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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,

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Presentation on theme: "Effect of extrinsic and intrinsic factors on the pharmacokinetics of darunavir/ritonavir (DRV/r) in HIV-1 patients: results of a randomised, controlled,"— Presentation transcript:

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, 2 F Tomaka, 1 S Spinosa-Guzman, 2 M De Pauw, 2 T Vangeneugden, 2 A Vandevoorde, 2 P Vis, 3 RM Hoetelmans 2 1 Tibotec Inc., Yardley, PA, USA; 2 Tibotec BVBA, Mechelen, Belgium; 3 Exprimo NV, Mechelen, Belgium

2 TITAN (TMC114-C214) study design 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) I LPV/r 400/100mg bid + OBR (n=297) I Screening phase (4 weeks) Treatment phase (96 weeks) 595 patients randomised and treated DRV/r = darunavir/ritonavir; LPV/r = lopinavir/ritonavir STI = structured treatment interruption; OBR = optimised background regimen Rollover and follow-up phase after 1 and 4 weeks

3 Week 48 primary and secondary efficacy outcomes in TITAN *p-values of superiority derived from a logistic regression model including treatment and baseline log 10 viral load as covariates and use of NNRTIs in the OBR as a factor Valdez-Madruga J, et al. Lancet 2007;370:49–58 77% 67% 0 20 40 60 80 Proportion of patients (%) DRV/r 600/100mg bid LPV/r 400/100mg bid Primary endpoint viral load <400 copies/mL p=0.008* 71% 60% 0 20 40 60 80 p=0.005* Secondary endpoint viral load <50 copies/mL Proportion of patients (%) DRV/r 600/100mg bid LPV/r 400/100mg bid

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 observed 1–3 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

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 (AUC 12h ) –plasma trough concentration (C 0h )

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  1 -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 Parameter DRV/r 600/100mg bid (N=298) Demographics Male, n (%)229 (77) Median age, years (range)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 log 10 viral load (SD)4.33 (0.79) Median baseline CD4 count, cells/mm 3 (range)235 (3–831) Use of NNRTIs in the OBR31 (10)

8 TITAN: DRV population PK estimates n=285 55,816 3,306 180,000 60,000 140,000 100,000 20,000 DRV AUC 12h (ng.h/mL) 14,000 4,000 10,000 8,000 6,000 12,000 2,000 0 DRV C 0h (ng/mL) 0 n=285 EC 50 for PI-resistant virus 550ng/mL (adjusted for protein binding) AUC 12h C 0h Data shown are median, IQR and range

9 PK comparisons across the TITAN and POWER trials for DRV/r 600/100mg bid Median (range) Trial NAUC 12h (ng.h/mL)C 0h (ng/mL) Baseline mean AAG, g/L (SE) TITAN285 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 ‡ Sekar V, et al. 16th IAC 2006. Abstract TUPE0078

10 ANCOVA analysis for DRV log 10 AUC 12h CovariateEstimateStandard errorp-value Baseline AAG (g/L)0.1710.018<0.001 EFV use in OBR (no vs yes)–0.0180.020NS NVP used in OBR (no vs yes)–0.0170.043NS Gender (female vs male)0.0400.0140.007 Region* (Asia vs North America)–0.0810.023<0.001 Weight (kg)0.00030.0004NS ANCOVA model for log 10 AUC 12h included baseline AAG and weight as covariates, and EFV use in OBR, NVP use in OBR, gender and region as factors NS = not statistically significant *All other regions (Africa, Europe and Australia, and Latin America) vs North America = NS

11 DRV exposure by use of EFV or NVP 55,472 55,816 20,000 60,000 140,000 100,000 180,000 EFV not used (n=259) EFV used (n=26) 63,239 55,744 NVP not used (n=280) NVP used (n=5) DRV AUC 12h (ng.h/mL) 0 EFVNVP Data shown are median, IQR and range

12 DRV exposure by baseline AAG 52,225 46,768 20,000 60,000 140,000 100,000 180,000 ≤0.75 (n=72) 0.75–0.93 (n=71) 66,510 60,274 0.93–1.15 (n=71) >1.15 (n=71) DRV AUC 12h (ng.h/mL) 0 AAG (g/L) Data shown are median, IQR and range

13 DRV exposure by gender 59,072 54,547 20,000 60,000 140,000 100,000 180,000 Female (n=67)Male (n=218) DRV AUC 12h (ng.h/mL) 0 Data shown are median, IQR and range

14 DRV exposure by race 62,280 56,368 54,150 45,749 50,668 20,000 60,000 140,000 100,000 180,000 Black (n=49) Caucasian/white (n=154) Hispanic (n=44) Oriental/Asian (n=27) Other (n=11) DRV AUC 12h (ng.h/mL) 0 Data shown are median, IQR and range

15 DRV exposure by hepatitis B or C co-infection status 55,14 8 58,732 20,000 60,000 140,000 100,000 180,000 Negative (n=236)Positive (n=48) DRV AUC 12h (ng.h/mL) 0 Data shown are median, IQR and range

16 DRV exposure by age (years) ≤30 (n=26) 31–45 (n=182) 45–55 (n=60) 55–65 (n=16) >65 (n=1) 48,841 55,600 59,870 54,566 58,896 20,000 60,000 140,000 180,000 100,000 DRV AUC 12h (ng.h/mL) Data shown are median, IQR and range

17 DRV exposure by body weight (kg) ≤61.90 (n=71) >61.90–71.21 (n=71) >71.21–78.81 (n=71) >78.81 (n=71) 55,296 56,533 57,339 54,161 20,000 60,000 140,000 180,000 100,000 DRV AUC 12h (ng.h/mL) Data shown are median, IQR and range

18 TITAN DRV PK subgroup analyses: summary Small gender and racial differences were seen in DRV exposure (AUC 12h ) –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 confirmed 1 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 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 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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