Abstracts

Rationale:
Complex polypharmacy is common in patients with developmental and epileptic encephalopathies (DEE), therefore, avoiding drug-drug interactions (DDI) is particularly important in this population. Many antiseizure medications (ASMs) are affected by CYP enzyme inhibitors, notably CYP2D6 (fenfluramine, carbamazepine), CYP3A4 (clobazam, cannabidiol, felbamate, carbamazepine), and CYP2C19 (fenfluramine, cannabidiol, phenobarbital, phenytoin). In addition, many patients use ≥3 ASMs concomitantly, some of which are CYP inhibitors themselves. P-glycoprotein (P-gp)-mediated efflux and renal transporters can also cause undesirable pharmacokinetic (PK) effects. As such, key considerations in the development of LP352 include avoiding CYP metabolism, P-gp efflux, and renal transporters, and instead relying on UDP-glucuronosyltransferase (UGT) disposition to create a favorable PK profile.

Methods:
Our study was designed to: a) confirm metabolism of LP352 via glucuronidation by UGT; b) assess LP352 disposition and potential to be affected by renal transporters; c) characterize the likelihood of LP352 to be affected P-gp efflux or by DDIs through the CYP metabolic pathway. This open-label study of 19 healthy volunteers was conducted in 2 parts: Part 1; the UGT metabolic pathway and role of renal transporters was assessed using a single 12 mg dose of LP352 in the presence of a UGT inhibitor (probenecid) and a renal transport inhibitor (cimetidine) compared with LP352 alone, and Part 2; the PK of steady-state 12 mg TID LP352 was assessed with a CYP and P-gp inhibitor (quinidine) compared to LP352 alone. Serial plasma samples were collected in both parts of the study. Safety parameters were monitored throughout.

Results:
Part 1: C_max and AUC values for LP352 were somewhat higher with probenecid/cimetidine versus LP352 alone. The observed ~80% increase in LP352 exposure is consistent with, and supportive of, in vitro data showing LP352’s disposition via UGT, and a low likelihood of being affected by renal transport inhibitors. Part 2: C_max and AUC values for LP352 were 33.6 ng/mL and 167.4 h.ng/mL in the presence of quinidine, and 30.8 ng/mL and 148.9 h.ng/mL for LP352 alone. This lack of quinidine effect on exposure reflects the fact that LP352 is not a substrate for CYP3A4, CYP2D6, or P-gp. Figure 1 shows the ratio of geometric least squares means comparing LP352 alone to administration with quinidine. The potential for LP352 to be affected by inhibition of CYP219 and CYP2C9 was not assessed because in vitro data indicate that these are unlikely metabolic pathways for LP352. LP352 was safe and generally well-tolerated, alone or in combination with other probe substrates.

Conclusions:
Given LP352’s disposition via UGTs and the current data, LP352 is unlikely to be subject to clinically significant CYP-mediated DDIs. Moreover, these data support a low likelihood of P-gp or renal transporter interactions in the disposition of LP352.

Funding:
This study was sponsored by Longboard Pharmaceuticals, Inc.