PAS-004’s new tablet showed linear, dose-proportional PK with a long half-life (~57 hours) and tight peak–trough control at steady state (Cmax/Cmin <2). In the 4 mg cohort, AUC was 1,120 ng·h/mL with Cmax 58.1 ng/mL and Cmin 37.6 ng/mL; the 8 mg cohort reached an AUC of 2,290 ng·h/mL with Cmax 118 ng/mL and Cmin 75.4 ng/mL. Dose-normalized exposures were roughly threefold higher than the capsule, and the 8 mg tablet delivered slightly greater AUC and Cmax than the 22 mg capsule. Both Cmax and Cmin sat above the cellular IC50 throughout the dosing interval. The core update: Pasithea reported tablet PK from its ongoing Phase 1/1b open-label study in adult NF1-associated plexiform neurofibromas (NCT06961565), alongside bridging to capsule data from its oncology Phase 1 (NCT06299839). The tablet demonstrates higher systemic exposure at lower doses, reduced interpatient variability, and similar Tmax relative to the capsule, aligning with preclinical formulation comparisons. For a MEK inhibitor program aimed at NF1-PN, the steadier exposure profile and dose proportionality are the operational headline, positioning the tablet as the go-forward formulation. Strategically, this is a formulation-led reset designed to de-risk downstream development. Higher exposure at a lower milligram strength, with less variability and flatter peaks, gives Pasithea a clearer path to define an RP2D grounded in exposure–response modeling rather than iterative dose escalation. It also creates a cleaner bridge between oncology and NF1-PN datasets by matching or exceeding capsule exposures with far less pill burden. In a space where class tolerability often dictates dose intensity and adherence, a Cmax/Cmin ratio under 2 is a pragmatic attempt to control peak-driven adverse events and simplify titration, without sacrificing target coverage. For sites and CROs, a stable, once-daily tablet can translate into fewer protocol deviations around dose holds, a lighter PK sampling grid after model qualification, and simpler pharmacy workflows versus high-count capsule regimens. Reduced between-subject variability tightens the confidence around exposure targets in a small, rare-disease population, improving the odds that a modestly sized Phase 2 could be adequately powered on pharmacologically active exposures. For sponsors and regulators, the tablet–capsule bridge provides a path to consolidate datasets without a separate, large-scale switch study, provided exposure matching is robust and supported by PD readouts. The long half-life will drive scheduling discipline for safety monitoring and washouts, but it also supports consistent target inhibition across the dosing interval. Vendors supporting bioanalytics, modeling and simulation, and supply chain should anticipate a pivot to tablet-only supply and a streamlined PK strategy once RP2D is set. What’s next is not the PK curve but whether steady-state coverage above IC50 translates into clinically meaningful volumetric tumor reductions and symptom improvement in adults with NF1-PN. The key deliverables are RP2D selection for the tablet, exposure–response linkage to early efficacy and tolerability, and clarity on variability under real-world dosing conditions, including any food-effect or drug–drug interaction constraints. If the PK advantages hold in larger cohorts, Pasithea can move faster into a tablet-based expansion while minimizing protocol amendments. The unresolved risks remain class-typical safety liabilities, the need to differentiate against existing MEK options, and operational execution around a long half-life that complicates interruption and restart rules. Watch for a near-term RP2D decision, PD biomarker corroboration, and first durability signals tied to volumetric endpoints to determine whether this formulation shift converts PK strength into clinical leverage.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
