Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h.
BACKGROUND
Attainment of intragastric pH < 6.0 may require high-dose continuously infused proton pump therapy.


OBJECTIVE
To assess the pharmacokinetic and pharmacodynamic dose-responses of continuous infusion regimens of lansoprazole.


METHODS
Healthy adult subjects were assigned to lansoprazole 60-mg intravenous bolus, followed by 6-mg/h continuous infusion; a 90-mg intravenous bolus followed by 6-, 7.5-, or 9-mg/h continuous infusion; or placebo.


RESULTS
Mean intragastric pH values for lansoprazole regimens ranged from 4.8 to 5.2 (0-24 h), 5.5 to 6.0 (>24 to 48 h) and 5.2 to 5.6 (0-48 h). Within these three intervals, the percentages of time intragastric pH exceeded 4, 5 and 6 ranged from 65% to 96%, 54% to 88% and 30% to 61% respectively. Pharmacokinetic parameters were dose-independent with steady-state plasma concentrations achieved within 6-12 h postdose and maintained over 48 h. The mean systemic clearance of lansoprazole was lower in CYP2C19 heterozygous metabolizers than in homozygous extensive metabolizers (9.2 vs. 16.5 L/h), with substantial variability resulting in overlapping ranges of clearance values for both subpopulations. All lansoprazole regimens were well-tolerated.


CONCLUSIONS
Lansoprazole administered as a 60-mg intravenous bolus followed by 6-mg/h continuous infusion produced intragastric pH effects comparable with those of higher dosage regimens.
Howden
C W
CW
Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. c-howden@northwestern.edu
Metz
D C
DC
Hunt
B
B
Vakily
M
M
Kukulka
M
M
Amer
F
F
Samra
N
N
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000293:Adolescent; D000328:Adult; D000897:Anti-Ulcer Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005745:Gastric Acidity Determination; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007262:Infusions, Intravenous; D064747:Lansoprazole; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009853:Omeprazole / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D054328:Proton Pump Inhibitors; D013270:Stomach / Q000187:drug effects
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole