Abstracts

Rationale: Because pharmacologic effects often correlate with drug plasma concentrations, maximum concentration (C_max) is a key bioequivalence metric. However, oral carbamazepine formulations bioequivalent on traditional metrics (eg, C_max) exhibited clinically important toxicity differences due to input rate differences (Tothfalusi L et al. Brit J Clin Pharmacol 2007;5:110-22). A placebo-controlled study of oral immediate-release TPM (TPM-IR) found a significant association between TPM concentrations and impaired verbal fluency in healthy adults (Marino SE et al. Epilepsy Behav 2012;24:365-72). We report results of two independent studies in healthy adults that compared TPM-IR with 1] the extended-release (XR) oral formulation SPN-538 (Trokendi XR^®; Supernus Pharmaceuticals, Inc.) (Johnson J et al. Neurology 2014;82(S43.002) or 2] an intravenous (IV) solution (Marino SE et al. Epilepsy Curr 2013;13(suppl 1):3.296). Together, these suggest a potential pharmacokinetic-pharmacodynamic (PK-PD) relationship whereby TPM input rate influences phonemic generative verbal fluency. Methods: SPN-538/IR study (N=33). Single-blind, randomized-sequence, crossover comparison of SPN-538 QD and TPM-IR BID. 3-wk titration to 200 mg; 10-day maintenance period. Verbal fluency testing: End of 24-hr dosing period (trough concentration, C_min) at steady-state for 50, 100, 150, and 200 mg/day. Intensive PK sampling on last treatment day, with single pre-AM sample at steady-state for each titration step. IV/IR study (N=10). Randomized, placebo-controlled, crossover study comparing acute 100-mg dose of TPM-IV (15-min administration) and oral TPM-IR. Verbal fluency testing: Pre-dose and 0.25, 2.5, 6 hrs post-dose. Intensive PK sampling up to 120 hrs post-dose. Results: SPN-538/IR study. Change from baseline verbal fluency scores consistently showed less impairment with SPN-538 vs TPM-IR. Differences were significant at 100 mg/day (P<0.001) and for overall treatment (P<0.05). Mean concentration at testing (C_min) was virtually identical for SPN-538 vs TPM-IR. IV/IR study. Negative changes in verbal fluency scores were observed as early as 15 min with both TPM-IV and TPM-IR; negative changes were consistently more pronounced with TPM-IV at all test points, although mean TPM concentration was higher at 2.5 and 6 hrs for oral TPM-IR. Conclusions: Differences in study designs, TPM doses, and time of verbal fluency testing post-dose confound the comparison of study results. However, results suggest a more complex PK-PD relationship than concentration-related effects of TPM on verbal fluency. The observed pattern of verbal fluency impairment — IV>IR and IR>SPN-538 — follows the pattern of input rate differences (rate constant: IV, 4/hr; TPM-IR, 2.25/hr, SPN-538, 0.092/hr). We will outline key elements of a study that could further explore the potential PK-PD relationship between TPM input rate and verbal fluency impairment. Funding: Supernus Pharmaceuticals, Inc. (SPN-538 vs TPM-IR). NIH/NINDS K01 NS050309 and NIH/NINDS R01 NS076665 (Principal Investigator: S.E. Marino)