Although there is a 20% decrease in concentration of each drug when co-administered, the authors’ concluded the concomitant use of these agents is not expected to cause any clinically significant drug interactions, and dose adjustments are not warranted
Darunavir/Cobicistat versus Dolutegravir
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Study Design
N=10 HIV infected patients, mainly males (n=8), under good immunological status underwent a consecutive series of therapeutic drug monitoring of dolutegravir and darunavir. Patients were switched from darunavir/ritonavir (800/100mg/daily) to darunavir/cobicistat (800/150mg/daily) while also subsequently taking dolutegravir 50mg/daily as part of the antiretroviral therapy. Blood samples measured before visit 1 and after visit 2 had to be taken 24 hours after the last drug intake, immediately before drug administration. Drug concentrations were assessed by high performance liquid chromatography and UV detection. Comparisons between the two visits were performed by paired t-tests.
Study Results
The switch from ritonavir to cobicistat resulted in a 100% increase of dolutegravir trough concentrations, whereas there was no difference in darunavir concentrations.
Concomitant administration of dolutegravir and cobicistat had no effect on serum creatinine concentrations.
Study Conclusions
This study confirms that a switch from ritonavir to cobicistat resulted in a comparable boosting effect on darunavir exposure. The study also found that cobicistat significantly increased dolutegravir trough concentrations in comparison to ritonavir.
References
Gervasoni, Riva, Capetti, Rizzardini. Increased dolutegravir exposure in hiv patient switched from ritonavir to cobicistat [abstract]. Conference On Retroviruses And Opportunistic Infections. Washington DC, USA. 2017; February 2017.
Dolutegravir vs Darunavir/Cobicistat
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Study Design
This phase 1, open label, 57 day, cross over, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65years, who were randomized to: i) group 1: dolutegravir (DTG) 50mg on days 1-14 followed by a 7 day wash out period, DTG+Darunavir/cobicistat (DRV/c) 50mg+800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out, and finally DRV/c 800/150mg on days 43-56 or ii) group 2: DRV/c 800/150mg on days 1-14 followed by a 7 day wash out period, DTG 50mg+DRV/c 800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out and finally DTG 50mg on days 43-56. All doses were administered once daily. Each group underwent intensive PK sampling (0-24 hr post-dose) on days 14, 35 and 56 and DTG/DRV/c concentrations were measured by validated LC-MS methods
Study Results
13 healthy volunteers have been screened, 12 baselined and 9 have completed all PK phases (1 subject withdrew for personal reasons and 2 are ongoing). Median age (range) was 31yrs (24-55), 1 was male, 4 self-reported as white and 5 as black African/Caribbean. DTG geometric mean ratios (GMR, DTG+DRV/c versus DTG alone) and 90% confidence intervals (CI) Cmax, AUC, C24h were 0.89 (0.79-1.02), 0.84 (0.73-0.96), 0.81 (0.66-0.98). DRV GMR (DRV/ c+DTG versus DRV/c alone, 90%CI) of DRV Cmax, AUC, C24h were 0.79 (0.71- 0.89), 0.87 (0.78-0.96), 0.82 (0.67-1.00), and of c Cmax, AUC, C24h were 0.86 (0.77-0.96), 0.88 (0.78-1.00) 0.98 (0.74-1.28), No grade 3 or 4 adverse events or laboratory abnormalities were observed.
Study Conclusions
Concentrations of DTG during co-administration with DRV/c decreased by <20% and those of DRV with DTG by <21%, suggesting this combination can be prescribed safely in the treatment of HIV-1, including in patients harboring resistance that benefit from optimal antiretroviral exposures
References
Elliott, ER, Cerrone, M, Else, L, Amara, A, Bisdomini, E, Saye, K. Pharmacokinetics of dolutegravir with and without darunavir/cobicistat. Conference On Retroviruses And Opportunistic Infections. Boston. ; March 2018.
Dolutegravir vs Darunavir/Cobicistat
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Study Design
This phase 1, open label, 57 day, cross over, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65years, who were randomized to: i) group 1: dolutegravir (DTG) 50mg on days 1-14 followed by a 7 day wash out period, DTG+Darunavir/cobicistat (DRV/c) 50mg+800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out, and finally DRV/c 800/150mg on days 43-56 or ii) group 2: DRV/c 800/150mg on days 1-14 followed by a 7 day wash out period, DTG 50mg+DRV/c 800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out and finally DTG 50mg on days 43-56. All doses were administered once daily. Each group underwent intensive PK sampling (0-24 hr post-dose) on days 14, 35 and 56 and DTG/DRV/c concentrations were measured by validated LC-MS methods
Study Results
13 healthy volunteers have been screened, 12 baselined and 9 have completed all PK phases (1 subject withdrew for personal reasons and 2 are ongoing). Median age (range) was 31yrs (24-55), 1 was male, 4 self-reported as white and 5 as black African/Caribbean. DTG geometric mean ratios (GMR, DTG+DRV/c versus DTG alone) and 90% confidence intervals (CI) Cmax, AUC, C24h were 0.89 (0.79-1.02), 0.84 (0.73-0.96), 0.81 (0.66-0.98). DRV GMR (DRV/ c+DTG versus DRV/c alone, 90%CI) of DRV Cmax, AUC, C24h were 0.79 (0.71- 0.89), 0.87 (0.78-0.96), 0.82 (0.67-1.00), and of c Cmax, AUC, C24h were 0.86 (0.77-0.96), 0.88 (0.78-1.00) 0.98 (0.74-1.28), No grade 3 or 4 adverse events or laboratory abnormalities were observed.
Study Conclusions
Concentrations of DTG during co-administration with DRV/c decreased by <20% and those of DRV with DTG by <21%, suggesting this combination can be prescribed safely in the treatment of HIV-1, including in patients harboring resistance that benefit from optimal antiretroviral exposures
References
Elliott, ER, Cerrone, M, Else, L, Amara, A, Bisdomini, E, Saye, K. Pharmacokinetics of dolutegravir with and without darunavir/cobicistat. Conference On Retroviruses And Opportunistic Infections. Boston. ; March 2018.
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