Food increases bioavailability of atazanavir, darunavir, lopinavir/ritonavir soft capsules and solution, nelfinavir, saquinavir(all formulations) and tipranavir, but decreases that of indinavir.Food only minimally affects bioavailability of amprenavir,fosamprenavir, lopinavir/ritonavir tablets and ritonavir. Mixingritonavir with enteral feeds does not affect pharmacokineticsof ritonavir.
Clinical evidence,mechanism, importance and management
A single 600mg dose of indinavir was given to 7 HIV-positive subjects immediately after various types of meal. The protein, carbohydrate, fat and high-viscosity meals reduced AUC of indinavir by 68%, 45%, 34 % and 30%, respectively. The fat meal was associated with largest inter-subject variation in bioavailability. The effect of protein meal was attributed to fact that it raised gastric pH and therefore impaired absorption of indinavir (a weak base). The impairment of indinavir absorption caused by other meals, which did not alter gastric pH, may have been due to delayed gastric emptying (See reference number 1). A similar study comparing a full breakfast with light breakfasts (toast or cereal) on indinavir absorption found that full breakfast reduced absorption of indinavir by 78 % and reduced its maximum serum levels by 86%, while light breakfasts had no significant effect (See reference number 2). The manufacturers advise that indinavir is given 1 hour before or 2 hrs after meals,or with low-fat light meals only (See reference number 3,4). The US information gives examples of a light meal,such as dry toast with jam, juice, and coffee with skimmed milk and sugar; or corn flakes, skimmed milk and sugar (See reference number 4).
The manufacturers of atazanavir note that administration with a light or high-fat meal decreased wide variation in plasma levels
Darunavir with Ritonavir. The manufacturers of darunavir notes that relative bioavailability of darunavir (with low-dose ritonavir) is 30 % lower when it is given without food, compared with intake with food. Therefore,darunavir tablets should be taken with ritonavir and with food. They say that type of food does not affect exposure to darunavir (See reference number 7,8).
Lopinavir/Ritonavir. A moderate-fat meal increased AUC and maximum level of lopinavir capsules by 48 % and 23%, respectively, and a high-fat meal by 96 % and 43%, respectively. The corresponding increases for lopinavir solution were 80 % and 54 % for moderate-fat meal, and 130 % and 56 % for high-fat meal (See reference number 9). The manufacturers of lopina
vir/ritonavir soft capsules and oral solution say that it should be taken with food (See reference number 9,10). No clinically significant difference was seen in bioavailability of lopinavir/ritonavir tablets between fasting and fed subjects, therefore manufacturers say that it can be taken with or without food (See reference number 10,11).
Nelfinavir. When nelfinavir 400 or 800mg was given to 12 healthy subjects in fasted state, AUC was only 27 % to 50 % of that observed when nelfinavir was given with a meal (See reference number 12). Nelfinavir should be taken with
Saquinavir. The manufacturer of saquinavir hard capsules and tablets notes that, in a crossover study in 22 HIV-positive patients taking saquinavir/ritonavir 1000/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a high-fat, high-calorie meal, AUC, maximum and minimum levels of saquinavir under fasting conditions were about 70 % lower than with a high-fat meal. There were no clinically significant differences in pharmacokinetic profile of ritonavir in fasting and fed conditions but ritonavir minimum level was about 30 % lower in fasting state, when compared with its administration with a meal (See reference number 15,16). Saquinavir/ritonavir should be given with,or up to 2 hrs after, a meal (See reference number 15-17).
Tipranavir. The US manufacturer states that bioavailability of tipranavir is increased if it is taken with a high-fat meal (See reference number 18). In a study,tipranavir capsules were given with a high-fat meal or a light snack of toast and skimmed milk. A high-fat meal enhanced AUC by 31%, but had minimal 16 % effect on peak tipranavir levels. The UK manufacturer states that food improves tolerability of tipranavir/ritonavir (See reference number 19). Both manufacturers recommend that tipranavir with ritonavir should be taken with
Amprenavir. Food resulted in a 25 % reduction in AUC of amprenavir, but no change in steady-state trough level. Consequently, manufacturers say it can be given with or without food,(See reference number 20,21) but US manufacturer says not with a high-fat meal (See reference number 21).
The manufacturer states that taking fosamprenavir tablet formulation with a high-fat meal did not alter plasma amprenavir pharmacokinetics (derived from fosamprenavir) when compared with taking this formulation in fasted state
Ritonavir. The US manufacturer notes that a meal increased absorption of ritonavir capsules by 13%, when compared with fasting state, whereas absorption of oral solution was decreased by 7 % (See reference number 24). See also Lopinavir and Saquinavir,above. Although these changes are modest manufacturers state that ritonavir capsules and solution are preferably taken with food (See reference number 24-26). There is also some evidence that mixing ritonavir with enteral feeds does not affect ritonavir pharmacokinetics. A 600mg dose of ritonavir oral solution was mixed with 240 mL of enteral feeds (either Advera or Ensure),chocolate milk or water within 1 hour of dosing. When given up to 15 minutes after a low-fat meal, pharmacokinetics of ritonavir in either of enteral feeds or milk were almost identical to those when ritonavir was given in water (See reference number 27).
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