODIN
1. Ortiz R, et al. AIDS 2008;22:1389–97
2. Cahn P, et al. AIDS 2011;25:929–39
GS-US-216-0130
Efficacy

Median CD4+ cell count increased by 167 cells/mm3
(range –193 to 1086 cells/mm3) from baseline to Week 48
GS-US-216-0130
Week 48 Treatment-Naïve Subgroup Analysis
Objective
• The objective of this subanalysis is to present the 48-week
efficacy, virology, safety, tolerability, pharmacokinetics, and
pharmacodynamics for the treatment-naïve cohort
3
3
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Safety, Efficacy, Virology, and
Pharmacokinetic Assessments
•
•
•
•
•
The primary endpoint was any grade 3 or grade 4 treatment-emergent
AE occurring up to Week 24
Secondary outcome measures included any treatment-emergent AE
and antiviral efficacy at Weeks 24 and 48
Resistance testing was performed in patients meeting the criteriaᵃ
Sparse blood samples for darunavir were collected at study visits from
all patients up to Week 48
Pharmacodynamic analyses explored any relationship between
darunavir pharmacokinetics and
–
–
Absence or presence of selected AEs (diarrhea, nausea, rash, or vomiting)
and worst change in laboratory parameters
Virologic response (VL <50 copies/mL)
ᵃVL ≥400 copies/mL and suboptimal virologic response (VL <1 log10 copies/mL reduction from baseline and
≥50 copies/mL at Week 8, confirmed at Week 12), or who had confirmed virologic rebound (VL <50
copies/mL followed by confirmed VL ≥400 copies/mL or >1 log10 copies/mL increase in VL from the nadir) or
discontinued (after Week 8) while receiving study drugs.
AE, Adverse Event; VL, Viral Load
3
4
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Week 48 Treatment-Naïve Subgroup
Analysis: Study Disposition
• Treatment-naïve patients included 94% of the overall trial
population (295/313 patients)
• Through 48 weeks, 13.9% (41/295) of patients discontinued,
mostly for AEs (n=15) and loss to follow-up (n=11)
3
5
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Safety and Tolerability
•
The primary endpoint of any grade 3 or 4 treatment-emergent AEs occurring
up to 24 weeks, regardless of causality, was observed in 15 patients (5%)
•
Week 48 data:
Incidence, n (%)
Any AE
Any drug-related AE
Serious Aes (grade 3-4)
AEs leading to discontinuation
270 (92)
122 (41)
21 (7)
15 (5)
AEs any grade, regardless of causality and occurring in ≥10% of
patients
Diarrhea
Nausea
Upper respiratory tract infection
Headache
80 (27)
69 (23)
43 (15)
35 (12)
3
6
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Safety and Tolerability (cont.)
• Three serious AEs (immune reconstitution syndrome, rash, and
maculopapular rash) were felt to be related to the study drug and
were reported in 1 patient each. There were no deaths
• The most common reasons for study drug discontinuation due to
an AE were rash and maculopapular rash (n = 3 for each), and
hypersensitivity and nausea (n = 2 for each)
• Over 48 weeks treatment-emergent grade 3 or 4 laboratory
abnormalities occurred in 58 (20%) patients
3
7
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Safety and Tolerability (cont.)
