The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS-d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4- and 1.4-fold, respectively, whereas peak exposure (Cmax) increased 6.2-fold and 1.3-fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1-mediated hepatic uptake of eluxadoline (during first-pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3-mediated basolateral uptake in the proximal renal tubules and MRP2-mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.

Drugs with μ-opioid receptor (OR) activity can be associated with abuse and misuse. The peripherally acting mixed μ-OR and κ-OR agonist and δ-OR antagonist eluxadoline is approved in the United States for the treatment of irritable bowel syndrome with diarrhea. In two separate crossover studies, we evaluated the oral and intranasal abuse potential of eluxadoline versus placebo and the active control oxycodone. Healthy recreational opioid users received eluxadoline 100, 300, and 1000 mg, oxycodone 30 and 60 mg, and placebo (oral study), or eluxadoline 100 and 200 mg, oxycodone 15 and 30 mg, and placebos matched to eluxadoline and oxycodone (intranasal study). In the oral study, Drug Liking Visual Analog Scale (VAS) peak (maximum) effect (Emax) score (primary endpoint) was significantly greater with eluxadoline 300 and 1000 mg versus placebo, but scores were significantly lower versus oxycodone. Following intranasal insufflation of eluxadoline, Drug Liking VAS Emax scores were not statistically different versus placebo, and were significantly lower versus oxycodone. Across other subjective measures, eluxadoline was generally similar to or disliked versus placebo. Pupillometry indicated no or minimal central effects with oral and intranasal eluxadoline, respectively. Adverse events of euphoric mood were reported with oral and intranasal eluxadoline but at a far lower frequency versus oxycodone. These data demonstrate that eluxadoline has less abuse potential than oxycodone in recreational opioid users.

AVB‐S6‐500 neutralized growth arrest‐specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target‐mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first‐in‐human (FIH) doses for AVB‐S6‐500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB‐S6‐500 clearance was incorporated into a standard two‐compartment model, providing parallel linear and nonlinear clearance. Observed AVB‐S6‐500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10‐fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model‐projected and clinically observed maximal concentration (Cmax) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (Cmax) and 45% (area under the serum concentration‐time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB‐S6‐500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.