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 (Cmax), time to Cmax (tmax), area under the concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUCt), 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 Cmax, AUCt, 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 AUCt and AUC∞ values that were approximately 25% lower than those observed after oral administration of a 15-mg tolvaptan tablet swallowed intact.