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 mu-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL).

Absorption:

Following oral administration of alvimopan capsules in healthy plasma subjects, the alvimopan concentration peaked at approximately 2 hours post-dose. No significant accumulation in the concentration of alvimopan was observed following twice daily 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 twice daily for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). 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 alvimopan. 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 (approximately 1.9-fold and 1.4-fold, respectively) in postoperative ileus patients than in healthy subjects.

Effect of Food: 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 postoperative ileus clinical trials, the preoperative dose of alvimopan 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.

Elimination:

Metabolism and Excretion: In vitro data suggest that alvimopan is not a substrate of CYP enzymes. 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 alvimopan ranged from 10 to 17 hours. The terminal half-life of the ‘metabolite’ ranged from 10 to 18 hours.

Specific Populations:

Geriatric Patients: 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.

Racial or Ethnic Groups: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or Black race. Plasma ‘metabolite’ concentrations were lower in Black and 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 healthy male subjects 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 (8.8)].

Male and Female Patients: There was no effect of sex on the pharmacokinetics of alvimopan or the ‘metabolite’.

Patients with 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, 2 of 16 patients with mild-to-moderate hepatic 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 controls [see Warnings and Precautions (5.4), Use in Specific Populations (8.6)].

Patients with 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 to 80 mL/min), moderate (CrCl 31 to 50 mL/min), or severe (CrCl less than 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 with 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 alvimopan. Patients with end-stage renal disease were not studied [see Warnings and Precautions (5.5), Use in Specific Populations (8.7)].

Patients with 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 in normal subjects. Concentrations of the ‘metabolite’ were lower in patients with Crohn’s disease.

Drug Interaction Studies:

Potential for Drugs to Affect Alvimopan Pharmacokinetics: Concomitant administration of alvimopan with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because alvimopan is metabolized mainly by non-CYP enzyme pathway. No clinical studies have been performed to assess the effect of concomitant administration of inducers or inhibitors of cytochrome P450 enzymes on alvimopan pharmacokinetics.

In vitro studies suggest that alvimopan and its ‘metabolite’ are substrates for p-glycoprotein. A population pharmacokinetic analysis did not reveal any evidence that alvimopan or ‘metabolite’ pharmacokinetics were influenced by concomitant medications that are mild-to-moderate p-glycoprotein inhibitors. No clinical studies of concomitant administration of alvimopan and strong inhibitors of p-glycoprotein (e.g., verapamil, cyclosporine, amiodarone, itraconazole, quinine, spironolactone, quinidine, diltiazem, bepridil) have been conducted.

A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. However, plasma concentrations of the ‘metabolite’ were lower in patients receiving acid blockers or preoperative oral antibiotics (49% and 81%, respectively). No dosage adjustments are necessary in these patients.

Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs: Alvimopan and its ‘metabolite’ are not inhibitors of CYP 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 in vitro at concentrations far in excess of those observed clinically.

Alvimopan and its ‘metabolite’ are not inducers of CYP 1A2, 2B6, 2C9, 2C19, and 3A4.

In vitro studies also suggest that alvimopan and its ‘metabolite’ are not inhibitors of p-glycoprotein.

These in vitro findings suggest that alvimopan is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein.