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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 Vandevoo

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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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 Vandevoo

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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)

  6. 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

  7. TITAN: baseline characteristics

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

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