to test the effectiveness of prophylactic vapreotide ther-apy to prevent complications after pancreatic surgery.But some major flaws do exist in this study’s design.First, vapreotide was administered subcutaneouslyrather than intravenously in this study. This leads to thepossibility that the drug might have been poorly ab-sorbed in the postoperative period when massive fluidshifts can shunt blood away from the skin. I believe thatcontinuous intravenous administration of this drugwould have been a better route of administration. In asimilar fashion, the drug has a half-life of elimination inthe plasma of approximately 80 minutes. Why was adrug-dosing interval of 12 hours chosen? This seems likefar too long between doses of medication. Again, a con-tinuous intravenous administration scheme would haveeliminated this concern about the study design. Thisdrug has an IC50 of about 5 nM for somatostatin recep-tor subtype 2 (sst 2). This raises the question of whethersst 2 receptors might have been suboptimally saturated.Did the authors consider using higher doses of this drugto achieve higher levels of receptor saturation? Finally, Iwould like to congratulate the authors for a well-performed, well-controlled trial that fairly evaluated theeffect of prophylactic effect of vapreotide therapy on thedevelopment of complications after pancreatic resection.

Reply

Michael G L Sarr, MD, FACS

Rochester, MN

I would like to thank Dr Woltering for his comments

and careful analysis. He has raised several questions thatI will address.

1. Why was vapreotide given subcutaneously ratherthan by a continuous intravenous infusion?

Response: Vapreotide was specifically designed as along-acting analogue of somatostatin, so its administra-tion subcutaneously not only provides a more prolongedphysiologic effect, but allows a more clinically accept-able means of administration.

2. Why a q12 hourly dosing schedule?Response: Although we cannot be certain of the du-

ration of inhibition of pancreatic exocrine secretin, asstated in the article, preliminary work in humans hasshown that exocrine secretion stimulated by intravenoussecretin/cholecystokinin between hours 4 and 5 aftersubcutaneous administration is strongly inhibited (by75%). Pharmacokinetic studies using vapreotide showthat after subcutaneous administration, the bioavailabil-ity was 67 � 15% with a first disposition half-life of0.3 � 1 hour and a terminal disposition half-life of7 � 2 hours. These data suggest that the biologic effectswould persist for longer than 5 hours but we have noobjective data to prove this contention.

3. With a 95% inhibitory concentration of 5 nM forsomatostatin receptor subtype 2, the dosage of vap-reotide might have been inadequate to saturate thereceptors.

Response: In vitro pharmacology helps direct dosing,but the ultimate test is in vivo biologic effects. The workabout in vivo effects in humans of 0.6 mg of vapreotidegiven subcutaneously shows a very potent inhibitory ef-fect on stimulated pancreatic exocrine secretion.

565Vol. 196, No. 4, April 2003 Vapreotide after Pancreatectomy