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Randomized Controlled Trial
. 2022 Feb;88(2):600-612.
doi: 10.1111/bcp.14975. Epub 2021 Jul 31.

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects

Wei Yin  1 , Fahimeh Mamashli  1   2 , Derek L Buhl  1 , Polyna Khudyakov  1 , Dmitri Volfson  1 , Ferenc Martenyi  3 , Hakop Gevorkyan  4 , Laura Rosen  1 , Arthur A Simen  1
Affiliations
Randomized Controlled Trial

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects

Wei Yin et al. Br J Clin Pharmacol. 2022 Feb.

Abstract

Aims: TAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071.

Methods: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect.

Results: TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition.

Conclusions: PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.

Keywords: Alzheimer's disease; Parkinson's disease; electrophysiology; pharmacokinetic-pharmacodynamic; phase I.

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Conflict of interest statement

W.Y., D.L.B., P.K., D.V., L.R. and A.A.S. are employees of Takeda Pharmaceuticals. F.M. was a paid consultant to Takeda through Signal Insight, LLC, and was an employee of Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Figures

FIGURE 1
FIGURE 1
Mean plasma steady‐state concentration‐time curves of TAK‐071 (linear [left panels] and semi‐log [right panels]) following multiple oral administration of TAK‐071 3, 9 or 15 mg to healthy non‐Japanese subjects or Japanese subjects. Cohort number is indicated in the figure legend
FIGURE 2
FIGURE 2
Cluster masks and power topography of significant differences between predose and postdose qEEG data under eyes‐open (left column) and eyes‐closed conditions (right column) conditions. Postdose > predose results are shown in panels A‐C and F‐H, and predose > postdose results are shown in panels D‐E and I. (A, F) low‐dose (40‐80 mg) TAK‐071, (B, G) low‐dose TAK‐071 + donepezil, (C, H) high‐dose (160‐180 mg) TAK‐071. The results from A‐C under eyes‐open and F‐H under eyes‐closed conditions show increased power in postdose compared to predose, and the topography was estimated via postdose minus predose at certain frequency bands within the significant cluster mask. (D‐E) Increased power in predose compared to postdose under eyes‐open and (I) high‐dose TAK‐071 under the eyes‐closed condition. (J) Electrode names and their locations number used in the y axis of the cluster masks in A‐I
FIGURE 3
FIGURE 3
Predose data was subtracted from postdose within the cluster mask and then averaged, giving one value for each subject. (A) Individual subject data from both eyes open and eyes closed marked with different colors for each dose group with corresponding uncorrected P value. (B) The same data from (A) but showing eyes open and eyes closed data pooled together. Corresponding P value from linear mixed model is shown for each dose group separately. The red line in each box plot is the mean, the shaded red area is the 95% confidence interval and the blue shaded area is one standard deviation
FIGURE 4
FIGURE 4
Cluster masks sum and connectivity matrix of significant differences between postdose and predose qEEG data under eyes‐closed conditions for (A) placebo, (B) placebo + donepezil, (C) low‐dose (40, 60 and 80 mg) TAK‐071 and (D) low‐dose (40, 60 and 80 mg) TAK‐071 + doenepezil. Note that in each plot the blue color means functional connectivity is reduced in postdose compared to predose
FIGURE 5
FIGURE 5
Comparison of the weighted phase lag index (wPLI) difference in postdose vs predose averaged across subjects under different drug doses for the eyes‐closed condition. The boxplot shows the median and the 25th and 75th percentiles of the data
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