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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).

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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,2F Tomaka,1 S Spinosa-Guzman,2 M De Pauw,2T 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
TITAN (TMC114-C214) study design

Screening phase (4 weeks)

Treatment phase (96 weeks)

  • LPV-naïve, treatment-experienced
  • Viral load >1,000 copies/mL
  • Stable HAART for ≥12 weeks (STI allowed)

DRV/r 600/100mg bid + OBR (n=298)

Rollover and follow-up phase after 1 and 4 weeks

ILPV/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
Week 48 primary and secondary efficacy outcomes in TITAN

Primary endpoint viral load <400 copies/mL

Secondary endpoint

viral load <50 copies/mL

p=0.008*

p=0.005*

77%

80

80

71%

67%

60%

60

60

Proportion of patients (%)

Proportion of patients (%)

40

40

20

20

0

0

DRV/r600/100mg bid

LPV/r400/100mg bid

DRV/r600/100mg bid

LPV/r400/100mg 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
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-1212. Sekar V, et al. 16th IAC 2006. Abstract TUPE00783. Sekar V, et al. 11th EACS 2007. Abstract 4.1/10

methods blood sampling for titan drv pk assessments and analysis
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
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 drv population pk estimates
TITAN: DRV population PK estimates

AUC12h

C0h

14,000

180,000

12,000

140,000

10,000

8,000

100,000

DRV C0h (ng/mL)

DRV AUC12h (ng.h/mL)

6,000

60,000

4,000

55,816

3,306

EC50 for PI-resistant virus 550ng/mL (adjusted for protein binding)

2,000

20,000

0

n=285

0

n=285

Data shown are median, IQR and range

pk comparisons across the titan and power trials for drv r 600 100mg bid
PK comparisons across the TITAN and POWER trials for DRV/r 600/100mg bid

*Sekar V, et al. 13th CROI 2006. Abstract J-121‡Sekar V, et al. 16th IAC 2006. Abstract TUPE0078

ancova analysis for drv log 10 auc 12h
ANCOVA analysis for DRV log10 AUC12h

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
DRV exposure by use of EFV or NVP

EFV

NVP

180,000

140,000

DRV AUC12h (ng.h/mL)

100,000

63,239

60,000

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 exposure by baseline AAG

180,000

140,000

DRV AUC12h (ng.h/mL)

100,000

66,510

60,000

60,274

52,225

46,768

20,000

0

≤0.75 (n=72)

0.75–0.93 (n=71)

0.93–1.15 (n=71)

>1.15 (n=71)

AAG (g/L)

Data shown are median, IQR and range

drv exposure by gender
DRV exposure by gender

180,000

140,000

DRV AUC12h (ng.h/mL)

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 exposure by race

180,000

140,000

100,000

DRV AUC12h (ng.h/mL)

62,280

60,000

56,368

54,150

50,668

45,749

20,000

0

Black (n=49)

Hispanic (n=44)

Other(n=11)

Oriental/Asian(n=27)

Caucasian/white (n=154)

Data shown are median, IQR and range

drv exposure by hepatitis b or c co infection status

180,000

140,000

DRV AUC12h (ng.h/mL)

100,000

60,000

58,732

55,148

20,000

0

Negative (n=236)

Positive (n=48)

DRV exposure by hepatitis B or C co-infection status

Data shown are median, IQR and range

drv exposure by age years

180,000

140,000

DRV AUC12h (ng.h/mL)

100,000

60,000

59,870

58,896

55,600

54,566

48,841

20,000

≤30(n=26)

31–45(n=182)

45–55(n=60)

55–65(n=16)

>65(n=1)

DRV exposure by age (years)

Data shown are median, IQR and range

drv exposure by body weight kg

180,000

140,000

DRV AUC12h (ng.h/mL)

100,000

60,000

57,339

56,533

55,296

54,161

20,000

>61.90–71.21(n=71)

>71.21–78.81(n=71)

≤61.90(n=71)

>78.81(n=71)

DRV exposure by body weight (kg)

Data shown are median, IQR and range

titan drv pk subgroup analyses summary
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
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
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

TITAN: acknowledgments
  • The patients and their families for their participation and support during the study
  • The TITAN study team, investigators and co-investigators:

Supported by Tibotec