Alvimopan pharmacokinetics (PK) & pharmacodynamics (PD) in patients with chronic constipation (CC)

Abstract

Background To characterize the PK/PD of alvimopan and its active metabolite (ADL 08–0011) in CC patients. Method Twenty females/three males with CC received placebo or 3 mg alvimopan (a peripherally‐acting μ‐opioid antagonist) BID for 7 days in a double‐blind, randomized, crossover study. The PK of alvimopan & metabolite were characterized. Whole bowel transit (WBT) & mean colonic transit time (MCTT) were determined. Total bowel movements (BM) & spontaneous complete BM (SCBM) were recorded. Safety was monitored. PD assessments were reported previously.a Results The geometric mean steady‐state (SS) AUCτ, Cmax, & Cmin of alvimopan were 10.7 ng*hr/mL, 2.1 ng/mL, & 0.3 ng/mL, respectively. Metabolite concentrations were variable. Metabolite concentrations were at steady‐state (SS) in ~50% of subjects on day 6 and were higher in patients that were at SS than those not at SS (AUC12= 98 and 48 hr*ng/mL, respectively). The relationship between concentrations of alvimopan or metabolite and response (WBT, MCTT, BM or SCBM) was explored. Simulations were used to predict doses to be used in further clinical trials. Conclusion Alvimopan PK in CC patients was similar to healthy volunteers, although Cmin was higher in CC patients. Metabolite concentrations were variable, but were in the range of those predicted. The relative contribution of plasma concentrations of parent and metabolite to activity remains unclear in CC. Clinical Pharmacology & Therapeutics (2005) 77, P49–P49; doi:

The Effects of a Short Course of Antibiotics on Alvimopan and Metabolite Pharmacokinetics

“…On average, most OBD patients would be expected to have concentrations of metabolite that are similar to or higher than those of alvimopan in the absence of antibiotics 5 – 7 . However, because of the large variability in metabolite pharmacokinetics, many OBD patients may have metabolite concentrations that are equal to or lower than alvimopan concentrations, and still others have little or no metabolite plasma exposure (see Figure 4, day 10 data).…”

“…On average, most OBD patients would be expected to have concentrations of metabolite that are similar to or higher than those of alvimopan in the absence of antibiotics. [5][6][7] However, because of the large variability in metabolite pharmacokinetics, many OBD patients may have metabolite concentrations that are equal to or lower than alvimopan concentrations, and still others have little or no metabolite plasma exposure (see Figure 4, day 10 data). Thus, the clinical relevance of the administration of ciprofloxacin on metabolite pharmacokinetics following alvimopan administration is likely to be patient dependent, where the interaction is not likely clinically relevant in those patients with little or no metabolite exposure initially (approximately 25% of OBD participants in phase II/III studies; Figure 4B3).…”

“…Thus, the metabolite is not required for efficacy in POI as alvimopan has been shown to accelerate GI recovery even though most patients received preoperative oral antibiotics. However, in OBD clinical trials, alvimopan was administered chronically, and plasma metabolite concentrations accumulated with steady state being reached within 1 week in most participants 7 . Thus, the efficacy and safety of alvimopan in the treatment of OBD may be due to both the parent drug (alvimopan) and the active metabolite, although the exact contribution of each is unknown.…”

Pharmacokinetics of Alvimopan and Its Metabolite in Healthy Volunteers and Patients in Postoperative Ileus Trials

“…, in laparotomies 1 , 2 ) or systemic administration of mu opioids. Alvimopan (Entereg; also referred to as ADL 08–2698 or SB767905) is a novel, oral, peripherally active mu‐opioid receptor (PAM‐OR) antagonist that accelerated GI recovery in phase III clinical trials without antagonizing the analgesic effects of opioids 3 , 4 , 5 . During early development, it was thought that alvimopan was not absorbed systemically and that it worked locally within the gut.…”

Safety and efficacy update: Alvimopan in postoperative ileus

“…In healthy humans, following oral dosing of alvimopan, the systemic exposure of ADL 08-0011 is markedly higher than that of the parent (Table 2). 43,46 ADL 08-0011 accumulates upon multiple daily dosing of alvimopan; after 5 days its plasma concentration remains relatively constant for up to 96 hours after the last dose, and then declines with a halflife of between 10 and 20 hours (Entereg® NDA 21-775 FDA advisory panel briefing document). There is an extremely high degree of inter-subject variability in the exposure of ADL 08-0011 following administration of alvimopan (Table 2).…”