Coadministration of lopinavir/ritonavir capsules and efavirenz resulted in a substantial decrease in lopinavir exposure. With efavirenz, an increase of the lopinavir/ritonavir capsule or oral solution doses by 33% should be considered (4 capsules/~6.5 ml twice daily instead of 3 capsules/5 ml twice daily). Caution is warranted since this dosage adjustment might be insufficient in some patients. Coadministration of lopinavir/ritonavir tablets (400/100 mg twice daily) and efavirenz (600 mg once daily) decreased lopinavir concentrations by 30-40%. When lopinavir/ritonavir tablets (500/125 mg twice daily) and efavirenz (600 mg once daily) were coadministered, lopinavir concentrations were similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz. The dosage of lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily when coadministered with efavirenz 600 mg once daily. 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-boosted lopinavir (400/100 mg every 12 hours) with efavirenz (600 mg), in 11 (efavirenz plus lopinavir/ritonavir) and 7 (lopinavir/ritonavir alone) subjects, resulted in no change in lopinavir Cmax, a 19% decrease in AUC and a 39% decrease in Cmin. Efavirenz AUC and Cmin both decreased by 16% but there was no alteration in Cmax. An increased dose of lopinavir/ritonavir (500/125 mg twice daily) was coadministered with efavirenz (600 mg once daily) to 19 subjects for 10 days. When compared to lopinavir/ritonavir alone (400/100 mg twice daily), lopinavir Cmax increased by 12%, there was no change in AUC and Cmin decreased by 10%. A higher dose of lopinavir/ritonavir (600/150 mg twice daily) was coadministered with efavirenz (600 mg once daily) to 23 subjects for 10 days. When compared to lopinavir/ritonavir alone (400/100 mg twice daily), lopinavir AUC and Cmax both increased by 36% and Cmin increased by 32%. The pharmacokinetics of ritonavir were unaltered at all doses.
Dose increase of lopinavir/ritonavir is recommended for all patients. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients. Lopinavir/ritonavir tablets should not be administered once daily in combination with efavirenz.

Kaletra must not be administered once daily in combination with efavirenz. Coadministration of efavirenz (600 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) decreased lopinavir AUC, Cmax and Cmin by 20%, 13% and 42%, respectively. Coadministration of lopinavir/ritonavir (500/125 mg twice daily) and efavirenz (600 mg once daily) had no effect on lopinavir concentrations relative to 400/100 mg twice daily administered alone. The Kaletra tablets dosage should be increased to 500/125 mg twice daily when coadministered with efavirenz.

Kaletra ONCE DAILY in combination with efavirenz is not recommended. The dose of Kaletra must be increased when administered in combination with efavirenz. The recommended dose of Kaletra tablets is 500/125 mg twice daily (such as two 200/50 tablets and one 100/25 tablet). The recommended dose of Kaletra oral solution for adults is 520/130 mg (6.5 mL) twice daily. Coadministration of efavirenz (600 mg once daily for 9 days) and lopinavir/ritonavir capsules (400/100 mg once daily for 9 days) to 11 HIV- subjects resulted in decreases in lopinavir Cmax, AUC and Cmin of 3%, 19% and 39% respectively, when compared to data from 7 subjects receiving lopinavir/ritonavir alone. Efavirenz Cmax decreased by 9% and AUC and Cmin both decreased by 16% (compared to data from 12 subjects receiving efavirenz alone). Coadministration of efavirenz (600 mg once daily for 9 days) and Kaletra tablets (500/125 mg twice daily for 10 days) was studied in 19 HIV- subjects. When compared to values obtained with Kaletra tablets alone (400/100 mg twice daily), coadministration at the higher dose increased lopinavir Cmax (12%) and AUC (6%), and decreased Cmin (10%). Coadministration of efavirenz (600 mg once daily for 9 days) and Kaletra tablets (600/150 mg twice daily for 10 days) was studied in 23 HIV- subjects. When compared to values obtained with Kaletra tablets alone (400/100 mg twice daily), coadministration at the higher dose resulted in an increased lopinavir Cmax (36%), AUC (36%) and Cmin (32%).

Two prospective, open-label, non-randomized studies evaluated amprenavir and lopinavir steady-state pharmacokinetics in HIV-infected patients on a background of nucleosides and amprenavir/lopinavir/ritonavir (750/533/133 mg twice daily) with (n=7) or without (n=12) efavirenz (Study 1) and after switching from amprenavir to fosamprenavir (1400 mg twice daily, n=10; Study 2). Efavirenz did not significantly alter amprenavir and lopinavir pharmacokinetic parameters in patients taking amprenavir/lopinavir. Switching to fosamprenavir resulted in an increase in amprenavir Cmin, AUC, and Cmax without changing lopinavir or ritonavir pharmacokinetics or overall tolerability.

