Liverpool HIV Interactions

Potential Interaction

Efavirenz (EFV)

_ZZDarunavir

Quality of Evidence: Moderate

Summary:

Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir at a dose lower than that licensed (300/100 mg twice daily) decreased darunavir Cmax (15%), AUC (13%) and Cmin (31%). Efavirenz Cmax, AUC and Cmin increased by 15%, 21% and 17%, respectively. The clinical significance has not been established. Coadministration of efavirenz and once daily darunavir/ritonavir (900/100 mg once daily) decreased darunavir AUC (14%), Cmax (8%) and Ctrough(57%). Ritonavir AUC and Ctrough were significantly reduced, but there was no significant effect on efavirenz AUC, Cmax or Ctrough. The combination should be used with caution. Clinical monitoring for CNS toxicity associated with increased efavirenz exposure may be indicated.

Description:

Coadministration of darunavir/ritonavir (300/100 mg twice daily, a dose lower than recommended) and efavirenz (600 mg once daily) decreased darunavir AUC, Cmax and Cmin by 13%, 15% and 31%, respectively. Efavirenz AUC, Cmax and Cmin increased by 21%, 15% and 17%, respectively. Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in suboptimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. This combination should be used with caution.
Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2015.

Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) increased efavirenz AUC, Cmax and Cmin by 21%, 15% and 17%, respectively. Darunavir AUC, Cmax and Cmin were decreased by 13%, 15% and 31%, respectively. Efavirenz decreases the plasma concentrations of darunavir as a result of CYP3A4 induction. Darunavir/ritonavir increases the plasma concentrations of efavirenz as a result of CYP3A4 inhibition. Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir coadministered with low dose ritonavir is given in combination with efavirenz.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

The interaction between darunavir/ritonavir and efavirenz was evaluated in clinical studies and no dose adjustment is needed for either drug. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) was studied in 12 subjects. Darunavir exposure decreased and efavirenz exposure increased. Darunavir Cmax, AUC and Cmin decreased by 15%, 13% and 31%, respectively. Efavirenz Cmax, AUC and Cmin increased by 15%, 21% and 17%, respectively.
Prezista Prescribing Information, Tibotec Inc, June 2012.

The effect of efavirenz (600 mg once daily) on a once daily regimen of darunavir/ritonavir (900/100 mg) was investigated in 12 HIV- subjects. Coadministration decreased darunavir trough concentration by 57% (p<0.001), AUC decreased by 14% (p=0.05) and Cmax decreased by 8% (p=0.23). Ritonavir trough concentrations and AUC were also significantly reduced by 54% and 26%, respectively. There was no significant effect on efavirenz trough concentrations (1% increase), AUC (9% decrease) or Cmax (20% decrease), but efavirenz half life was significantly increased by 66% in the combination phase. Although trough concentrations of darunavir were significantly reduced, all remained above the EC50 of wild-type virus.
Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers. Soon GH, Shen P, Yong EL, et al. Antimicrob Agents Chemother, 2010, 54(7): 2775-2780.

The pharmacokinetic interaction between a non-licensed dose of darunavir/ritonavir (300/100 mg twice daily) and efavirenz (600 mg twice daily) was investigated in HIV-negative subjects. In the presence of darunavir/ritonavir, efavirenz Cmin and Cmax increased by ~17% and AUC increased by 21%. Coadministration decreased darunavir Cmin by 31% and decreased AUC by 13%. Since the clinical significance of the changes in AUC and Cmin seen during coadministration has not been established, this combination should be used with caution. Similar findings are expected with the approved darunavir/ritonavir 600/100 mg twice daily dose.
Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers. Sekar VJ, De Pauw M, Marien K, et al. Antiviral Ther, 2007, 12(4): 509-514.

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