Chemical formula: C₃₂H₃₅N₅O₅ Molecular mass: 569.662 g/mol PubChem compound: 11250029
Eluxadoline is a locally acting, mixed mu opioid receptor (μOR) agonist and delta opioid receptor (δOR) antagonist. Eluxadoline is also an agonist at the kappa opioid receptor (κOR). The binding affinities (Ki) of eluxadoline for human μOR and δOR are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of eluxadoline for human κOR has not been determined; however, the Ki for guinea pig cerebellum κOR is 55 nM. In animals, eluxadoline interacts with opioid receptors in the gut. Eluxadoline has demonstrated efficacy in normalizing GI transit and defecation in several models of stress induced or post GI inflammation-altered GI function in animals. Eluxadoline has very low oral bioavailability and exerts no detectable central nervous system (CNS)-mediated effects when administered orally to animals at effective doses. Eluxadoline also reverses hyperalgesic responses in an animal model of acute colitis-induced visceral pain.
Since bioavailability is limited, the pharmacodynamic activity of eluxadoline is based predominantly on local action within the GI tract. Supporting the lack of systemic pharmacodynamic effects are results from an oral abuse liability study in recreational opioid users that showed oral doses up to 1,000 mg did not produce significant pupillary constriction or significant drug liking. An abuse liability study with 100 mg and 200 mg intranasal doses of eluxadoline resulted in higher systemic concentrations of eluxadoline that produced changes in pupil diameter but were associated with drug disliking. In patients with IBS-D, no signal for central nervous system-mediated adverse events was identified. Taken together these results suggest that when using the medicinal product as directed at therapeutic doses patients will not experience significant central nervous system effects or adverse events consistent with a drug of abuse.
Eluxadoline’s systemic exposure following oral administration is low and is consistent with its local action in the GI tract. The active substance has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Mean plasma elimination half-life is 5 hours with high inter-subject variability. Eluxadoline is primarily cleared as such via the biliary system with the kidney playing a minimal role in elimination. Eluxadoline is not an inducer/inhibitor of major CYP enzymes, however, eluxadoline has some potential for the metabolism based inactivation of CYP3A4. It is a substrate and an inhibitor of the hepatic uptake transporter OATP1B1; and a substrate for the hepatic efflux transporter MRP2. Hepatic impairment or coadministration with cysclosporine results in significant increases in plasma concentrations of eluxadoline.
The absolute bioavailability of eluxadoline has not been determined but is estimated to be low due to limited absorption and first pass effects. The absorption of eluxadoline was rapid under fasting conditions, with a median Tmax value of 2 hours. The administration of eluxadoline with a high fat meal significantly decreased both Cmax (50%) and AUC (60%) without any effect on Tmax. Upon administration of multiple oral doses twice daily, there was no accumulation of active substance.
In a population pharmacokinetic analysis, the estimated apparent volume of distribution of eluxadoline was 27,100 L. In healthy subjects, eluxadoline was moderately (81%) bound to plasma proteins.
Eluxadoline is primarily excreted in the feces, either as unabsorbed active substance or via the biliary system with the kidney playing a minimal role in elimination.
In vitro studies demonstrated that eluxadoline was stable in human hepatocytes, liver and intestinal microsomes, and that the only minor and inactive metabolite of eluxadoline detected was the acyl glucuronide metabolite (M11) formed through glucuronidation of the methoxybenzoic acid moiety.
Following a 1,000 mg oral dose in healthy male volunteers, M11 was detected in urine but not in systemic circulation.
Eluxadoline exists predominantly as the (S,S)-diastereomer (>99%) and undergoes little or no chiral conversion in vivo.
Eluxadoline has a low potential for drug-drug interactions based on limited in vitro CYP inhibition/induction and given that eluxadoline is not a substrate for CYPs at clinically meaningful concentrations.
Eluxadoline is a substrate of the hepatic uptake transporter OATP1B1. Co-administration of eluxadoline with cyclosporine (an OATP1B1 inhibitor) increased eluxadoline exposure by approximately 5-fold.
