RESUMEN
BACKGROUND: Delayed recovery of gastrointestinal (GI) motility is a common complication following surgery. TZP-101/ulimorelin is a macrocyclic peptidomimetic ghrelin receptor agonist with GI promotility effects that significantly accelerates time to recovery of GI motility compared to placebo following partial colectomy. It is also well tolerated. The objectives of this analysis were to identify predictors of GI motility recovery in patients undergoing partial colectomy and to evaluate whether these factors affect ulimorelin acceleration of GI recovery. METHODS: Covariate analysis assessed the effect of eight variables-age, sex, body mass index, type of surgery (right colectomy, left colectomy, other), duration of surgery, blood loss, total opioid consumption, country-on recovery of GI motility in 236 patients randomized to ulimorelin (n = 168) or placebo (n = 68). The primary endpoint was the recovery of GI function (time from the end of surgery to first bowel movement). Stepwise regression identified a parsimonious model of the smallest subset of variables best predicting GI recovery. RESULTS: Recovery was shorter for segmental/subtotal colectomies vs. right colectomies (P = 0.016) and longer with increased total opioid use (P = 0.037). The remaining variables had no statistically significant effect on GI recovery. Effects of ulimorelin 480 µg/kg (the most effective dose) on time to GI tract recovery remained statistically and clinically significant (hazard ratio = 1.81, P = 0.014) when adjusted for surgery type and/or total opioid use. CONCLUSIONS: Two factors, type of surgery and total opioid use, independently modified times to recovery of GI motility following partial large bowel resection surgery. Acceleration of recovery of GI motility by ulimorelin was independent of these factors.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Colectomía , Fármacos Gastrointestinales/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Ghrelina/agonistas , Compuestos Macrocíclicos/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos Opioides/efectos adversos , Método Doble Ciego , Femenino , Fármacos Gastrointestinales/administración & dosificación , Humanos , Compuestos Macrocíclicos/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Recuperación de la Función/efectos de los fármacos , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. METHODS: Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 microg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. RESULTS: TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 microg/kg) and 1.67 (P = .03) for the most efficacious dose (480 microg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P Asunto(s)
Ghrelina/agonistas
, Ileus/tratamiento farmacológico
, Compuestos Macrocíclicos/administración & dosificación
, Cuidados Posoperatorios/métodos
, Proctocolectomía Restauradora/efectos adversos
, Relación Dosis-Respuesta a Droga
, Método Doble Ciego
, Femenino
, Estudios de Seguimiento
, Humanos
, Ileus/etiología
, Infusiones Intravenosas
, Compuestos Macrocíclicos/uso terapéutico
, Masculino
, Persona de Mediana Edad
, Estudios Retrospectivos
, Resultado del Tratamiento