Do not give etravirine with unboosted atazanavir, but the drug can be combined safely with boosted atazanavir.
Atazanavir/Ritonavir versus Etravirine
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Study Design
Healthy subjects were given boosted and unboosted atazanavir in combination with etravirine, and the pharmacokinetic parameters were measured.
Study Results
When atazanavir (ATV; 400 mg once daily (QD)) was administered concurrently with etravirine (ETR; 200 mg twice daily (BID)) in healthy subjects (n=14), the pharmacokinetic (PK) parameters of ATV were decreased due to induction of CYP3A4-mediated metabolism by ETR. It was noted that there was significant decrease in ATV Cmin, which may lower antiviral activity of ATV. Coadministration with ATV increased PK parameters of ETR due to inhibition of CYP3A4-mediated metabolism by ATV.
When healthy subjects (n=13) administered ritonavir-boosted atazanavir (ATV/r) 300/100 mg QD concurrently with ETR 200 mg BID,compared to when ETR was given with unboosted ATV, PK parameters of ETR were less affected and ATV Cmin was increased to the plasma concentration level that is not considered clinically relavant.1 When the same regimen was given to the treatment-experienced HIV-infected patients (n=22), PK interaction between ATV/r and ETR in HIV-infected patients was less likely than in healthy subjects. One of the possible reasons for a smaller effect on PKs of both ATV and ETR was reduced CYP3A activity in HIV-infected patients compared to healthy subjects.
In the same clinical trial, the increased dose of ATV/r (400/100 mg QD) was given with ETR (200mg BID) in treatment-experienced HIV-infected patients (n=22) to evaluate (1) if higher dose of ATV/r can offset the potential reduction in ATV exposure and (2) if higher dose of ATV/r affect ETR exposure. Increasing the dose of ATV/r from 300/100 mg to 400/100 mg resulted in a less than proportional increase in ATV exposure.2 However, the relationship between dose increment and ATV exposure in the presence of ETR should be interpreted with caution as the PK of ATV exhibits nonlinear disposition. In addition, increasing the dose of ATV/r further reduced ETR exposure; geometric mean ratios (GMRs; ATV/r +ETR/ ETR) [90% CIs] of ETR AUC was decreased from 1.24 [0.88,1.76] to 0.84 [0.60, 1.18].
Study Conclusions
ETR should not be coadministered with unboosted-ATV due to the potential for decreased antiretroviral efficacy of ATV.
ETR may be coadministered with ATV with low-dose (100mg) ritonavir (ATV/r).1,3 Although concomitant use of ETR with ATV/r decreased ATV Cmin, the manufacturer of ETR concluded that the reduction is not considered clinically relevant. In addition, the ETR AUC observed in HIV-infected patients who concomitantly receved ETR (200 mg BID) with ATV/r (300/100 mg QD) was similar to the ETR AUC observed in patients who concomitantly received ETR and darunavir/ritonavir in the Phase 3 trials. For these reasons, ETR (200 mg BID) and ATV/r can be coadministered without dose adjustments; If concomitant use of ETR and ATV/r is necessary in HIV-infected, treatment experienced patients, use standard dose of ETR (200mg BID) with ATV/r 300/100mg QD.
References
Orrell C, Felizarta F, Nell A. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, hiv-1-infected patients. Aids Research And Treatement. 2015; : .
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