Heat-stable ritonavir tablet equivalent to soft gel capsule; may be approved next year

A new 100 mg tablet formulation of the protease inhibitor ritonavir (Norvir) appears to be equivalent to the current soft-gel capsule formation in terms of side-effects and boosting potential, according to data presented to the XVII International AIDS Conference in Mexico City last week. The new tablet formulation, which like the Kaletra tablet, is heat-stable and does not require refrigeration, will be submitted for registration in the US and EU by the end of the year, says its developer, Abbott.

Ever since 2005, when Abbott developed a tablet formulation of Kaletra using melt extrusion (Meltrex) technology, expectations had been high that a tablet formulation of ritonavir – which is used to boost all currently approved protease inhibitors (PIs) as well as Schering’s investigational CCR5 antagonist, vicriviroc, and Gilead’s investigational integrase inhibitor, elvitegravir – would soon follow.

However, according to Dr Barry Bernstein, Abbott’s Global Project Head who presented the data on the new ritonavir tablet, its development has been hindered by formulation problems. The first formulation developed crystals at high temperatures, making it an unviable prospect for much of the developing world, and the second absorbed so much moisture from the atmosphere at room temperature that it swelled to double its size, also increasing the risk of crystal formulation.

A third formulation appears not to suffer from its predecessors’ problems and was compared with the ritonavir soft-gel capsule in 93 healthy male (53%) and female (47%) volunteers in a phase 1 study, M10-307. The majority (90%) were of white ethnicity, with an average age of 29.2 years (range: 19.0-55.0) and an average weight of 74.8 kg (range: 45.0-105.0).

Blood samples were taken for 36 hours after each dose to determine the maximum plasma concentration (C_max) of the formulation and the area under the curve (AUC). Values were taken and compared for both the tablet and soft-gel capsule.

The investigators found that although AUC was broadly similar between the two formulations (the tablet AUC was a non-significant 10 - 13% higher than the soft-gel capsule), C_max was 26% higher for the tablet compared with the soft-gel capsule, an increase that Dr Bernstein characterised as "modest".

A similar number of participants in each arm (21% on the tablet , 24% on the soft-gel capsule) experienced at least one adverse event, although these were broadly similar in both arms: headache (8% vs. 9%); nausea (3% vs. 4%); dizziness (2% vs. 6%); and diarrhoea (2% vs. 3%).

Dr Bernstein then presented data from previous studies of the tablet formulation of Kaletra – which results in a 20% higher ritonavir AUC and a 35% higher ritonavir C_max compared with the Kaletra soft-gel capsule – to show that Abbott anticipates the ritonavir tablet to be safe and to result in a "not substantially different" PI boosting effect compared with the ritonavir soft-gel capsule.

Dr Bernstein told the conference that the company is currently completing a food effect study as well as examining stability in a variety of temperature conditions, and that "we are confident that we will be able to submit the package by the end of the year" to the FDA and EMEA.

If approval arrives in 2009, Abbott intends to register the new tablet as broadly worldwide as Kaletra. However, the four year development delay may result in future lost opportunities for Abbott. Last month Gilead announced that it has begun human studies of a product that could replace ritonavir, and which could be used in future fixed-dose combinations to rival the convenience of Kaletra.