Once daily Kaletra: dose escalation rarely the answer for those with low plasma levels

Even after dose escalation, plasma concentrations of once-daily Kaletra (lopinavir/ritonavir) rarely reach therapeutic levels in some patients, according to a study published in the July 1^st edition of AIDS. The Dutch investigators found that increasing the once-daily dose could also result in more side-effects and problems with pill burden.

A recently published study showed that a significant number of patients receiving a once-daily Kaletra dose of lopinavir/ritonavir 800/200mg as part of a highly active antiretroviral therapy (HAART) combination had lower plasma trough concentrations of Kaletra than individuals taking HAART which included a twice daily dose of lopinavir/ritonavir 400mg/100mg.

Dutch investigators wished to determine the pharmacokinetics of Kaletra dosed as lopinavir/ritonavir 800/200mg once a day and the effect of a dose increase in Kaletra in patients with suboptimal plasma concentrations of the drug.

A total of 20 individuals were included in the study (ten treatment-experienced and ten treatment-naïve) and were prescribed lopinavir/ritonavir 800/200mg once daily in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). After two weeks of treatment, blood was drawn to measure concentrations of lopinavir.

The daily dose of Kaletra was increased by one pill (133/33mg lopinavir/ritonavir) if optimal plasma concentrations of the drug were not reached. After another two weeks, drug levels were again measured, and the dose of Kaletra was increased by another pill for patients with suboptimal plasma levels.

Analysis of the first blood sample indicated that 14 individuals had lopinavir trough concentrations comparable to those seen in patients receiving Kaletra twice-daily. However six individuals had suboptimal plasma concentrations of lopinavir and were eligible for dose-escalation. Follow-up data were available for four individuals, all of whom were naïve to antiretrovirals at baseline. After the first dose escalation, which increased the single daily dose of Kaletra to 933/233mg lopinavir/ritonavir, none of the patients had met the target plasma trough concentrations of lopinavir.

The dose was then increased to 1066/266mg lopinavir/ritonavir once a daily. This achieved an optimal lopinavir plasma trough level in one patient. However, one patient stopped treatment because of increased pill burden, another stopped because of severe and persistent diarrhoea, and one patient stopped because of virologic failure.

“The main findings of this study were that the pharmacokinetic profile of once daily lopinavir/ritonavir 800/200mg in 20 HIV-infected patients was similar to data presented on once-daily lopinavir/ritonavir with nucleosides administered twice a day”, write the investigators. They add, “more importantly, the present study gives insight into the effect of dose adjustment in patients who did not reach the predefined lopinavir” trough levels.

"Only one patient reached an optimal trough concentration of lopinavir after dose escalation", comment the investigators, but they add that experience with nelfinavir (Viracept) has shown the dose escalation is only effective in a “minority of patients. This observation indicates that dose adjustments also may not have the desired effect for other protease inhibitors.”

However, they also suggest that the gastrointestinal tract may be unable to absorb increased doses of Kaletra, and the “occurrence of diarrhoea at higher doses could be an important factor.”