CLINICAL PHARMACOLOGY
Mechanism of Action
Alvimopan is a selective antagonist of the cloned human μ-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of [3H]-alvimopan from the human μ-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 μM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels.
Postoperative ileus is the impairment of gastrointestinal motility after intra-abdominal surgery or other non-abdominal surgeries. Postoperative ileus affects all segments of the gastrointestinal tract and may last from 5 to 6 days, or even longer. This may potentially delay gastrointestinal recovery and hospital discharge until its resolution. It is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluids in the bowel, and delayed passage of flatus and defecation. Postoperative ileus is the result of a multifactorial process that includes inhibitory sympathetic input, release of hormones, neurotransmitters, and other mediators (e.g., endogenous opioids). A component of postoperative ileus also results from an inflammatory reaction and the effects of opioid analgesics. Morphine and other μ-opioid receptor agonists are universally used for the treatment of acute postsurgical pain; however, they are known to have an inhibitory effect on gastrointestinal motility and may prolong the duration of postoperative ileus.
Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract μ-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations where alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of μ-opioid agonists.
Pharmacodynamics
In exploratory studies in healthy volunteers, alvimopan 3 mg three times daily appeared to reduce the delay in gastrointestinal transit produced by morphine 30 mg twice daily as measured by radio-opaque markers.
In a study designed to evaluate potential effects on cardiac conduction, alvimopan did not cause clinically significant QTc prolongation at doses up to 24 mg twice daily for 7 days. The potential for QTc effects at higher doses has not been studied.
Pharmacokinetics
Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the "metabolite". It is also a μ-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL).
Absorption: Following oral administration of ENTEREG Capsules in healthy volunteers, plasma alvimopan concentration peaked at approximately 2 hours postdose. No significant accumulation in alvimopan concentration was observed following twice daily (BID) dosing. The mean peak plasma concentration was 10.98 (±6.43) ng/mL and mean AUC0-12h was 40.2 (±22.5) ng•h/mL after dosing of alvimopan at 12 mg BID for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). Plasma concentrations of alvimopan increased approximately proportionally with increasing doses between 6 and 18 mg, but less than proportionally from 18 to 24 mg.
There was a delay in the appearance of the "metabolite", which had a median Tmax of 36 hours following administration of a single dose of alvimopan. Concentrations of the "metabolite" were highly variable between subjects and within a subject. The "metabolite" accumulated after multiple doses of ENTEREG. The mean Cmax for the "metabolite" after alvimopan 12 mg twice daily for 5 days was 35.73±35.29 ng/mL.
Concentrations of alvimopan and its 'metabolite' are higher (~1.9-fold and ~1.4-fold, respectively) in POI patients than in healthy volunteers.
Food Effects: A high-fat meal decreased the extent and rate of alvimopan absorption. The Cmax and AUC were decreased by approximately 38% and 21%, respectively, and the Tmax was prolonged by approximately 1 hour. The clinical significance of this decreased bioavailability is unknown. In POI clinical trials, the preoperative dose of ENTEREG was administered in a fasting state. Subsequent doses were given without regard to meals.
Distribution: The steady state volume of distribution of alvimopan was estimated to be 30±10 L. Plasma protein binding of alvimopan and its "metabolite" was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the "metabolite" were bound to albumin and not to alpha-1 acid glycoprotein.
Metabolism and Elimination: The average plasma clearance for alvimopan was 402 (±89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its "metabolite" by gut microflora. The "metabolite" was eliminated in the feces and in the urine as unchanged "metabolite", the glucuronide conjugate of the "metabolite", and other minor metabolites. The mean terminal phase half-life of alvimopan after multiple oral doses of ENTEREG ranged from 10 to 17 hours. The terminal half-life of the "metabolite" ranged 10 to 18 hours.
Special Populations:
Age: The pharmacokinetics of alvimopan, but not its "metabolite", were related to age, but this effect was not clinically significant and does not warrant dosage adjustment based on increased age.
Race: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or black race. Plasma "metabolite" concentrations were lower in black and in Hispanic patients (by 43% and 82%, respectively) than in Caucasian patients following alvimopan administration. These changes are not considered to be clinically significant in surgical patients. Japanese male healthy volunteers had an approximately 2-fold increase in plasma alvimopan concentrations, but no change in metabolite pharmacokinetics. The pharmacokinetics of alvimopan have not been studied in subjects of other East Asian ancestry. Dosage adjustment in Japanese patients is not required [see Use in Specific Populations].
Gender: There was no effect of gender on the pharmacokinetics of alvimopan or the 'metabolite'.
Hepatic Impairment: Exposure to alvimopan following a single 12-mg dose tended to be higher (1.5 to 2 fold, on average) in patients with mild or moderate hepatic impairment (as defined by Child-Pugh Class A and B, n = 8 each) compared with healthy controls (n = 4). There were no consistent effects on the Cmax or half-life of alvimopan in patients with hepatic impairment. However, two of 16 patients with mild to moderate impairment had longer than expected half-lives of alvimopan indicating that some accumulation may occur upon multiple dosing. The Cmax of the "metabolite" tended to be more variable in patients with mild or moderate hepatic impairment than in matched normal subjects. A study of 3 patients with severe hepatic impairment (Child-Pugh Class C), indicated similar alvimopan exposure in 2 patients and an approximately 10-fold increase in Cmax and exposure in 1 patient with severe hepatic impairment when compared with healthy control volunteers [see Warnings and Precautions and Use in Specific Populations].
Renal Impairment: There was no relationship between renal function (i.e., creatinine clearance [CrCl]) and plasma alvimopan pharmacokinetics (Cmax, AUC, or half-life) in patients with mild (CrCl 51-80 mL/min), moderate (CrCl 31-50 mL/min), or severe (CrCl <30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate and control renal impairment groups but longer in the severe renal impairment group. Exposure to the "metabolite" tended to be 2- to 5-fold higher in patients with moderate or severe renal impairment compared to patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and "metabolite" in patients with severe renal impairment receiving multiple doses of ENTEREG. Patients with end-stage renal disease were not studied [see
Warnings and Precautions and Use in Specific Populations].
Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or Cmax). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics and exposure tended to be 2-fold higher in patients with quiescent disease than in those with active disease or normal subjects. Concentrations of the "metabolite" were lower in patients with Crohn's disease.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two year carcinogenicity studies have been conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma and sarcoma in the skin/subcutis, and osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area).
Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test or the mouse micronucleus test. The pharmacologically active "metabolite" ADL 08-0011 was negative in the Ames test, chromosome aberration test in CHO cells and mouse micronucleus test.
Alvimopan at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on the body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
Animal Toxicology and/or Pharmacology
A single oral dose of 500 mg/kg of alvimopan was not lethal to mice and rats.
Reproduction studies have been performed in pregnant rats at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on the body surface area) and intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on the body surface area) and in pregnant rabbits at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to alvimopan.
|
