Transcript Effect of extrinsic and intrinsic factors on the

Effect of extrinsic and intrinsic factors on the
pharmacokinetics of darunavir/ritonavir (DRV/r)
in HIV-1 patients: results of a randomised,
controlled, Phase III study (TITAN)
VJ Sekar,1 E De Paepe,2 B Van Baelen,2
F Tomaka,1 S Spinosa-Guzman,2 M De Pauw,2
T Vangeneugden,2 A Vandevoorde,2 P Vis,3 RM Hoetelmans2
1Tibotec
Inc., Yardley, PA, USA; 2Tibotec BVBA, Mechelen, Belgium;
3Exprimo NV, Mechelen, Belgium
TITAN (TMC114-C214) study design
Screening phase
(4 weeks)
• LPV-naïve,
treatmentexperienced
Treatment phase
(96 weeks)
DRV/r 600/100mg bid
+ OBR (n=298)
• Viral load >1,000
copies/mL
• Stable HAART
for ≥12 weeks
(STI allowed)
I
Rollover and
follow-up
phase after
1 and 4
weeks
LPV/r 400/100mg bid
+ OBR (n=297)
I
595 patients
randomised
and treated
DRV/r = darunavir/ritonavir; LPV/r = lopinavir/ritonavir
STI = structured treatment interruption; OBR = optimised background regimen
Week 48 primary and secondary
efficacy outcomes in TITAN
Secondary endpoint
viral load <50 copies/mL
Primary endpoint
viral load <400 copies/mL
p=0.008*
80
67%
60
40
20
0
DRV/r
LPV/r
600/100mg bid 400/100mg bid
Proportion of patients (%)
Proportion of patients (%)
80
p=0.005*
77%
71%
60
60%
40
20
0
DRV/r
LPV/r
600/100mg bid 400/100mg bid
*p-values of superiority derived from a logistic regression model including treatment and
baseline log10 viral load as covariates and use of NNRTIs in the OBR as a factor
Valdez-Madruga J, et al. Lancet 2007;370:49–58
TITAN PK analysis:
background and objective
• The efficacy, safety, pharmacokinetics and
pharmacodynamics of DRV/r 600/100mg bid were
evaluated in POWER 1, 2 and 3 as well as TITAN
–
no clinically relevant relationships between DRV exposure
and efficacy or safety were observed1–3
• This analysis assessed the effect of extrinsic and
intrinsic factors on DRV pharmacokinetic (PK)
parameters at Week 48 in the TITAN trial
1.Sekar V, et al. 13th CROI 2006. Abstract J-121
2. Sekar V, et al. 16th IAC 2006. Abstract TUPE0078
3. Sekar V, et al. 11th EACS 2007. Abstract 4.1/10
Methods: blood sampling for TITAN
DRV PK assessments and analysis
• Two samples were taken at Weeks 4 and 24
–
–
first blood sample immediately before DRV/r intake
second blood sample at least 1 hour after the first
• One sample was also taken at each of Weeks 8,
48, 72 and 96 (or withdrawal)
–
no time restrictions with respect to DRV/r intake
• Steady-state empirical Bayesian estimates at
Week 48 were determined for
–
–
area under the curve up to 12 hours post-dose (AUC12h)
plasma trough concentration (C0h)
Methods: TITAN PK analysis
• A DRV population PK model (based on data in healthy
volunteers and HIV-1-infected patients)1 was applied to the
sparse DRV plasma concentration data
• An analysis of covariance (ANCOVA) model was applied with
the following as covariates
–
–
–
–
–
baseline a1-acid glycoprotein (AAG) level
concomitant use of efavirenz (EFV) and nevirapine (NVP)
region (Africa, Asia, Europe and Australia, Latin America
and North America)
gender
body weight
• Descriptive statistics were calculated for population PK
parameters overall and by subgroup for
–
–
–
the subgroups of the ANCOVA model
hepatitis B or C co-infection status
age and race
1. Vis P, et al. 15th PAGE 2006. Abstract 964
TITAN: baseline characteristics
Parameter
DRV/r 600/100mg bid
(N=298)
Demographics
Male, n (%)
Median age, years (range)
229 (77)
40 (18–68)
Caucasian, n (%)
161 (54)
Black, n (%)
54 (18)
Hispanic, n (%)
44 (15)
Oriental/Asian, n (%)
28 (9)
Hepatitis B or C co-infected, n (%)
52 (18)
Median weight, kg (range)
71.2 (37.5–146.1)
Disease characteristics
Mean baseline log10 viral load (SD)
4.33 (0.79)
Median baseline CD4 count, cells/mm3 (range)
