Rifampin, a strong inducer of CYP3A, results in reduced Darunavir levels and increased hepatotoxicity. Hence, the use of these drugs together is not currently recommended.
Darunavir/Ritonavir versus Rifampin
^
Study Design
This was an in vitro study were researchers took cryopreserved primary human hepatocytes and treated with either RIF (rifampin) alone or together with RTV (ritonavir) or were left untreated. Test compounds were replenished every day for a total of 72 hours. After this the cells were treated with DRV (darunavir) for one hour.
Resultant DRV concentrations were quantified using HPLC-UV. Apparent intrinsic clearance (CLint) of DRV was calculated, and expressed as the mean ± SD (μl/min/106 hepatocytes) of a total of three biological replicates.
Study Results
Control group cells were treated with DRV alone and exhibited a CLint of 13.2 ± 1.5μl/min. Following incubation with 10µM RIF, DRV CLint was increased to 20.5 ± 4.7 μl/min. 1 μM RTV was sufficient to overcome the effect of 10µM RIF reducing DRV CLint by -15% compared to the control.
Regression analysis showed that that RTV concentrations were associated with a percentage inhibition of (β = 20.7, p = 0.001)
Study Conclusions
Studying findings suggested that RIF-induced elevations in DRV CLint were overcome by co-administration with RTV. These show the relative impact of pharmacoenhancers in the presence of RIF. The authors do not suggest the need for dose adjustments when using these agents together, and further human trials are needed. Until such time, use clinical judgement when these drugs are utilized concomitantly.
References
Roberts O, Back DJ, Khoo S, Owen A, Siccardi M. Interaction of darunavir/ritonavir and darunavir/cobicistat with rifampicin in vitro [abstract 459]. Conference On Retroviruses And Opportunistic Infections. Boston, MA, USA. 2016; February 2016.
Darunavir/Ritonavir versus Rifampin
^
Study Design
Two adjusted doses of Darunavir/Ritonavir (DRV/r, 1600/200 mg daily and
800/100 mg 12 hourly) were selected with Rifampin (RIF) for comparison to plasma exposures with DRV/r 800/100 mg daily without RIF, in a cross-over design. Baseline DRV steady state PK was determined and RIF added for 7 days, then the dose of r was increased to 200 mg; 7 days later the dose of DRV was increased; after another 7 days
participants were crossed over to the alternative adjusted DRV dose. DRV was
measured in plasma samples after observed doses at baseline and after each
dose adjustment. Clinical adverse events, ALT, and bilirubin were monitored every 2 to
3 days during treatment with RIF.
Study Results
Seventeen of a planned 28 PLWH were enrolled and started on study
treatment before the study was stopped due to high rates of hepatotoxicity.
Only 4 participants completed the study. Six (35%) of the participants were
withdrawn for DAIDS grade 3 (n=3) or 4 (n=3) ALT elevations developing after
9-12 days of RIF; 3 participants were symptomatic. Hepatotoxicity resolved in
all cases after withdrawal of study treatment and participants were successfully
re-established on their standard of care ART regimen. Plasma concentrations of DRV at 24 hours were 2719, 209, and 1176 ng/ml and AUC24 were 261184, 39074, and 59751 ng*hr/ml for patients on DRV/r 800/100 mg QD, DRV/r 1600/200 mg QD + RIF, and DRV/r 800/100 mg BID + RIF respectively.
Study Conclusions
Adjusted doses of DRV/r with RIF were associated with
unacceptable risk of hepatotoxicity and there was a marked reduction in DRV
trough concentrations with the QD adjusted dose in our study.
References
Ebrahim, I, Maartens, G, Smythe, W, Orrell, C, Wiesner, L, Mcilleron, H. Pharmacokinetics and safety of adjusted darunavir/ritonavir with rifampin in plwh. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019.
Darunavir/Ritonavir versus Rifampin
^
Study Design
This was an in vitro study were researchers took cryopreserved primary human hepatocytes and treated with either RIF (rifampin) alone or together with RTV (ritonavir) or were left untreated. Test compounds were replenished every day for a total of 72 hours. After this the cells were treated with DRV (darunavir) for one hour.
Resultant DRV concentrations were quantified using HPLC-UV. Apparent intrinsic clearance (CLint) of DRV was calculated, and expressed as the mean ± SD (μl/min/106 hepatocytes) of a total of three biological replicates.
Study Results
Control group cells were treated with DRV alone and exhibited a CLint of 13.2 ± 1.5μl/min. Following incubation with 10µM RIF, DRV CLint was increased to 20.5 ± 4.7 μl/min. 1 μM RTV was sufficient to overcome the effect of 10µM RIF reducing DRV CLint by -15% compared to the control.
Regression analysis showed that that RTV concentrations were associated with a percentage inhibition of (β = 20.7, p = 0.001)
Study Conclusions
Studying findings suggested that RIF-induced elevations in DRV CLint were overcome by co-administration with RTV. These show the relative impact of pharmacoenhancers in the presence of RIF. The authors do not suggest the need for dose adjustments when using these agents together, and further human trials are needed. Until such time, use clinical judgement when these drugs are utilized concomitantly.
References
Ebrahim, I, Maartens, G, Smythe, W, Orrell, C, Wiesner, L, Mcilleron, H. Pharmacokinetics and safety of adjusted darunavir/ritonavir with rifampin in plwh. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019.
Darunavir/Ritonavir versus Rifampin
^
Study Design
This was an in vitro study were researchers took cryopreserved primary human hepatocytes and treated with either RIF (rifampin) alone or together with RTV (ritonavir) or were left untreated. Test compounds were replenished every day for a total of 72 hours. After this the cells were treated with DRV (darunavir) for one hour.
Resultant DRV concentrations were quantified using HPLC-UV. Apparent intrinsic clearance (CLint) of DRV was calculated, and expressed as the mean ± SD (μl/min/106 hepatocytes) of a total of three biological replicates.
Study Results
Control group cells were treated with DRV alone and exhibited a CLint of 13.2 ± 1.5μl/min. Following incubation with 10µM RIF, DRV CLint was increased to 20.5 ± 4.7 μl/min. 1 μM RTV was sufficient to overcome the effect of 10µM RIF reducing DRV CLint by -15% compared to the control.
Regression analysis showed that that RTV concentrations were associated with a percentage inhibition of (β = 20.7, p = 0.001)
Study Conclusions
Studying findings suggested that RIF-induced elevations in DRV CLint were overcome by co-administration with RTV. These show the relative impact of pharmacoenhancers in the presence of RIF. The authors do not suggest the need for dose adjustments when using these agents together, and further human trials are needed. Until such time, use clinical judgement when these drugs are utilized concomitantly.
References
Ebrahim, I, Maartens, G, Smythe, W, Orrell, C, Wiesner, L, Mcilleron, H. Pharmacokinetics and safety of adjusted darunavir/ritonavir with rifampin in plwh. Conference On Retroviruses And Opportunistic Infections. Seattle . ; March 2019.
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