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Is Kaletra a once daily protease inhibitor?
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Reported for NATAP by Graeme Moyle, MD
9th EACS Conference in Warsaw
Oct 29, 2003
With the recent approval of atazanavir as a QD PI and fosamprenavir for either once daily or twice daily usage, the market for compact protease inhibitors that can be used for once daily therapy is rapidly expanding. Some previous pharmacokinetic data and results of a small study had supported the idea that in individuals without prior protease inhibitor experience lopinavir/r (Kaletra) may be given once daily. The pharmacokinetic data from the previous pilot study, however, indicated that a subset of individuals have quite low trough exposures of lopinavir at 24 hours, indicating the large ‘pharmacokinetic cushion’ (often marketed under the expression "a high inhibitory quotient (IQ)’) is eroded by using Kaletra once daily. Whether this is important to longer term efficacy is being tested in a larger randomised controlled trial. The data presented at the 9th EACS conference however was only through week 24, an insufficient duration to really test the credibility of the data. It was not indicated whether this presentation was a planned interim analysis and whether subsequent statistical analyses at 48 weeks would take into account the impact of this preliminary analysis on the statistical integrity of the study.
Of note, the study is also the first study to use the once daily backbone of tenofovir and FTC. It is intriguing why this backbone was chosen given that tenofovir is known to modestly decrease lopinavir exposures (although in routine clinical practice no dosage adjustments are recommended).
The study randomised 115 individuals to receive Kaletra once daily (six capsules with food) and 75 individuals to Kaletra twice daily (three capsules with food twice daily) together with the NRTIs. Participants were antiretroviral naive with viral load > 1000 copies/ml and any CD4 cell count. The median viral load was 4.8 log and median CD4 count 214 to 232 cells/ml. At week 24, 16 percent of subjects in each group had discontinued therapy although the reasons for discontinuation differed. Adverse events were the cause of discontinuation in 11% of the Kaletra QD and just 3% of the Kaletra BD patients. Kaletra BD patients were more likely to leave the study for reasons such as poor adherence, loss to follow-up or consent withdrawal. By intention to treat missing equals failure (ITT M=F) analysis 57% of patients in each group had a viral load less than 50 copies/ml at week 24. The study was insufficiently powered to indicate whether this similar response represented statistical equivalence. For the observed or as treated data 68 percent of the Kaletra QD and 70 percent of the Kaletra BD patients were less than 50 copies/ml at 24 weeks. Rises in CD 4 cell count were 128 in the Kaletra QD and 103 in the Kaletra BD groups.
There were no significant differences between the rates of the most common moderate to severe clinical adverse effects. However, diarrhoea was reported in 12% of the Kaletra QD and only 5% of the Kaletra BD patients. There were trends to the Kaletra QD group having a relatively smaller impact on lipids. Looking at patients who developed total cholesterol values above 240 mg/dl, this level of cholesterol was present in 1% of participants in the QD group at baseline and 6% at week 24, whereas in the Kaletra BD group 3% had cholesterol values in this range at baseline and 18% by week 24. In both groups the rising cholesterol was a mixture of both LDL and HDL cholesterol with a similar number of individuals in each group achieving HDL cholesterol values greater than 40 mg/dl at week 24. Similar effects were observed when triglycerides were considered. It is possible that the impression of a better lipid profile with Kaletra in the study may represent the influence of tenofovir as an NRTI which may have a favourable lipid profile.
The study remains ongoing and clearly we would want not only 48 weeks data but also comparative data with some of the more compact once daily protease inhibitors before we would consider using Kaletra routinely as a QD agent. |
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