235 (3–831)
Use of NNRTIs in the OBR
31 (10)
TITAN: DRV population PK estimates
AUC12h
180,000
C0h
14,000
140,000
10,000
DRV C0h (ng/mL)
DRV AUC12h (ng.h/mL)
12,000
100,000
60,000
8,000
6,000
4,000
55,816
3,306
2,000
20,000
0
0
n=285
n=285
EC50 for
PI-resistant
virus 550ng/mL
(adjusted for
protein
binding)
Data shown are median, IQR and range
PK comparisons across the TITAN and
POWER trials for DRV/r 600/100mg bid
Median (range)
Trial
Baseline mean
AAG, g/L (SE)
N
AUC12h (ng.h/mL)
C0h (ng/mL)
TITAN
285
55,816
(32,437–177,680)
3,306
(1,517–13,198)
0.98 (0.02)
POWER 1 and 2*
119
61,668
(33,857–106,490)
3,539
(1,255–7,368)
1.03 (0.04)
POWER 3‡
292
59,929
(28,064–147,500)
3,806
(1,233–10,761)
1.04 (0.02)
*Sekar V, et al. 13th CROI 2006. Abstract J-121
V, et al. 16th IAC 2006. Abstract TUPE0078
‡Sekar
ANCOVA analysis for DRV log10 AUC12h
Covariate
Estimate
Standard error
p-value
Baseline AAG (g/L)
0.171
0.018
<0.001
EFV use in OBR (no vs yes)
–0.018
0.020
NS
NVP used in OBR (no vs yes)
–0.017
0.043
NS
Gender (female vs male)
0.040
0.014
0.007
Region* (Asia vs North America)
–0.081
0.023
<0.001
Weight (kg)
0.0003
0.0004
NS
NS = not statistically significant
*All other regions (Africa, Europe and Australia, and Latin America) vs North America = NS
ANCOVA model for log10 AUC12h included baseline AAG and weight as
covariates, and EFV use in OBR, NVP use in OBR, gender and region as factors
DRV exposure by use of EFV or NVP
EFV
NVP
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
63,239
55,816
55,472
55,744
20,000
0
EFV not used
(n=259)
EFV used
(n=26)
NVP not used
(n=280)
NVP used
(n=5)
Data shown are median, IQR and range
DRV exposure by baseline AAG
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
52,225
66,510
60,274
46,768
20,000
0
≤0.75
(n=72)
0.75–0.93
0.93–1.15
(n=71)
(n=71)
AAG (g/L)
>1.15
(n=71)
Data shown are median, IQR and range
DRV exposure by gender
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
59,072
54,547
20,000
0
Female (n=67)
Male (n=218)
Data shown are median, IQR and range
DRV exposure by race
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
62,280
56,368
54,150
45,749
50,668
20,000
0
Black
(n=49)
Caucasian/white
(n=154)
Hispanic
(n=44)
Oriental/Asian
(n=27)
Other
(n=11)
Data shown are median, IQR and range
DRV exposure by hepatitis B or C
co-infection status
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
55,14
8
58,732
20,000
0
Negative (n=236)
Positive (n=48)
Data shown are median, IQR and range
DRV exposure by age (years)
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
55,600
59,870
58,896
54,566
48,841
20,000
≤30
(n=26)
31–45
(n=182)
45–55
(n=60)
55–65
(n=16)
>65
(n=1)
Data shown are median, IQR and range
DRV exposure by body weight (kg)
DRV AUC12h (ng.h/mL)
180,000
140,000
100,000
60,000
56,533
55,296
57,339
54,161
20,000
≤61.90
(n=71)
>61.90–71.21
(n=71)
>71.21–78.81
(n=71)
>78.81
(n=71)
Data shown are median, IQR and range
TITAN DRV PK subgroup analyses: summary
•
Small gender and racial differences were seen in DRV exposure
(AUC12h)
–
–
•
•
•
•
females 8% higher than males
Blacks 15% higher than Caucasians, and Asians 16% lower than
Caucasians
Considering the inter-individual variability in DRV
pharmacokinetics, these differences were not considered to be
clinically relevant
No clinically relevant differences in safety and efficacy were
observed between gender and race
Differences in exposure according to AAG levels are likely related
to the high binding of DRV to AAG
DRV exposure was not affected by
–
–
–
–
concomitant use of the NNRTIs EFV or NVP at baseline
age
body weight
hepatitis B or C co-infection
TITAN DRV PK analysis: conclusions
•
Small differences observed in DRV exposure according to race
and gender are not considered to be clinically relevant