Incidence, n (%)
Grade 3-4 AEs occurring in ≥2 patients
Hypersensitivity
Peripheral neuropathy
Maculopapular rash
All patients (N=295)
Grade 3
2 (1)
2 (1)
2 (1)
Grade 4
1 (0.3)
0
0
Treatment-emergent grade 3-4 laboratory abnormalities occurring in ≥2% patients (N = 292)
Increased creatine kinase
Increased alanine aminotransferase
Increased aspartate aminotransferase
Increased amylase
Increased lipase
22 (8)
9 (3)
7 (2)
7 (2)
7 (2)
•
Serum creatinine increased from baseline by Week 2 (median, 0.10
mg/dL) and then remained stable through Week 48 (median, 0.08 mg/dL
increase from baseline)
–
One patient discontinued because of a renal tubular disorder; the event was
categorized as mild and not serious, and resolved upon changing therapy to
darunavir/ritonavir plus abacavir/lamivudine
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Virologic response (%)
Patients Who Achieved
<50 Copies/mL at 48-Weeks (FDA Snapshot
Analysis) According to Baseline VL
•
•
•
100
80
83
84
81
Overall
(N = 295)
Baseline VL
≤100,000
copies/mL (n = 173)
Baseline VL
>100,000 copies/mL
(n = 122)
60
40
20
0
Virologic response was 84% (n = 247/295; CI: 79%-87%) at Week 24, and 83% (n =
244/295; CI: 78%-87%) at Week 48
The median CD4+ cell count increased by 169 cells/mm3 (range1931,086
cells/mm3) from baseline to Week 48
In ARTEMIS, the Week 48 virologic response was 83% (285/343) using the FDA
snapshot analysis
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Patients who Achieved
VL <50 copies/mL (%)
Virologic Response (Observed <50 Copies/mL at
Week 48) by Darunavir PK Quartile
100
80
60
40
20
0
100
80
60
40
20
0
97
93
>78,400-99,100
>99,100-117,000
96
31,70078,400
98
>117,000-218,000
AUC24h quartiles (ng•h/mL)
96
99
72-1,170
>1,170-1,985
91
>1,985-2,770
98
>2,770-6,530
C0h quartiles (ng/mL)
•No clinically relevant relationships between darunavir AUC24h or
C0h and the absence or presence of AEs and worst change in
laboratory abnormalities at Week 48
AUC24h, Area Under the Concentration–Time Curve over 24 Hours; C0h, Predose Plasma Concentration;
VL, Viral
40
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Week 48 Treatment-Naïve Subgroup
Analysis:
Efficacy (FDA Snapshot Analysis )
Virologic Failures (at Week 48)
VL >50 copies/mL
Discontinued drug for other reasons, last available VL ≥50 copies/mL
Discontinued due to lack of efficacy
No Virologic Data (at Week 48)
Discontinued drug due to AEs
Discontinued drug for other reasons, last available VL <50 copies/mL
Missing data during the window, but were on drug
n=24 (8%)
9
15
0
n=27 (9%)
15
10
2
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Week 48 Treatment-Naïve
Subgroup Analysis: Virology
• One of the 8 patients who met the criteria for
resistance testing was found to harbor a new
primary RAM (M184V), which emerged while the
patient was receiving emtricitabine
– The isolate showed phenotypic resistance to both FTC/3TC
GS-US-216-0130 Week 48 Treatment-Naïve Subgroup Analysis
Conclusions
• Darunavir/cobicistat 800/150mg once daily and 2 N[t]RTIs were
well tolerated during the 48-week study, with safety findings
consistent with those previously reported for darunavir and for
cobicistat1,2
• This once-daily darunavir/cobicistat-based regimen yielded an 83%
virologic response rate in treatment-naïve patients comparable to
that in ARTEMIS (83%; FDA snapshot analysis). As in ARTEMIS,
virologic responses were similar irrespective of baseline VL
• There was no relationship between darunavir PK (AUC24h or C0h)
and virologic response or safety, consistent with historical data for
darunavir/ritonavir 800/100 mg once daily3
1. Ortiz R, et al. AIDS. 2008;22(12):1389-1397.
2. Gallant JE, et al. J Infect Dis. 2013;208(1):32-39.
3. Kakuda TN, et al. J Antimicrob Chemother. 2014;69(10):2591-605.
43
Pooled data from the DRV/r 800/100mg OD arms of the ARTEMIS and
ODIN studies used as comparator data for the GS-216-0130 study with
DRV/cobi 800/150mg OD
indirect comparison of the virological response at Wk 48 of
DRV/cobi in the Phase IIIb study vs.
DRV/r observed in previous Phase III trials
TESTING FOR NON-INFERIORITY !!
