The co-administration of Reyataz/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co-administration is not recommended.

Although not studied, the coadministration of Reyataz/ritonavir and an additional protease inhibitor would be expected to increase exposure of the other protease inhibitor. Such coadministration is not recommended.

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended. Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atrioventricular block in patients with underlying structural heart disease and preexisting conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients.

The impact on the PR interval of coadministration of Kaletra with other drugs that prolong the PR interval (including atazanavir) has not been evaluated. As a result, coadministration of Kaletra with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. 

Coadministration of lopinavir/ritonavir (400 mg/100 mg, twice daily) with atazanavir (300 mg, once daily) was studied in HIV positive patients. Atazanavir Cmin, Cmax and AUC increased ~124%, ~12% and ~117%, respectively. Lopinavir Cmin, Cmax and AUC decreased ~1%, ~21% and ~15%, respectively. The effects on lopinavir PK values were not considered significant. 

This phase I, open-label, 3-period, fixed sequence pharmacokinetic study was in healthy volunteers (n=15). Period I was atazanavir/ritonavir (300/100 mg once daily); period II was atazanavir (300 mg once daily) plus lopinavir/ritonavir (400/100 mg twice daily); period III was atazanavir/ritonavir (300/100 mg once daily) plus lopinavir/ritonavir (400/100 mg once daily). Pharmacokinetic analysis was performed on the last day of each dosing period. The main findings were: atazanavir Cmin was 45% higher in period II vs period I, AUC did not differ and there was a trend to lower Cmax; the additional ritonavir in period III did not significantly increase atazanavir Cmin, AUC or Cmax compared to period II; the additional ritonavir in period III increased lopinavir Cmin by 28% compared with period II. The authors conclude that a combination of lopinavir/ritonavir (400/100 mg twice daily) plus atazanavir (300 mg once daily) gives appropriate pharmacokinetic profiles and could be further evaluated in treatment-experienced patients. 

The pharmacokinetics of lopinavir and atazanavir were determined in 16 HIV+ subjects receiving lopinavir/ritonavir (400/100 mg twice daily) and atazanavir (300 mg once daily). Values were compared to HIV+ historical controls receiving lopinavir/ritonavir (400/100 mg twice daily, n=15), saquinavir/lopinavir/ritonavir (1000/400/100 mg twice daily, n=25) or atazanavir/ritonavir (300/100 mg once daily, n=15). Lopinavir plasma concentrations were higher when given with atazanavir, than when given alone or with saquinavir (AUC 115.7 vs 85.2 vs 85.1 µg/ml.h; Cmax 12.2 vs 9.5 vs 10.0 µg/ml; Cmin 9.1 vs 5.6 vs 5.5 µg/ml). No difference was observed when atazanavir was given with lopinavir/ritonavir vs alone for AUC (48.2 vs 45.2 µg/ml.h) and Cmax (3.95 vs 4.44 µg/ml); however, Cmin was higher when given with lopinavir/ritonavir (1.07 vs 0.58 µg/ml). The increase in atazanavir Cmin is likely to be due to the additional dose of ritonavir when given twice daily with lopinavir. 

The effect of adding lopinavir (400/100 mg twice daily) to atazanavir/ritonavir (300/100 mg once daily) or adding atazanavir (300 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily) was investigated in HIV-infected subjects. For patients initially receiving atazanavir/ritonavir once daily, ritonavir was stopped and lopinavir/ritonavir twice daily added, thus doubling the daily dose of ritonavir. The addition of lopinavir/ritonavir had no effect on atazanavir AUC (53899 vs 49197 ng/ml.h, alone vs combination), Cmax (3996 vs 3425 ng/ml) or Cmin (860 vs 796 ng/ml). The addition of atazanavir to lopinavir/ritonavir resulted in non-significant decreases in lopinavir AUC (85415 vs 70057 ng/ml.h alone vs. combination) and Cmax (9096 vs 7505 ng/ml), but significantly decreased lopinavir Cmin (4049 vs 2840 ng/ml). The clinical significance of the decreased lopinavir exposure is unknown and warrants further investigation. 

HIV+ subjects taking lopinavir/ritonavir (400/100 mg twice daily) added in atazanavir (300 mg once daily) on day 1 and pharmacokinetics over 12 hours were determined on day 7. Atazanavir was then stopped and after a 14-day washout, pharmacokinetic sampling for lopinavir repeated. Lopinavir pharmacokinetics were not significantly different when lopinavir was taken with or without atazanavir. Atazanavir Cmin values were similar to historical controls.