Eluxadoline is a substrate of the hepatic efflux transporter MRP2. Co-administration of eluxadoline with probenecid (MRP2 inhibitor) resulted in approximately 1.4-fold increase in exposure to eluxadoline. No dose adjustment is necessary.
Eluxadoline is an inhibitor of the hepatic uptake transporter OATP1B1. Co-administration of eluxadoline with rosuvastatin (an OATP1B1 substrate) resulted in an up to 1.4-fold increase in exposure of rosuvastatin and the major active metabolite, n-desmethyl rosuvastatin compared to administration of rosuvastatin alone. No dose adjustment is necessary for co-administered OATP1B1 substrates. However, caution should be exercised in patients receiving high doses of OATP1B1 substrates.
In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2C8 and CYP2D6 at clinically relevant concentrations. CYP2E1 was slightly inhibited (50% inhibitory concentration [IC50] of approximately 20 μM [11 μg/mL]), although this is not expected to result in any clinically meaningful interactions.
In vitro studies in human liver microsomes showed that eluxadoline is not a direct inhibitor of CYP3A4 at clinically relevant concentrations [IC50 =450 μM] but in human intestinal microsomes, eluxadoline was a metabolism dependent inhibitor of CYP3A4 with kinact of 0.1 min1 and KI of 450 μM (256 μg/mL). However, in a clinical study in healthy subjects, administration of eluxadoline 100 mg twice daily for one week, with a single oral dose of 4 mg of midazolam resulted in no change to the midazolam Cmax and a slight decrease in AUC (~10%). Cmax and AUC for the metabolite 1-hydroxy-midazolam increased by ~14% and 7% respectively, suggesting that eluxadoline may be a mild inducer of CYP3A4 and may decrease the exposure of concomitantly administered CYP3A4 substrates.
In vitro studies indicated that eluxadoline is a substrate and an inhibitor of the hepatic uptake transporter OATP1B1; a substrate for the hepatic efflux transporter MRP2 and is not a substrate or inhibitor of the P-gp and BCRP transporters.
Following a single oral dose of 300 mg [14C] eluxadoline in healthy male subjects, 82.2% of the total [14C] eluxadoline was recovered in faeces in 336 hours and less than 1% was recovered in urine in 192 hours.
Given eluxadoline’s local action in the GI tract, low F oral and lack of metabolism, prospective clinical studies regarding differences in age, body mass index (BMI), ethnicity, and gender were deemed unnecessary. Pharmacokinetic data for healthy volunteers pooled across Phase 1 studies (using the 100 mg single oral dose) and analyzed for potential differences based on sex, age, race, and BMI demonstrated no significant differences.
In ESRD participants not yet on dialysis relative to matched, healthy participants with normal renal function, eluxadoline plasma Cmax was 2.2-fold higher and AUC0-t was 4.2-fold higher. Unchanged eluxadoline recovered in urine was 0.01% and 0.05% of dose in ESRD and healthy participants, respectively. Although exposure of eluxadoline was significantly increased in ESRD participants not yet on dialysis compared with matched, healthy participants with normal renal function, such an increase is unlikely to be of clinical significance because the geometric mean Cmax and AUC0-t in the participants with ESRD was in the same range as observed in several larger studies in healthy volunteers.
The apparent clearance of eluxadoline is markedly reduced and half-life increases in hepatic-impaired patients. Following single oral 100 mg dose in subjects with varying degrees of liver impairment and healthy subjects, eluxadoline plasma levels were on average 6-fold, 4-fold, and 16-fold elevated in mild, moderate, and severe hepaticimpaired subjects (Child Pugh Class A, B, C), respectively, while half-life increased 3-5 fold.
The plasma levels in patients with a genetic predisposition for poor function of OATP1B1 transporter are increased and in these patients a higher rate of adverse events, especially with regard to gastrointestinal events, as well as CNS effects might be expected.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development. In rat, eluxadoline was excreted into milk in an approximately dose proportional manner with maximal concentrations less than plasma concentrations.
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