The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial

Marianne J Chapman, Adam M Deane, Stephanie L O'Connor, Nam Q Nguyen, Robert J L Fraser, Duncan B Richards, Kimberley E Hacquoil, Lakshmi S Vasist Johnson, Matthew E Barton, George E Dukes, Marianne J Chapman, Adam M Deane, Stephanie L O'Connor, Nam Q Nguyen, Robert J L Fraser, Duncan B Richards, Kimberley E Hacquoil, Lakshmi S Vasist Johnson, Matthew E Barton, George E Dukes

Abstract

Background: The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients.

Methods: A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively.

Results: Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment.

Conclusions: When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients.

Trial registration: The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).

Keywords: Absorption; Camicinal; Critical illness; Enteral nutrition; Gastric emptying; Motilin agonist.

Figures

Fig. 1
Fig. 1
Consort diagram. Next of kin consent was provided for six patients who subsequently did not receive study drug because of the following: feeding tube found to be in the duodenum, found to be hepatitis C positive after consent given, consent given and subsequently withdrawn, patient withdrawn by investigator (not in best interest of patient to continue), liver function tests elevated meeting exclusion criteria, patient died after consent given but prior to receiving study treatment. EN enteral nutrition, GRV gastric residual volumes
Fig. 2
Fig. 2
3-OMG (mean ± SEM) plasma concentrations vs. time in the placebo and 50 mg dose groups. 3-OMG 3-O-methyl glucose

References

    1. Alberda C, Gramlich L, Jones N, Jeejeebhoy K, Day AG, Dhaliwal R, et al. The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study. Intensive Care Med. 2009;35:1728–37. doi: 10.1007/s00134-009-1567-4.
    1. Martindale RG, McClave SA, Vanek VW, McCarthy M, Roberts P, Taylor B, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit Care Med. 2009;37:1757–61. doi: 10.1097/CCM.0b013e3181a40116.
    1. Chapman MJ, Nguyen NQ, Deane AM. Gastrointestinal dysmotility: evidence and clinical management. Curr Opin Clin Nutr Metab Care. 2013;16:209–16. doi: 10.1097/MCO.0b013e32835c1fa5.
    1. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003;27:355–73. doi: 10.1177/0148607103027005355.
    1. Dive A, Miesse C, Galanti L, Jamart J, Evrard P, Gonzalez M, et al. Effect of erythromycin on gastric motility in mechanically ventilated critically ill patients: a double-blind, randomized, placebo-controlled study. Crit Care Med. 1995;23:1356–132. doi: 10.1097/00003246-199508000-00008.
    1. Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ. Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med. 2000;28:2334–7. doi: 10.1097/00003246-200007000-00026.
    1. MacLaren R, Kuhl DA, Gervasio JM, Brown RO, Dickerson RN, Livingston TN, et al. Sequential single doses of cisapride, erythromycin, and metoclopramide in critically ill patients intolerant to enteral nutrition: a randomized, placebo-controlled, crossover study. Crit Care Med. 2000;28:438–44. doi: 10.1097/00003246-200002000-00025.
    1. Boivin MA, Levy H. Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill. Crit Care Med. 2001;29:1916–9. doi: 10.1097/00003246-200110000-00011.
    1. Reignier J, Bensaid S, Perrin-Gachadoat D, Burdin R, Tenaillon A. Erythromycin and early enteral nutrition in mechanically ventilated patients. Crit Care Med. 2002;30:1237–41. doi: 10.1097/00003246-200206000-00012.
    1. Nguyen NQ, Chapman MJ, Fraser RJ, Bryant LK, Holloway RH. Erythromycin is more effective than metoclopramide in the treatment of feed intolerance in critical illness. Crit Care Med. 2007;35:483–9. doi: 10.1097/01.CCM.0000253410.36492.E9.
    1. Nguyen NQ, Chapman M, Fraser RJ, Bryant LK, Burgstad C, Holloway RH. Prokinetic therapy for feed intolerance in critical illness: one drug or two? Crit Care Med. 2007;35:2561–7. doi: 10.1097/01.CCM.0000286397.04815.B1.
    1. MacLaren R, Kiser TH, Fish DN, Wischmeyer PE. Erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric nutrition in critically ill patients. JPEN J Parenter Enteral Nutr. 2008;32:412–9. doi: 10.1177/0148607108319803.
    1. Van Zanten AR, Van Der Meer YG, Venhuizen WA, Heyland DK. Still a place for metoclopramide as a prokinetic drug in critically ill patients? JPEN J Parenter Enteral Nutr. 2015;39:763–6. doi: 10.1177/0148607114567711.
    1. Deane AM, Fraser RJ, Chapman MJ. Prokinetic drugs for feed intolerance in critical illness: current and potential therapies. Crit Care Resusc. 2009;11:132–43.
    1. Vantrappen G, Janssens J, Peeters TL, Bloom SR, Christofides ND, Hellemans J. Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci. 1979;24:497–500. doi: 10.1007/BF01489315.
    1. Peeters TL, Muls E, Janssens J, Janssens J, Urbain J-L, Bex M, et al. Effect of motilin on gastric emptying in patients with diabetic gastroparesis. Gastroenterology. 1992;102:97–101. doi: 10.1016/0016-5085(92)91788-6.
    1. Sanger GJ, Westaway SM, Barnes AA, Macpherson DT, Muir AI, Jarvie EM, et al. GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurogastroenterol Motil. 2009;21:657–64. doi: 10.1111/j.1365-2982.2009.01270.x.
    1. Westaway SM, Brown SL, Fell SC, Johnson CN, MacPherson DT, Mitchell DJ, et al. Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-pi peridinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate. J Med Chem. 2009;52:1180–9. doi: 10.1021/jm801332q.
    1. Dukes GE, Barton M, Dewit O, Hicks K, Vasist I, Van Hecken A, et al. Pharmacokinetics, safety/tolerability, and effect on gastric emptying of the oral motilin receptor agonist, GSK962040, in healthy male and female volunteers. Neurogastroenterol Motil. 2009;21:84.
    1. Dukes GE, Barton M, Dewit O, Stephens K, Vasist I, Young M, et al. Safety/tolerability, pharmacokinetics (PK), and effect on gastric emptying (GE) with 14-days repeat oral dosing of the motilin receptor agonist, GSK962040, in healthy male and female volunteers. Neurogastroenterol Motil. 2010;22:14–5.
    1. Desachy A, Clavel M, Vuagnat A, Normand S, Gissot V, François B. Initial efficacy and tolerability of early enteral nutrition with immediate or gradual introduction in intubated patients. Intensive Care Med. 2008;34:1054–9. doi: 10.1007/s00134-007-0983-6.
    1. Deane AM, Wong GL, Horowitz M, Zaknic AV, Summers MJ, Di Bartolomeo AE, et al. Randomized double-blind crossover study to determine the effects of erythromycin on small intestinal nutrient absorption and transit in the critically ill. Am J Clin Nutr. 2012;95:1396–402. doi: 10.3945/ajcn.112.035691.
    1. Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care. 2013;17:R35. doi: 10.1186/cc12544.
    1. Deane AM, Zaknic AV, Summers MJ, Chapman MJ, Lange KL, Ritz MA, et al. Intrasubject variability of gastric emptying in the critically ill using a stable isotope breath test. Clin Nutr. 2010;29:682–6. doi: 10.1016/j.clnu.2010.03.007.
    1. Deane AM, Chapman MJ, Fraser RJ, Summers MJ, Zaknic AV, Storey JP, et al. Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med. 2010;38:1261–9. doi: 10.1097/CCM.0b013e3181d9d87a.
    1. Deane AM, Summers MJ, Zaknic AV, Chapman MJ, Di Bertolomeo AE, Bellon M, et al. Glucose absorption and small intestinal transit in critical illness. Crit Care Med. 2011;39:1282–8. doi: 10.1097/CCM.0b013e31820ee21f.
    1. Ritz MA, Fraser R, Edwards N, Di Matteo AC, Chapman MJ, Butler R, et al. Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test. Crit Care Med. 2001;29:1744–9. doi: 10.1097/00003246-200109000-00015.
    1. Kar P, Jones KL, Horowitz M, Chapman MJ, Deane AM. Measurement of gastric emptying in the critically ill. Clin Nutr. 2014;34:557–64. doi: 10.1016/j.clnu.2014.11.003.
    1. Gungabissoon U, Hacquoil K, Bains C, Irizarry M, Dukes G, Williamson R, et al. Prevalence, risk factors, clinical consequences, and treatment of enteral feed intolerance during critical illness. JPEN J Parenter Enteral Nutr. 2014;39:441–8. doi: 10.1177/0148607114526450.
    1. Chapman MJ, Nguyen NQ, Fraser RJ. Gastrointestinal motility and prokinetics in the critically ill. Curr Opin Crit Care. 2007;13:187–94. doi: 10.1097/MCC.0b013e3280523a88.
    1. Chapman MJ, Fraser RJ, Matthews G, Russo A, Bellon M, Besanko L, et al. Glucose absorption and gastric emptying in critical illness. Crit Care. 2009;13:1–8.
    1. Deane AM, Rayner CK, Keeshan A, Cvijanovic N, Marino Z, Ngyuen NQ, et al. The effects of critical illness on intestinal glucose sensing, transporters, and absorption. Crit Care Med. 2014;42:57–65. doi: 10.1097/CCM.0b013e318298a8af.
    1. Ali Abdelhamid Y, Cousins CE, Sim JA, Bellon MS, Nguyen NQ, Horowitz M, et al. Effect of critical illness on triglyceride absorption. JPEN J Parenter Enteral Nutr. 2015;39:966–72. doi: 10.1177/0148607114540214.
    1. Bryant LK, Fraser RJ, Vozzo R, Zacharakis B, Matthews GM, Butler R. Stimulation of small intestinal burst activity in the postprandial state differentially affects lipid and glucose absorption in healthy adult humans. Am J Physiol Gastrointest Liver Physiol. 2004;287:1028–34. doi: 10.1152/ajpgi.00091.2004.
    1. Horowitz M, Maddern GJ, Chatterton BE, Collins PJ, Harding PE, Sharman DJ, et al. Changes in gastric emptying rates with age. Clin Sci (Lond) 1984;67:213–8. doi: 10.1042/cs0670213.
    1. Ritz MA, Chapman MJ, Fraser RJ, Finnis M, Butler R, Cmielewski P, et al. Erythromycin dose of 70 mg accelerates gastric emptying as effectively as 200 mg in the critically ill. Intensive Care Med. 2005;31:949–54. doi: 10.1007/s00134-005-2663-8.
    1. Otterson MF, Sarna SK. Gastrointestinal motor effects of erythromycin. Am J Physiol. 1990;259:355–63.
    1. Landzinski J, Kiser TH, Fish DN, Wischmeyer PE, MacLaren R. Gastric motility function in critically ill patients tolerant vs intolerant to gastric nutrition. JPEN J Parenter Enteral Nutr. 2008;32:45–50. doi: 10.1177/014860710803200145.
    1. Chapman MJ, Besanko LK, Burgstad CM, Fraser RJ, Bellon M, O’Connor S, et al. Gastric emptying of a liquid nutrient meal in the critically ill: relationship between scintigraphic and carbon breath test measurement. Gut. 2011;60:1336–43. doi: 10.1136/gut.2010.227934.
    1. Hsu CW, Sun SF, Lee DL, Lin SL, Wong KF, Huang HH, et al. Impact of disease severity on gastric residual volume in critical patients. World J Gastroenterol. 2011;17:2007–12. doi: 10.3748/wjg.v17.i15.2007.
    1. Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795–803. doi: 10.1001/jama.2011.1985.
    1. Reignier J, Mercier E, Le Gouge A, Boulain T, Desachy A, Bellec F, et al. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial. JAMA. 2013;309:249–56. doi: 10.1001/jama.2012.196377.
    1. Blaser AR, Starkopf J, Kirsimagi U, Deane AM. Definition, prevalence, and outcome of feeding intolerance in intensive care: a systematic review and meta-analysis. Acta Anaesthesiol Scand. 2014;58:914–22. doi: 10.1111/aas.12302.
    1. Elke G, Felbinger TW, Heyland DK. Gastric residual volume in critically ill patients: a dead marker or still alive? Nutr Clin Pract. 2015;30:59–71. doi: 10.1177/0884533614562841.

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