Food Effects on Protease Inhibitor Bioavailability?

Angela D.M. Kashuba, BScPhm, PharmD, DABCP


October 02, 2001


What are the effects of food on HIV medication? Among the nucleoside reverse transcriptase inhibitors, didanosine has food interactions, as does the nonnucleoside reverse transcriptase inhibitor efavirenz, and every single protease inhibitor (PI). However, it has been said that food restrictions on PIs may be removed when the drug is used with ritonavir boosting. Is this correct?

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Food indeed contributes to the pharmacokinetic variability of protease inhibitors (PIs).[1] The exact mechanism(s) are poorly understood. As determined by measuring the area under the concentration time curve (AUC), a high-fat meal increases the bioavailability of saquinavir by ~670%, nelfinavir by ~200% to 300%, and ritonavir capsules by ~15%. Conversely, food can decrease the bioavailability of indinavir by ~77%, amprenavir by ~21%, and ritonavir liquid by ~7%. Therefore, when these PIs are given as single ("unboosted") agents in an antiretroviral regimen, it is recommended that saquinavir and nelfinavir be taken with food, and indinavir be taken in a fasted state or with a light snack. Ritonavir and amprenavir can be taken with or without food, but a high-fat meal should be avoided with amprenavir.

Ritonavir has been shown to reduce the food effects of indinavir pharmacokinetics. Two investigations have found that 100-400 mg of ritonavir twice daily, taken in combination with indinavir, reverses the effect of both low-fat and high-fat meals on indinavir absorption.[2,3] Ritonavir may also reduce the food effects of saquinavir. A recent investigation[4] examined the effects of a high-fat (~45g) and normal-fat (~20g) breakfast on saquinavir pharmacokinetics in 6 individuals taking saquinavir 1000 mg with ritonavir 100 mg twice daily. In these 6 patients, all measures of saquinavir exposure were not significantly different (P > .35) between the 2 meals, although the trend was toward slightly higher exposures with a high-fat meal (AUC0-12h increased by ~24%, C12hincreased by ~12%).

However, the addition of ritonavir does not necessarily eliminate food effects with all PIs. One example is the lopinavir/ritonavir combination product. Bertz and colleagues[5] determined that when lopinavir/ritonavir was taken with a low-fat breakfast, AUC, Ctrough and Cmin were increased by 12%, 30%, and 44%, respectively, compared with historical pharmacokinetic data for lopinavir/ritonavir taken without regard to food. In addition, intersubject variability in AUC and Ctrough was reduced when a standardized meal was given: the coefficient of variation decreased from 54% to 40% for the AUC, and from 73% to 41% for the Ctrough. Not surprisingly, ritonavir AUC also increased by 21% with the standardized breakfast. Because of these results, it is recommended that lopinavir/ritonavir be taken with food to maximize bioavailability and minimize inter- (and intra-) individual variability.

Currently, no data exist on whether food effects occur with the PI combinations of nelfinavir/ritonavir or amprenavir/ritonavir. Because of this, and because most patients find it convenient to take their twice-daily regimens with meals, it would be prudent for patients to continue to take nelfinavir/ritonavir with a moderate- to low-fat meal, and to take amprenavir/ritonavir prior to meals, or with a low-fat snack.