Interactions Between Protease Inhibitors and Acid-reducing Agents: A Systematic Review

L. Béïque; P. Giguère; C. la Porte; J. Angel

Disclosures

HIV Medicine. 2007;8(6):335-345. 

In This Article

Abstract and Introduction

Objective: The purpose of this article is to provide a systematic review of the available pharmacokinetic and clinical data on drug interactions between protease inhibitors (PIs) and acid-reducing agents, and their clinical relevance.
Methods: A literature search was performed using Medline and EMBASE, abstracts of the previous 2 years of major conferences were searched and the drug information service of the manufacturer of every currently available PI was contacted. All data were summarized, and verified by at least two authors.
Results: A total of 1231 references were identified, 22 of which were studies of pharmacokinetic interactions between PIs and acid-suppressive agents and a further 12 of which provided pharmacokinetic and/or clinical data.
Conclusions: Many pharmacokinetic studies show a lack of a drug interaction between at least one acid-reducing agent and most PIs. Little clinical information is available, except on interactions between atazanavir and acid-reducing agents. This is probably a consequence of the complexity of the interaction.

Background and Rationale. Protease inhibitors (PIs) constitute an important component of highly active antiretroviral therapy. For some PIs, the concomitant use of acid-reducing medications can result in a clinically significant decrease in their plasma concentrations, which can eventually lead to treatment failure.

As demonstrated by the results of several surveys conducted internationally, the use of acid-reducing agents is widespread among patients infected with HIV.[1,2,3] This widespread use of acid-reducing agents raises important concerns regarding potential drug interactions with PIs, especially given that some of the potent acid-reducing agents, such as omeprazole in the USA, are available without a prescription. A review on the concomitant use of PIs and acid-reducing agents was recently published;[4] however, the lack of rigour in the search strategy resulted in a number of references that were not identified and not considered.[5,6,7,8,9,10,11,12,13,14,15,16]

The purpose of this article is to provide a systematic review of the available pharmacokinetic (PK) and clinical data on drug interactions between PIs and acid-reducing agents, and their clinical relevance.

Pharmacological Considerations. It is well established that proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs) and antacids all raise gastric pH to different degrees and for different durations.[17] The PPIs are the most potent acid-reducing agents and tend to have a longer lasting effect than H2RAs, whereas the antacids are the least potent acid-reducing drugs and tend to have the shortest duration of action.[17,18] The acid-reducing agents also generally show a dose-related effect.[18,19,20] The type of acid-reducing drug, the dose and the time of administration of each agent are important to consider when comparing the results of different drug interaction studies.

The majority of the PK studies reviewed in this article were conducted in healthy volunteers, and observations are assumed to be the same as those that would be observed in the HIV-infected population. It is important to keep in mind, however, that differences between healthy volunteers and HIV-infected patients, as well as within the HIV-infected population, may cause differences in drug exposures.[21,22]

Another point to consider when interpreting the results is that of polymorphisms of the cytochrome P450 2C19, by which all PPIs are metabolized to varying degrees.[23,24,25] It has been shown that approximately 3% of Caucasians and 15 to 20% of the Asian population are slow metabolizers of substrates of this cytochrome.[23] In slow metabolizers, the concentrations of omeprazole and lansoprazole have been reported to be at least 5 times higher than in the rest of the population.[26] Polymorphisms were not controlled for in the majority of the PK studies, and may have had an impact on the outcomes. An example may be found in a study in 19 healthy volunteers who received atazanavir/ritonavir 300/100 mg once a day (qd) with or without omeprazole 20 mg qd. Five of the subjects showed a >50% decrease in the area under the curve (AUC) and minimum concentration (Cmin) for atazanavir, whereas the other subjects experienced little to no change in atazanavir exposure. The reason for this observation was not elucidated, but could have been related to genetic polymorphism.[12]

The clinical assessment and management of a drug interaction may be supported by the use of therapeutic drug monitoring (TDM) of antiretrovirals, which has been the subject of recent review articles.[27,28]

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