A dose increase to 533/133 mg was advised when lopinavir/ritonavir capsules were coadministered with efavirenz. As this dose increase is not possible with the new tablet formulation (200/100 mg lopinavir/ritonavir per tablet), the coadministration of 2 tablets of lopinavir/ritonavir (400/100 mg twice daily) with efavirenz (600 mg once daily) was studied in 21 HIV- subjects. Subjects received 3 lopinavir/ritonavir capsules (400/100 mg twice daily for 10 days) followed by 2 lopinavir/ritonavir tablets with efavirenz for 10 days. Lopinavir PK parameters were determined on days 10 (3 capsules alone) and 20 (2 tablets + EFV). Mean (± sd) lopinavir Cmax, AUC and Ctrough values on day 10 were 11.8±3.3 µg/ml, 95.7±33.7 µg.h/ml and 6.8±3.3 µg/ml, respectively. Cmax, AUC and Ctrough values obtained on day 20 were 10.5±4.0 µg/ml, 84.9±17.8 µg.h/ml and 5.0±2.7 µg/ml, respectively. Coadministration of efavirenz with the lopinavir/ritonavir tablet decreased lopinavir AUC and Ctrough by ~20% and 27%, respectively, compared to the capsule formulation administered alone. The concentrations obtained with the tablet + EFV were within the range of concentrations previously demonstrated to be efficacious in clinical trials.

As the new lopinavir/ritonavir tablet is a fixed dose combination of 200/50 mg (the capsule dose is 133/33 mg), a dose increase to 533/133 mg when lopinavir/ritonavir is coadministered with efavirenz will not be possible. This study evaluated the pharmacokinetics of lopinavir/ritonavir (600/150 mg twice daily) with efavirenz (600 mg once daily). When compared to lopinavir/ritonavir (400/100 mg twice daily) given alone, lopinavir Cmax and AUC were moderately increased (36%); ritonavir Cmax increased 92% and ritonavir AUC increased 78%. The regimens were generally well tolerated.

Coadministration of an NNRTI (n=25; NVP n=9, EFV n=16) with lopinavir/ritonavir (400/100 mg twice daily) resulted in a 39% decrease in lopinavir Ctrough but no change in Cmax, compared in patients taking lopinavir/ritonavir (400/100 mg twice daily alone n=125). There was no difference in lopinavir Ctrough between patients taking efavirenz and nevirapine. There was no difference in lopinavir Ctrough between patients taking lopinavir (400/100 mg twice daily, n=125) and those taking lopinavir/ritonavir (533/133 mg twice daily, n=32) with an NNRTI (NVP n=3, EFV n=29). There was no statistically significant difference in ritonavir Ctrough or Cmax in patients taking lopinavir/ritonavir 400/100 mg twice daily with or without an NNRTI but patients taking lopinavir ritonavir 533/133 mg twice daily with an NNRTI had higher ritonavir Ctrough and Cmax. The number of patients with lopinavir concentrations below the 3000 ng/ml threshold was higher in those taking lopinavir/ritonavir 400/100 with an NNRTI compared to those without an NNRTI. However, the number of patients with suboptimal levels was comparable between those taking lopinavir/ritonavir 400/100 mg alone to those taking lopinavir/ritonavir 533/133 mg plus an NNRTI. Similar results were observed when a lower threshold (1500 ng/ml) was used.

The coadministration of efavirenz with 2 NRTIs (n=19) or with 2 NRTIs plus lopinavir/ritonavir (400/100-532/132 mg twice daily, n=40) was studied in treatment experienced patients. No statistically significant modification in efavirenz plasma concentrations between the two groups was observed.

The steady-state pharmacokinetics of lopinavir/ritonavir (400/100 and 533/133 mg twice daily) when dosed in combination with efavirenz, plus two NRTIs, were assessed in 57 multiple PI-experienced but NNRTI-naive HIV+ subjects. When codosed with efavirenz, the 400/100 mg regimen resulted in lower lopinavir concentrations, (trough concentration = 3.66±2.64 µg/ml) than were observed in previous studies of lopinavir/ritonavir administered without efavirenz. Increasing the lopinavir/ritonavir dose to 533/133 mg increased lopinavir AUC, Cmax, and Cmin by 46, 33, and 141%, respectively. Ritonavir AUC, Cmax, and Cmin values were increased by 48, 46 and 63%, respectively. The lopinavir trough concentration (5.88±5.53 µg/ml) achieved with the 533/133 mg dose was similar to historical data obtained with lopinavir/r 400/100 mg in the absence of efavirenz (5.49±4.02 µg/ml).

The coadministration of efavirenz to 4 patients receiving lopinavir/ritonavir resulted in lopinavir Cmin values of 7625 (2870-11200) ng/ml and Cmax values of 14100 (3990-17300) ng/ml. Mean lopinavir concentrations in a group of patients (n=4) receiving lopinavir/ritonavir alone were 5690 (1420-11120) ng/ml for Cmin and 12400 (3920-17300) ng/ml for Cmax. Efavirenz concentrations were 23100 (600-5775) ng/ml for Cmin and 3445 (1000-10173) ng/ml for Cmax.

An interaction study of Kaletra (lopinavir/ritonavir) and efavirenz was performed in healthy volunteers and HIV+ individuals all of whom received Kaletra (400 lopinavir/100 ritonavir mg twice daily) and efavirenz (600 mg once daily). In healthy volunteers, efavirenz had no effect on the pharmacokinetics of ritonavir, with efavirenz Cmax, AUC and Cmin being reduced by 16% or less in the presence of Kaletra. In healthy volunteers, efavirenz resulted in a 19% decrease in the AUC of lopinavir and a 39% decrease in the Cmin of lopinavir; there was no change in the Cmax of lopinavir. In HIV+ individuals, the decrease in lopinavir was 25% for AUC and 44% for Cmin. No dosage adjustment of efavirenz is required when administered with Kaletra. However, Kaletra should be increased by 33% from 400/100 mg to 533/133 mg when coadministered with efavirenz.