Relative bioavailability of tolvaptan administered via nasogastric tube and tolvaptan tablets swallowed intact

Purpose The bioavailability of a crushed tolvaptan tablet suspended in water and administered by nasogastric (NG) tube was compared to the bioavailability from the tablet administered whole. Methods In a randomized crossover study, 28 healthy adults received a single 15-mg dose of tolvaptan on two occasions (one dose given as an intact tablet swallowed whole and the other as a crushed tablet in suspension given by NG tube), with a washout interval of ≥7 days. During each administration period, blood samples were collected at 15 time points over 36 hours. A validated liquid chromatography–tandem mass spectrometry assay was used to obtain plasma tolvaptan concentrations. Plasma tolvaptan time–concentration data were analyzed using noncompartmental methods, and pharmacokinetic data including maximum concentration ( C max), time to C max ( t max), area under the concentration–time curve (AUC) from time zero to the time of the last measurable concentration (AUC t ), and AUC extrapolated to infinity (AUC∞) resulting from oral and NG tube tolvaptan delivery were compared via repeated-measures, mixed-effects analysis of variance. Due to differences in total drug exposure seen, an in vitro experiment was conducted on three dose levels to quantify drug sequestration. Results The ratios of geometric mean C max, AUC t , and AUC∞ values (expressed as a percentage) with NG tube versus oral tolvaptan administration were 88.9%, 74.3%, and 74.2%, respectively; the latter two values were not within the specified bioequivalence tolerance limits (80–125%). In vitro analysis showed that approximately 11% of all tolvaptan doses evaluated was sequestered by the NG tube. Conclusion In healthy adults, a single 15-mg dose of tolvaptan administered as a crushed tablet suspended in water by NG tube resulted in AUC t and AUC∞ values that were approximately 25% lower than those observed after oral administration of a 15-mg tolvaptan tablet swallowed intact.