•
DRV PK results for DRV/r 600/100mg bid in TITAN confirm
previous findings in treatment-experienced patients in POWER
1, 2 and 3
•
The lack of PK/PD relationship for safety and efficacy of DRV/r
was also confirmed1
•
Analysis of data from the ARTEMIS trial in treatment-naïve
patients will provide information on DRV PK parameters for
once-daily DRV/r 800/100mg
•
Ongoing studies will further evaluate the potential impact of
gender and race on DRV/r (GRACE) and compare once-daily
versus twice-daily DRV/r in treatment-experienced patients with
zero DRV resistance-associated mutations (TMC114-C229)
1. Sekar V, et al. 11th EACS 2007. Abstract 4.1/10
TITAN: acknowledgments
• The patients and their families for their participation and support during the study
• The TITAN study team, investigators and co-investigators:
Argentina: Pedro Cahn, Arnaldo Casiró, Isabel Cassetti,
Daniel David, Marcelo Losso, Sergio Lupo
Australia: David Cooper, Robert Finlayson, Jenny Hoy,
Patricia Martinez, Marilyn McMurchie, Cassy Workman
Austria: Armin Rieger, Norbert Vetter
Belgium: Nathan Clumeck, Jean-Christophe Goffard,
Lutgarde Lynen
Brazil: Clóvis Arns Da Cunha, Beatriz Grinsztejn, Cláudio
Gonsalez, José Valdez-Madruga, Rogério Pedro, José
Henrique Pilotto, Mauro Schechter, Artur Timerman
Canada: John Gill, Norbert Gilmore, Donald Kilby, Patrice
Junod, Anita Rachlis, Benoit Trottier, Chris Tsoukas, Sharon
Walmsley
Chile: Juan Ballesteros, Rebeca Northland, Carlos Pérez
Denmark: Henrik Nielsen
France: Jacques Durant, Pierre-Marie Girard, Christine
Katlama, Christian Michelet, Jean-Michel Molina, Gilles
Pialoux, Christophe Piketty, Dominique Salmon, Daniel
Vittecoq, Patrick Yeni
Germany: Keikawus Arastéh, Gerd Fätkenheuer, Heribert
Knechten, Antonius Mutz, Dieter Schuster, Albrecht Stoehr,
Andreas Trein
Greece: Georgios Panos
Guatemala: Eduardo Guillermo, Arathoon Perez, Carlos
Rodolfo Mejia-Villatoro
Hungary: Dénes Banhegyi
Italy: Andrea Antinori, Giampiero Carosi, Roberto Esposito,
Adriano Lazzarin, Francesco Mazzotta, Anna Orani, Stefano
Rusconi, Laura Sighinolfi, Fredy Suter
Malaysia: Adeeba Kamarulzaman, Christopher Lee
Mexico: Jaime Andrade
Netherlands: Kees Brinkman, Bart J Rijnders, Herman G
Sprenger
Panama: Nestor Rodolfo Sosa Montalván
Portugal: Teresa Branco, António Diniz, Rui Sarmento e Castro
Puerto Rico: Javier O. Morales Ramirez
Russia: Oleg Kozyrev, Grigory Moshkovich, Alexander Pronin,
Oleg Romanenko, Elena Vinogradova, Alexey Yakovlev
South Africa: Ezio Baraldi, Francesca Conradie, Gulam
Hoosan Latiff, Lerato Mohapi, Catherine Orrell, Osman Ebrahim,
David Spencer
Spain: José Ramon Arribas, Angel Daniel Podzamczer, Maria
Perez Elias
Switzerland: Milos Opravil
Thailand: Ploenchan Chetchotisakd, Kiat Ruxrungtham, Wichai
Techasathit,
United Kingdom: Philippa Easterbrook, Anton Louis Pozniak
United States: Ben Barnett, John Baxter, Paul Benson, Daniel
S Berger, Jack D Bissett, Cynthia Brinson, Alfred F Burnside,
Thomas Campbell, Amy E Colson,, Edwin DeJesus, Robin
Henry Dretler, Robert Eng, Charles F Farthing, W Jeffrey
Fessel, Michael Frank, W David Hardy, Dushyantha T
Jayaweera, Thomas T Jefferson, Joseph Gregory Jemsek,
Harold P Katner, Clifford A Kinder, Harry W Lampiris, Marc
Joseph LaRiviere, Jason Mark Leider, Steven I Marlowe, David
A McDonough, Jose Montero, Karam Mounzer, Robert A Myers,
Dorece Norris, Frank J Palella Jr, Gerald Pierone Jr, Bruce S
Rashbaum, Afsoon D Roberts, Barry M Rodwick, Peter J Ruane,
Kunthavi Sathasivam, Stefan Schneider, Shannon Ray
Schrader, Anita R Scribner, Michael Sension, Peter Shalit,
William Rodney Short, Stephen M Smith, Alan Taege, Melanie A
Thompson, Bienvenido G Yangco
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