Ketoproof? A systematic classification of pharmaceutical excipients for ketogenic diet therapy

Ketogenic diet therapy (KDT) is an evidence-based treatment for refractory epilepsy, particularly in children. Strict adherence to carbohydrate restriction is essential to maintain ketosis, yet many medications contain excipients that can disrupt this balance. Pharmacists play a crucial role in evaluating and adjusting medication regimens for patients on KDT, but limited transparency regarding excipient content often makes this process inefficient and inconsistent. Although some regional databases exist, no systematic and comprehensive resources have been developed for broader use.

This study aimed to systematically classify pharmaceutical excipients and label all medications marketed in the Netherlands according to their compatibility with KDT ("Ketoproof" status) using a transparent, reproducible framework that can serve as the foundation for safer prescribing and international standardization.

A retrospective cross-sectional database analysis was conducted using data from the Dutch G-Standaard (June 2023-March 2024), a national pharmaceutical reference database used in the Netherlands. All excipients authorized in medications marketed in the Netherlands were extracted and classified based on chemical composition, metabolic fate, and administration route. Excipients were assigned a Ketoproof status through a structured decision flowchart, expert consensus, and quality control review. Finally, pharmaceutical products were labeled by cross-referencing their excipient profiles against the classified dataset.

A total of 1047 excipients were identified. Of these, 778 (74%) were successfully classified: 590 (56%) as Ketoproof and 188 (18%) as non-Ketoproof. The remaining 269 (26%) were unclassified. Excipients requiring expert consensus included polyols and sugar alcohols, organic acids, and coloring and flavoring agents, which were carefully assessed for clinical relevance. Among 28,721 pharmaceutical products analyzed, 41% (n = 11,781) were labeled as Ketoproof. The full dataset was integrated into KetoMed, a web-based tool designed to support healthcare professionals in reviewing medications for patients on KDT.

This study presents the first systematic classification of pharmaceutical excipients for KDT compatibility. The transparent, evidence-informed framework enables structured labeling of medications and supports safer prescribing for patients undergoing KDT. Broader adoption and international collaboration are recommended to establish consensus on excipient classification, enhance regulatory transparency, and integrate Ketoproof labeling into clinical decision-support systems to optimize ketogenic therapy management.