Pharmacokinetics of two generic co-formulations of lopinavir/ritonavir for HIV-infected children: a pilot study of paediatric Lopimune versus the branded product in healthy adult volunteers.

1 maart 2010
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OBJECTIVES: To determine the pharmacokinetic profiles of lopinavir and ritonavir in two newly developed generic co-formulations for HIV-infected children (Lopimune paediatric tablets and granules, 100/25 mg of lopinavir/ritonavir, Cipla Pharmaceuticals), and to compare these with the branded product (Kaletra). METHODS: This Phase I, comparative, open-label, three-period, single-dose, crossover study was designed as a pilot study to exclude large (>40%) differences in the exposure to lopinavir. Single doses of medication, normalized to 400 mg of lopinavir, were administered on an empty stomach, 1 week apart. A 32 h pharmacokinetic curve was recorded. In an additional part of the study, in five of the same volunteers, a pharmacokinetic curve was recorded after administration of the Lopimune granules and Kaletra oral solution, both with food. RESULTS: Twelve healthy subjects were enrolled (four females). The median (range) age, height and body weight were 24 (21-55) years, 1.79 (1.63-1.95) m and 72 (51-87) kg, respectively. The median [interquartile range (IQR)] AUC(0-t) of lopinavir was 71.8 (48.8-93.5), 38.7 (28.7-52.2) and 58.7 (42.5-79.4) mg.h/L with Kaletra tablets, Lopimune granules and Lopimune paediatric tablets, all taken on an empty stomach, respectively. The respective C(max) values were 7.2 (5.8-8.3), 4.6 (4.1-5.2) and 6.5 (5.0-7.1) mg/L after intake of the different formulations. When comparing the Lopimune formulations with the reference product Kaletra, for all parameters the differences were statistically significant (P <or= 0.015). Ritonavir exposure was also lower after intake of the generic formulations versus Kaletra. When the five subjects took the Lopimune granules or Kaletra solution with food, the median (IQR) AUC(0-t) of lopinavir was 58.5 (55.4-77.6) and 49.6 (39.1-58.1) mg.h/L, respectively. CONCLUSIONS: Large differences in pharmacokinetic parameters can be excluded for Lopimune paediatric tablets when compared with the branded product and t