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Pharmacokinetic (PK) and pharmacodynamic analyses of once- and twice-daily darunavir/ritonavir (DRV/r) in the ODIN trial
 
 
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Background

In the Phase III, randomised, open-label ODIN trial, treatment-experienced HIV-1-infected adults with no screening DRV resistance-associated mutations received DRV/r 800/100mg qd or DRV/r 600/100mg bid (both arms + ≥2 NRTIs). At Week 48, 72.1% qd vs 70.9% bid patients achieved HIV-1 RNA <50 copies/mL (95% CI = -6.1 to 8.5%, p<0.001; ITT-TLOVR), confirming non-inferiority of DRV/r qd. The relationship between DRV PK and efficacy and safety following treatment with DRV/r is explored.

Methods

Sparse blood sampling for PK evaluations was taken at Weeks 4, 8, 24 and 48 to determine DRV trough concentrations (C0h) and exposure (AUC24h, calculated as AUC12h x 2 for bid) using a population pharmacokinetic model. Relationships between PK parameters and efficacy (change in log10 HIV-1 RNA and virological response [HIV-1 RNA <50 copies/mL]) were assessed using ANCOVAs. Relationships between PK parameters and occurrence of adverse events of interest and laboratory lipid abnormalities were evaluated using descriptive statistics.

Results

PK data were available for 280 DRV/r qd patients and 278 bid patients. Median (range) C0h was 1896 (184-7881) ng/mL for DRV/r qd and 3197 (250-11,865) ng/mL for DRV/r bid. Median (range) AUC24h for DRV/r qd was 87,788 (45,456-236,920) ng.h/mL and 109,401 (48,934-323,820) ng.h/mL for bid. No relevant relationships were observed between DRV PK and efficacy: changes from baseline in HIV-1 RNA log10 copies/mL at Week 48 for pooled data by DRV AUC24h quartile ranges (≤79,576; 79,577-100,376; 100,377-119,356; >119,356 ng.h/mL) were -2.06, -2.22, -2.19, and -2.08 log10 copies/mL, respectively. The % patients achieving HIV-1 RNA <50 copies/mL by these quartile ranges were 82.0%, 88.5%, 82.6% and 76.5% (observed data), respectively. In a logistic regression analysis adjusting for baseline viral load, AAG levels and number of sensitive NRTIs in the optimised background regimen, there were no relevant relationships between PK and virological response. No apparent relationships were observed between DRV PK and occurrence of rash-, cardiac-, GI-, liver-, lipid- and glucose-related AEs or laboratory lipid abnormalities.

Conclusions

Dosing with DRV/r 800/100mg qd resulted in lower C0h and AUC24h compared to DRV/r 600/100mg bid; however, comparable efficacy between DRV/r qd and bid confirmed adequate DRV concentrations were achieved following qd dosing. No relevant relationships were observed between DRV PK and efficacy or safety at Week 48.

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Pharmacokinetics of darunavir/ritonavir and atazanavir/ritonavir once daily over 72 hours following drug cessation.

Marta Boffito1*, Akil Jackson1, Alieu Amara2, David Back2, Saye Khoo24 , Chris

Higgs1, Natalia Seymour1, Brian Gazzard1, Graeme Moyle1 5

6

17 St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK;

28 Department of Pharmacology, University of Liverpool, Liverpool, UK

ABSTRACT

Background: To investigate the pharmacokinetics of darunavir/ritonavir and atazanavir/ritonavir once-daily, over 72 hours (h) following drug intake cessation.

Methods: Volunteers received darunavir/ritonavir 800/100mg once-daily for 10 days followed by a seven-day wash-out period and atazanavir/ritonavir 300/100mg once-daily for 10 days. Full pharmacokinetic profiles were assessed for each phase on day 10 over 72h. Pharmacokinetic parameters were determined over 24h and to the last measurable concentration by non-compartmental methods.

Results: Seventeen subjects completed the study. Geometric mean (GM) terminal elimination half-life to 72h of darunavir was 6.48h and lower compared to the 0-24h half-life (10.70h). Terminal elimination half-life of atazanavir was 6.74h and lower than the 0-24h half-life (13.72h). All subjects but one had darunavir concentrations higher than the target for protease-resistant HIV isolates of 550ng/mL (equivalent to the protein binding corrected IC50 for wild-type virusx10) 24 and 14 out of 17 at 30h post-dose (GM 1088 and 851ng/mL). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150ng/mL (equivalent to the protein binding corrected IC50 for wild-type virusx10) 24 and 30h post-dose (GM 693 and 392ng/mL). Two/17 and five/17 subjects were above target 48h post-dose while on darunavir/ritonavir and atazanavir/ritonavir. Ritonavir half-life72h was 6.84h with darunavir and 6.07 with atazanavir.

Conclusions: This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rate of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6h after the end of the ideal dosing interval of 24h which were above the cut-off used to define therapeutic concentrations.

 
 
 
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