Methods
Patient population and studies
Patients were HIV-1-infected, treatment-naïve or experienced with no darunavir RAMs at baseline.
Patient level data on once-daily darunavir 800mg treatment
from three Phase III trials were included for analysis of
virological response at Week 48, assessed with the FDA
Snapshot algorithm pooled data from the
darunavir/ritonavir 800/100mg once-daily arms of the
ARTEMIS and ODIN studies were used as comparator
data for the GS-216-0130 study with darunavir/cobicistat
800/150mg once daily
Inclusion and exclusion criteria were largely similar among
the three trials
Statistical Analysis





The analysis focused on the 48-week results of each of the
studies, in order to have a common timepoint.
Unadjusted virological response rates (HIV-1 RNA <50 copies/mL
at Week 48, FDA Snapshot analysis) were compared between
darunavir/cobicistat and pooled data for darunavir/ritonavir, and
noninferiority evaluated.
A sensitivity analysis of virological response (HIV-1 RNA <50
copies/mL) at Week 48, based on the time-to-loss of virological
response (TLOVR) algorithm, was also conducted.
To adjust the relative treatment effect for confounding bias,
covariates were added in a logistic regression model (age, gender,
race, baseline CD4+ T-cell counts (cell/mm3), baseline HIV-1 RNA
(log10 copies/mL), HIV disease status and previous antiretroviral
use)
The noninferiority margin was set at 0.531 on the odds-ratio
scale, which corresponded to a 12% noninferiority margin on
the risk-difference scale
Figure 1. Observed response rates (Snapshot and
TLOVR) at Week 48 for darunavir/ritonavir and
darunavir/cobicistat.
Adjusted response rates
Table 3 shows the effects of the treatment regimen on virological response when
adjusted for the differences in baseline characteristics and patient adherence, using
standard statistical methods to adjust for confounding factors
the 95% CI lower boundaries for adjusted odds ratios comparing darunavir/cobicistat
with darunavir/ritonavir at Week 48 (Snapshot: 0.576 and TLOVR: 0.534), were above
the noninferiority margin of 0.531, thus demonstrating non-inferiority.
Conclusions
This analysis of the pooled Phase III data of the 800mg once-daily
darunavir dose consistently showed darunavir/cobicistat to have
noninferior efficacy compared to darunavir/ritonavir.
The results indicate that the choice of boosting agent (cobicistat
versus ritonavir) has no impact on virological outcome for
darunavir.
This finding is as expected, based on the similar darunavir
concentrations obtained with cobicistat- and ritonavir-boosted darunavir.
Once-daily darunavir/cobicistat is appropriate for use in HIV-1-infected,
treatment-naïve and treatment-experienced patients with no darunavir
RAMs.
The fixed-dose combination tablet of darunavir/cobicistat
800/150mg eliminates the need to take a boosting agent in a
separate tablet when taking once-daily darunavir, reducing the pill
burden for patients.
REZOLSTA
Drug-Drug Interaction Profile
 No drug-drug interaction studies with DRV/COBI have
been conducted
 The drug-drug interaction potential of the FDC DRV/COBI is
based on the interactions observed with the single agents
– COBI, like RTV, is a potent CYP3A inhibitor so drugs that are CYP3A
substrates and affected by DRV/rtv are also likely to have a similar
interaction with DRV/COBI
– Unlike RTV, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19 or UGT1A1. Caution is required during the first two
weeks of treatment with COBI, particularly if doses of any
concomitantly administered medicinal products have been titrated or
adjusted during use of ritonavir
51
Principali differenze di interazione tra
DRV/r e DRV/c
 Per la maggior parte, interazioni
coincidenti con quelle di DRV/r
 DRV/c NON è invece raccomandato con:
– EFV
– ETV
– NVP
– Rifabutina/Rifapentina
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54
55
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The future: more ARVs, more FDCs
and STRs
Protease inhibitors
ATV/COBI
DRV/COBI
DRV/COBI/FTC/TAF
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