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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 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 I LPV/r 400/100mg bid + OBR (n=297) I TITAN (TMC114-C214) study design TITAN is an ongoing, randomised, controlled, Phase III trial. It is an international 96-week study, with the primary analysis at Week 48. Patients were screened for eligibility and had to be: - treatment-experienced but naïve to lopinavir - have documented HIV infection - have a viral load of greater than 1,000 copies/mL - to have been on stable HAART therapy for 12 weeks or more. Initially, patients on - a structured treatment interruption (STI) of at least 4 weeks were permitted to be enrolled. A total of 595 patients were randomised to treatment of either, DRV 600mg with 100mg RTV or LPV 400mg, again with the same low dose of RTV. Both treatments were administered twice daily, and all patients also received an optimised background regimen. This consisted of at least 2 antiretrovirals from the NRTI and NNRTI classes. LPV/r patients were encouraged to switch to new formulation upon its approval by the regulatory authorities. At the time of this analysis 18% had switched to the new formulation. 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* 80 77% 80 67% 71% 60% 60 60 Proportion of patients (%) Proportion of patients (%) 40 40 Week 48 primary and secondary efficacy outcomes in TITAN The primary endpoint of the study was the proportion of patients reaching a viral load less than 400 copies/mL, based on the TLOVR algorithm. The primary objective of the trial was to determine whether DRV/r was non-inferior to LPV/r treatment at Week 48 for the <400 copies/mL endpoint. If non-inferiority was established, testing for superiority of one treatment arm over another was pre-defined as a secondary endpoint. The proportion of patients reaching a viral load <50 copies/mL was a secondary efficacy endpoint, which was also based on the TLOVR algorithm. At Week 48 in the intent-to-treat population, 77% of patients receiving DRV/r and 67% of patients receiving LPV/r reached the primary endpoint of a viral load <400 copies/mL, where the p-value for superiority of DRV/r over LPV/r was The secondary endpoint of viral load <50 copies/mL was achieved by 71% of DRV/r patients and 60% of LPV/r patients in the intent-to-treat population. The p-value for superiority of DRV/r over LPV/r was 20 20 DRV/r 600/100mg bid LPV/r 400/100mg bid DRV/r 600/100mg bid LPV/r 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

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 Abstract J Sekar V, et al. 16th IAC Abstract TUPE Sekar V, et al. 11th EACS 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 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 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)

8 TITAN: DRV population PK estimates
AUC12h C0h 180,000 14,000 12,000 140,000 10,000 8,000 DRV AUC12h (ng.h/mL) 100,000 DRV C0h (ng/mL) 6,000 60,000 PK data were available in 285 patients 55,816 4,000 3,306 2,000 EC50 for PI-resistant virus 550ng/mL (adjusted for protein binding) 20,000 n=285 n=285 Data shown are median, IQR and range

9 Baseline mean AAG, g/L (SE)
PK comparisons across the TITAN and POWER trials for DRV/r 600/100mg bid Median (range) Trial N AUC12h (ng.h/mL) C0h (ng/mL) Baseline mean AAG, g/L (SE) 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 Abstract J-121 ‡Sekar V, et al. 16th IAC Abstract TUPE0078

10 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 Gender (female vs male) 0.040 0.014 0.007 Region* (Asia vs North America) –0.081 0.023 Weight (kg) 0.0003 0.0004 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
180,000 140,000 DRV AUC12h (ng.h/mL) 100,000 60,000 63,239 55,816 55,472 55,744 20,000 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 ≤0.75 (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 Female (n=67) Male (n=218) Data shown are median, IQR and range

14 DRV exposure by race 180,000 140,000 DRV AUC12h (ng.h/mL) 100,000
60,000 62,280 56,368 54,150 50,668 45,749 20,000 Black (n=49) Caucasian/white (n=154) Hispanic (n=44) Oriental/Asian (n=27) Other (n=11) Data shown are median, IQR and range

15 DRV exposure by hepatitis B or C co-infection status
55,148 58,732 20,000 60,000 140,000 100,000 180,000 Negative (n=236) Positive (n=48) DRV AUC12h (ng.h/mL) Hepatitis B infection status was confirmed by hepatitis B surface antigen. Hepatitis C infection status was confirmed by hepatitis C virus (HCV) antibody and HCV RNA. The latter was performed only if HCV antibody testing was positive, except for severely immunocompromised subjects (with a last available CD4+ cell count <100 cells/mm3) for whom a qualitative HCV RNA test was performed if the original HCV antibody test was negative. 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 AUC12h (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 AUC12h (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 (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 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: 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 We would like to thank all the patients and their families for their participation and support during the study, also the TITAN study team for their help with its design, conduct and analysis, and the investigators and co-investigators of the trial. They are all listed here. Supported by Tibotec


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