Abbott Laboratories, the manufacturers of ritonavir-boosted lopinavir (Kaletra) announced the development of a new tablet formulation of the protease inhibitor on July 27th at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro.
Kaletra is currently available in soft gel capsules comprising lopinavir and ritonavir at doses of 133 and 33mg, respectively, with the standard dose being three capsules twice a day with food. The soft gel capsules require storage in a refrigerator.
The new tablet formulation’s chief advantages over the existing soft gel formulation are a reduced pill burden of two tablets twice a day and easier storage – the tablets do not require storage in a refrigerator. Each tablet contains 200mg lopinavir and 50mg ritonavir.
The new formulation produces similar blood levels of both lopinavir and ritonavir to the existing soft-gel capsule. However, patients taking the new tablet formulation of the drug are less likely to experience extreme peaks and troughs in blood drug levels.
Although data comparing the clinical benefits of the new tablet to the existing formulation have not yet been presented, these findings suggest that the tablet may eventually be a more attractive option for HIV-positive patients.
The tablet formulation of Kaletra is produced using melt extrusion technology (Meltrex). This process allows the drug to be dispersed evenly throughout the tablet, rather than existing as large crystals up to 150µm in diameter, mixed with excipients in the soft gel capsules. This improves the ability of the drug to enter the bloodstream, as well as allowing storage at room temperature.
Dr George Hanna presented data from three studies including 141 HIV-negative volunteers. These assessed plasma levels of the new tablet formulation after it was provided in a fasting state, after a moderate fat meal and after a high fat meal.
Pharmacokinetic parameters, including total drug exposure and maximum concentrations of the drug (Cmax) were calculated. The bioequivalence of the two formulations of the drug at a dose of 400 / 100mg was assessed after dosing with a moderate fat meal.
The total drug exposure for the tablet formulation of Kaletra was similar to that of the soft gel formulation under the reference moderate fat meal conditions, with maximal concentrations of lopinavir being 24% greater and total drug exposure increasing by 18%. Maximal ritonavir concentration was also increased, by 35%, while total drug exposure was elevated by 20%. Dr Hanna said, "modest elevations are not expected to alter the safety or clinical profile of lopinavir / ritonavir therapy."
In addition, the pharmacokinetics of the tablet under all the study meal conditions were similar to the soft gel formulation after dosing with a moderate fat meal.
Variability in drug exposure and Cmax of the tablet was compared to the soft gel formulation when dosed with each of the study meal conditions. Food did not have a significant effect on the blood levels of either lopinavir or ritonavir.
Furthermore, significantly fewer individuals taking the tablet experienced extreme highs or lows in plasma concentrations of the drug compared to individuals taking the existing soft gel Kaletra. The investigators conclude, “the tablet is expected to provide more consistent lopinavir and ritonavir levels day to day as meal conditions vary.”
The researchers also found that the new tablet version had few side-effects, with the majority reported being mild in severity. The incidence of moderate or severe side-effects was lower in the patients taking the tablet formulation (0.7 vs. 1.1%), as was the incidence of diarrhoea (0.3 vs. 1.1%). The investigators noted that the “tablet formulation was safe and well tolerated with single or multiple dose administrations.”
They conclude, “lopinavir / ritonavir levels were similar between tablet and soft gel capsule formulations under reference meal conditions. There was considerably less food effect with the tablet formulation, and pharmacokinetic variability was significantly reduced under all meal conditions compared to the soft gel capsule.”
Responding to a question from the audience, Dr Hanna confirmed that Abbott were currently investigating applying Meltrex technology to ritonavir (Norvir). Although he could not estimate when a similar version of ritonavir would be available, he said that many of the lessons learned during the development of the new Kaletra tablets were helping in their development of ritonavir tablets.
Awni W et al. Significantly reduced food effect and pharmacokinetic variability with a novel lopinavir/ritonavir tablet formulation. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WeOa0206, 2005.