Coadministration of ritonavir (500 mg every 12 hours) with efavirenz (600 mg) increased ritonavir morning AUC, Cmax and Cmin by 18%, 24%, and 42%, respectively; following the evening dose, there was no change in ritonavir AUC or Cmax, but a 24% increase in Cmin. Efavirenz AUC, Cmax, and Cmin increased by 21%, 14%, and 25%, respectively. When efavirenz was given with ritonavir 500 mg or 600 mg twice daily, the combination was not well tolerated (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred). Sufficient data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not available. When using efavirenz with low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, due to possible pharmacodynamic interaction. 

Coadministration of ritonavir (500 mg every 12 hours, for 8 days) with efavirenz (600 mg, daily, for 10 days) to 11 subjects resulted in increases in ritonavir Cmax, AUC and Cmin of 24%, 18% and 42%, respectively, following the morning dose; following the evening dose, there was no change in ritonavir Cmax or AUC, but a 24% increase in Cmin. Ritonavir caused increases in efavirenz Cmax, AUC and Cmin of 14%, 21% and 25%, respectively. Combining efavirenz with ritonavir was associated with higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes and adverse clinical experiences is recommended when efavirenz is used in combination with ritonavir.

Coadministration of efavirenz (600 mg once daily) and ritonavir (500 mg twice daily) increased efavirenz AUC by 21% and ritonavir AUC by 17%. A higher frequency of adverse events (e.g., dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes) have been observed when efavirenz is co-administered with ritonavir dosed as an antiretroviral agent.

The effect of low dose ritonavir (100 mg) on efavirenz concentrations was assessed in a group of patients taking a ritonavir-boosted PIs with efavirenz (600 mg) and compared those taking 2 NRTIs with efavirenz. Efavirenz concentrations were about 40% greater in patients taking a ritonavir-boosted PI but efavirenz Ctrough were within the therapeutic range in 90% patients.

Coadministration of efavirenz (600 mg once daily) and ritonavir (500 mg every 12 h) has shown that efavirenz inhibited the metabolism of ritonavir. This resulted in a 18% increase in ritonavir AUC and 24% increase in ritonavir Cmax after the morning dose of ritonavir. There was no change in AUC or Cmax after the evening dose. Efavirenz AUC increased by 21% and Cmax increased by 14% in the presence of ritonavir.

Ritonavir (400 mg) + Saquinavir
The effect of adding efavirenz (600 mg once daily) on the pharmacokinetics of saquinavir/ritonavir (400/400 mg bd) was studied in 8 HIV+ subjects. Efavirenz had no effect on the AUC, Cmax or Cmin of saquinavir or ritonavir after 6 weeks of therapy. After 6 months of therapy, saquinavir and ritonavir Cmin were stable, however, there was a 27% decrease in saquinavir AUC and a 30% decrease in ritonavir AUC (compared to 6 week data). Therefore, efavirenz does not affect the pharmacokinetics of saquinavir or ritonavir when given in at a dose of 400/400 mg bd. The AUC and Cmax, but not the half life, of saquinavir and ritonavir decreased after long term administration suggesting changing bioavailability over time.

The pharmacokinetics of saquinavir/ritonavir (400/400 mg bd) and efavirenz (600 mg once daily) were studied in 12 healthy volunteers. The addition of efavirenz led to ~10% reduction in saquinavir trough concentrations and a slight increase in ritonavir trough concentrations. Efavirenz concentrations were >1000 ng/ml in 11/12 subjects. Overall, there was no significant change in the pharmacokinetics of saquinavir, ritonavir or efavirenz.

Efavirenz/Amprenavir and 2nd PI
This study, ACTG5043, was developed when the routine use of boosted protease inhibitors was not considered standard of care, and the optimal approach to combining PIs with efavirenz was under investigation. ACTG5043 had a relatively complex design and examined PK interactions between amprenavir and efavirenz, both by themselves and when nelfinavir, indinavir, ritonavir, or saquinavir was added. A PK study was conducted after the administration of single doses of amprenavir (600 mg, day 0). Subjects (n=56) received efavirenz (600 mg once daily) for 10 days and restarted amprenavir (600 mg twice daily) with efavirenz for days 11 to 13 with a PK study on day 14. A second PI (nelfinavir 1250 mg twice daily; indinavir 1200 mg twice daily; ritonavir 100 mg twice daily; or saquinavir 1600 mg twice daily) was added to amprenavir and efavirenz on day 15, and a PK study was conducted on day 21. Controls continued amprenavir and efavirenz without a second PI. Amprenavir AUC was 46-61% lower with efavirenz (day 14 vs day 0; P values of <0.05). In the nelfinavir, indinavir, and ritonavir groups, day 21 amprenavir AUCs with efavirenz were higher than AUCs for efavirenz alone. The authors conclude that efavirenz lowered amprenavir AUC, but NFV, IDV or RTV compensated for efavirenz induction.

Nelfinavir/Ritonavir + Efavirenz (once daily)
The effect of efavirenz (600 mg once daily) on nelfinavir/ritonavir (1875/200 mg once daily) was studied in 24 healthy subjects. Following the addition of efavirenz, nelfinavir geometric mean AUC, Cmax and Cmin increased by 30%, 29% and 48% respectively. Nelfinavir Cmin increased in 21/24 subjects and decreased in 3/24 subjects. Ritonavir geometric mean AUC, Cmax and Cmin decreased by 20%, 24% and 12% respectively. Efavirenz exposure was similar to historical data.