Paper: Comparison of the relative oral bioavailability of tolvaptan administered via nasogastric tube to tolvaptan tablets swallowed intact (ACCP Virtual Poster Symposium (May 22-24, 2012))

Tuesday, May 22, 2012

Elizabeth B. McNeely, PharmD¹, J. Heyward Hull, PharmD, MS¹, Kirkwood F. Adams Jr., MD², Jasmine Talameh, PharmD¹, Brian Simmons, PharmD, MSCR¹, Jill Henry, PharmD¹, Kim L. R. Brouwer, PharmD, PhD¹ and J. Herbert Patterson, PharmD, FCCP³
1University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC
2University of North Carolina, School of Medicine, Chapel Hill, NC
3University of North Carolina, Eshelman School of Pharmacy and School of Medicine, Chapel Hill, NC

PDF file

Objectives: Compare the relative bioavailability and pharmacokinetics (PK) of tolvaptan 15-mg, administered via nasogastric (NG) tube versus orally in healthy adults.

Methods: In this randomized, two-treatment crossover study, 28 healthy fasted adults (providing 80% power) received two 15-mg single doses of tolvaptan each given with 240 mL of water (one tablet swallowed intact, and one tablet crushed and given by NG tube), with a ≥7-day washout period between doses. During each period, 15 blood samples were collected at designated times for 36 hours and urine output collected for 24 hours after tolvaptan administration. Plasma tolvaptan concentrations were analyzed using a validated LC-MS/MS assay. Individual plasma tolvaptan concentration-time data were analyzed using non-compartmental methods. Relative tolvaptan absorption by the two routes was compared using a repeated-measures, mixed-effects ANOVA. Results for PK parameter estimates were reported as CI_90% about geometric-mean ratios.

Results: Of 29 subjects enrolled, 28 completed both periods and were included in the analysis (Table). Although only a modest decrease was seen in C_max ratio, an ~25% decrease was seen in both AUC_t and AUC_∞(but only a 2.8% decrease in 24-hour urine output) after tolvaptan administration by NG tube.

Parameter
(n=28)

Geometric Means
     NG        ORAL

Ratio (%)

CI_90%

AUC_t (ng*h/mL)^a

   381          512

74.3

68.1 - 81.0

AUC_∞ (ng*h/mL)^a

   391          527

74.2

68.1 - 80.9

C_max     (ng/mL)^b

  77.6          87.3

88.9

80.1 - 98.6

^a areas-under-the-curve to time of last measured concentration & infinity ^b maximum concentration

Conclusions: After dedicated NG tube administration of a 15-mg crushed tablet, CI_90% for AUCs were not within 80-125%, therefore bioequivalence to an oral tablet cannot be concluded. Nevertheless, with appropriate clinical monitoring, NG tube administration appears to be a viable alternative for tolvaptan administration. Analyses are underway to determine the basis for reduced tolvaptan absorption when given by NG tube.

25 Comparison of the relative oral bioavailability of tolvaptan administered via nasogastric tube to tolvaptan tablets swallowed intact