Pilot PK study of two generic paediatric formulations of lopinavir/ritonavir vs originator products

Affordable protease inhibitors in suitable formulations for children are urgently needed.

De Kanter and colleagues from the University Nijmegan, the Netherlands, showed pharmacokinetic (PK) data from a phase I, open-label crossover study to
evaluate two generic paediatric formulations of lopinavir/ritonavir developed by Cipla Pharmaceuticals (Lopimune tablets and granules 100/25mg). This was
a pilot study designed to exclude large (>40%) differences in the exposure to lopinavir achieved using the generic formulations compared to the
originator product (Kaletra).

Twelve HIV-negative adult volunteers were randomised to receive the following sequences of regimen ABC, ACB, BCA, BAC, CAB, CBA: A=Kaletra tablets, B=Lopimune granules and C=Lopimune paediatric tablets. They were given single doses of medication (400mg lopinavir) on an empty stomach at one-week intervals and a 32-hour PK curve was recorded. A 32- hour PK curve was also recorded for 5/12 volunteers after receiving lopinavir granules and Kaletra oral formulation both with food.

The volunteers were a median age 24 (range 21-55) years, height 1.79 (range 1.63-1.95) meters and weight 72 (range 51-87) kg. One third of the group were women.

The investigators found the median lopinavir AUC0-t was 71.8 h.mg/L (IQR 48.7-93.5) with Kaletra tablets (A), and 38.7 h.mg/L (IQR 28.7-52.2) and 58.7 h.mg/L (IQR 42.5-79.4) with Lopimune granules (B) and Lopimune tablets (C) respectively. With Kaletra tablets as a reference these differences were statically significant, B vs A, p=0.003 and C vs A, 0.015. Cmax median values were 7.2 mg/L (IQR 5.8-8.3), 4.6 mg/L (IQR 4.1-5.2) and 6.5mg/L (IQR 5.0-7.1); B vs A, p=0.003 and C vs A, p= 0.012.

The investigators also noted lower ritonavir concentrations with the Lopimune formulations compared to Kaletra.

A sub-group of volunteers received Lopimune granules (n=5) and Kaletra oral solution (n=4) with food. In this comparison, the median lopinavir AUC0-t was 62.1 h.mg/L (IQR 43.8-126.3) with Kaletra tablets, and 58.5 (IQR 55.4-77.6) and 49.6 h.mg/L (IQR 39.1-58.1). Cmax median values were 7.2 mg/L (IQR 4.6-9.1), 6.4 mg/L (IQR 5.5-7.6) and 5.2 mg/L (IQR 4.3-5.7).

The investigators concluded that it is possible to exclude large differences in PK parameters for the Lopimune paediatric tablets, compared to Kaletra, when received on an empty stomach. Large differences can also be excluded for the Lopimune granules when these are received with food.

They added that, based on these results, it was acceptable to start PK and dose finding trials of the Lopimune paediatric tablets and granules even though the Cipla bioequivalence study was not yet complete.

COMMENT

This study did not test the effect of different compositions of meals on the absorption of LPV/r. They used a standardised normal European/Dutch breakfast, to see if the absorption would be better with food than without, as this is the case with the absorption of lopinavir from Kaltera oral solution. The absorption from the granules might be dependent on the amount of fat in the meal as is stated in the Summary of Product Characteristics.

Since this small study, the Cipla formulation has changed and has been slightly refined, so there is an ongoing bioequivlance study. CHAPAS 2, which will look at these products in children, is waiting on these results before it begins (probably around March). CHAPAS 2 will be able to investigate absorption among breastfeeding children and also those who are malnourished.

Ref: de Kanter et al. The pharmacokinetics of two generic co-formulations of lopinavir/ritonavir for HIV-infected children: a pilot study of pediatric lopimune formulations vs the branded product in healthy volunteers. 12th EACS, Cologne, November 11-14, 2009. Abstract PE15.2/1.