Purpose of the study PR prolongation has been reported with HIV protease inhibitors such as atazanavir. We evaluated the potential for PR prolongation with LPV/r and RTV. Methods Phase I, multiple-dose, open-label, placebo-controlled, randomized study conducted according to a crossover design. Study drugs were dosed for 3 days to allow for maximal exposure, as RTV-mediated CYP3A4 inhibition is complete and induction is minimal. LPV/r was dosed at 400/100 mg BID and at supratherapeutic 800/200

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... BID. RTV was dosed at 400 mg BID. Digital EKGs and pharmacokinetic samples were obtained on study Day 3. Absolute PR interval on Day 3 and change from baseline were evaluated. Exposure-PR response modeling was performed. Summary of results Substantially higher LPV (30-50% for 400/100 mg BID and 3-fold for 800/200 mg BID) and RTV (2-fold) concentrations were achieved on Study Day 3 compared to historical steady-state values of LPV/r 400/100 mg BID and RTV 600 mg BID. Mean PR changes from baseline ranged from 11.6-24.4 msec (LPV/r 400/100 mg BID), 22.0-31.2 msec (LPV/r 800/200 mg BID) and 11.0-24.0 msec (RTV 400 mg BID), all p < 0.0001 compared to placebo. No subject had a PR interval greater than 286 msec. No subject experienced 2nd or 3rd degree atrioventricular block. Conclusion Based on the exposure-response model, it is estimated that the mean PR effect plateaus and has reached its maximum with the supratherapeutic 800/200 mg BID dose. At steady state, LPV/r is expected to produce clinically insignificant increases in PR interval of 18 to 20 msec and low dose ritonavir (100-400 mg daily) is expected to prolong PR by 4.8 to11.6 msec. LPV/r and RTV do not result in clinically significant increases in PR interval. However, this effect should be considered when co-administering LPV/r or RTV with other drugs known to prolong PR interval or in patients with co-morbid conditions.