The Impact of Dietary Interventions on the Pharmacokinetics of Antifungal Drugs: A Systematic Review with Meta-analyses.

Background and objective: Managing food-drug interactions may help to optimize the efficacy and safety of antifungal therapy. This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to evaluate how food, beverages, antacids, and mineral supplements influence the pharmacokinetic (PK) parameters or pharmacokinetic/pharmacodynamic (PK/PD) indices of 14 orally administered antifungal drugs.

Methods: We considered all studies evaluating the effects of food, beverages, antacids, and mineral supplements on PK parameters and PK/PD indices of oral antifungal drugs for inclusion. We excluded in vitro, in silico, animal studies, reviews, and alcohol-related investigations. Searches were conducted in Medline (via PubMed), Embase, and Cochrane Library from database inception to June 2024. We evaluated the risk of bias using the National Institutes of Health (NIH) tool for before-after studies and the Cochrane tool for parallel and cross-over trials. We performed meta-analyses when two or more studies with comparable designs were available; otherwise, results were summarized qualitatively.

Results: The review included 73 studies from 68 reports. Only studies investigating the effect of dietary interactions on PK parameters were found. Meta-analyses were conducted for seven antifungal drugs, while qualitative synthesis covered the remaining drugs. Open-label, cross-over studies accounted for 58% of trials, aligning with Food and Drug Administration (FDA) recommendations. A high risk of bias appeared in 33% of studies, while only 7% showed low risk. Among 11 antifungals with food-effect data, seven (64%) exhibited clinically important interactions. High positive food effects (area under the concentration-time curve (AUC) or peak serum concentration (C_max) increased by > 45%) were seen for griseofulvin, itraconazole capsules and tablets (except rice-based meals), and posaconazole immediate-release tablets and suspension. A moderate positive impact of high-fat meals (AUC or C_max increased in the range of 35-45%) occurred for ibrexafungerp and oteseconazole. A high negative food effect was observed on the absorption of voriconazole and itraconazole oral suspension or super bioavailable (SUBA) capsules (AUC or C_max decreased by > 40%). Antacids strongly reduced itraconazole and ketoconazole absorption, while nutritional supplements improved posaconazole bioavailability. Acidic beverages such as Coca Cola substantially enhanced the absorption of itraconazole, ketoconazole, and posaconazole, whereas orange juice significantly reduced itraconazole bioavailability.

Conclusion: Interactions were influenced by such factors as drug physicochemical properties, type of dietary intervention, drug formulation, and patient characteristics. Although the review largely filled the existing gaps in recommendations, we judged the overall quality of evidence as low owing to outdated studies, methodological inconsistencies, and uneven data availability. Further research involving PK/PD indices is needed to link the postprandial changes in the bioavailability of antifungal drugs with their clinical efficacy.

Other: The protocol of the systematic review was registered in March 2024 in the Open Science Framework (OSF) Registries ( https://doi.org/10.17605/OSF.IO/HAVK9 ).