Atypical population pharmacokinetics of hydromethylthionine in patients with Alzheimer's disease explains unexpected phase 3 trial results.

AIM: Tau aggregation contributes to the pathology of Alzheimer's disease (AD). Tau aggregation inhibitors (TAI) are potential disease-modifying drugs for AD and other tauopathies. Hydromethylthionine (HMT) is a potent orally administered TAI, which also has tau-independent symptomatic activity. The purpose of this analysis was to characterize HMT pharmacokinetics (PK) in healthy volunteers and AD patients. METHODS: Data from five Phase I studies and the TRx-237-039 Phase 3 study (mild to moderate AD and mild cognitive impairment) were combined, including single doses of hydromethylthionine mesylate (HMTM) (4-100 mg), multiple dose regimens (8-80 mg/day) and long-term data (16 mg/day) over a maximum of 104 weeks. In TRx-237-039, methylthioninium chloride (MTC, 4 mg twice weekly), which also delivers HMT, was intended to maintain blinding for urine discoloration without therapeutic activity based on linear PK modelling of earlier trial data. The PK model characterized active HMT, regardless of its source. Plasma HMT data from 710 participants with 7784 measurements were analysed using non-linear mixed effects modelling. RESULTS: The model described inter-individual variability, time-varying (U-shaped) clearance, and the impact of clinically relevant covariates on the PK. The U-shaped clearance over 24 months led to increasing plasma levels at 12 months that were 3 × (HMTM) and 5 × (MTC) above linear model predictions. CONCLUSIONS: The exposure increase at 12 months and the dual pharmacology of HMT explain the unexpected symptomatic activity of low dose MTC. The data suggest it is not possible to maintain comparable urinary discolouration without therapeutic activity in a standard placebo-controlled trial design.