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Differing Effects of Low- and High-Fat Meals on New Raltegravir Formulation
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14th European AIDS Conference. October 16-19, 2013. Brussels
EACS: A Single Dose Food Effect Study of Raltegravir (RAL) Formulations Once Daily Tablet - (10/17/13)
EACS: Once-Daily Raltegravir for 48 Weeks as Maintenance Therapy in Paris - (10/21/13)
EACS: Merck Presents New Pharmacokinetic Data on ISENTRESS® (raltegravir) at 14th European AIDS Conference - (10/25/13)
Mark Mascolini
A high-fat meal affected levels of a reformulated raltegravir tablet less than a low-fat meal, according to results of a three-period study in healthy volunteers [1]. One aim of this trial and other ongoing research is to develop a raltegravir formulation that can be dosed once daily.
Merck scientists are developing a new raltegravir formulation and testing it at a once-daily 1200-mg dose taken in two tablets. The current raltegravir formulation requires twice-daily dosing with a 400-mg tablet for a total dose of 800 mg. This food-effect study tested two 600-mg tablets of the new formulation taken at the same time and three 400-mg tablets of the current formulation taken at the same time. The current formulation can be taken with or without food.
The study involved 36 healthy men and women from 18 to 55 years old. Eighteen of them took the current raltegravir tablet and 18 took reformulated raltegravir. Participants gave blood samples before dosing then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 hours after the single dose. Each participant took raltegravir after fasting, after a low-fat meal, and after a high-fat meal. Using log-transformed data, the research team calculated ratios of geometric means comparing each fed condition with the fasted condition for each formulation.
Study participants had no clinical or laboratory serious adverse events, and no one dropped out of the study because of an adverse event. The researchers saw no consistent treatment-related changes in lab values, vital signs, or electrocardiogram readings.
With the current raltegravir formulation, compared with the fasting state, a low-fat meal lowered raltegravir concentrations, while a high-fat meal raised concentrations:
Current formulation, low-fat meal versus fasting:
71% decrease in area under the concentration-time curve (AUC)
75% decrease in maximum concentration (Cmax)
18% decrease in 24-hour concentration (C24hr)
Current formulation, high-fat meal versus fasting:
26% increase in AUC
23% decrease in Cmax
70% increase in C24hr
With the new raltegravir formulation, compared with the fasting state, a low-fat meal lowered raltegravir concentrations (but less so than the current formulation), whereas a high-fat meal had little impact on AUC while lowering Cmax and C24h:
New formulation, low-fat meal versus fasting:
40% decrease in AUC
52% decrease in Cmax
16% decrease in C24hr
New formulation, high-fat meal versus fasting:
3% increase in AUC
28% decrease in Cmax
12% decrease in C24hr
In a separate multiple-dose study, a 1200-mg dose of reformulated raltegravir resulted in a steady-state C24h of 83 nM, compared with 82 nM with 1200 mg of the current formulation.
The Merck team is assessing the possible clinical significance of these food effects through viral dynamics pharmacokinetic/pharmacodynamic modeling and simulation. They are also conducting multiple-dose studies, with an eye toward testing reformulated raltegravir as a once-daily regimen.
Reference
1. Krishna R, Rizk ML, Schulz V, Ingelse B, Larson P. A single dose food effect study of raltegravir formulations. 14th European AIDS Conference. October 16-19, 2013. Brussels. Abstract PE10/17.
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