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Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease
Hayato S, Takenaka O, Sreerama Reddy SH, Landry I, Reyderman L, Koyama A, Swanson C, Yasuda S et al.. CPT: pharmacometrics & systems pharmacology, 2022-09-27
Topic: Amyloid, tau and blood-test diagnosis
Lecanemab is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregate species, while demonstrating low affinity for Aβ monomer. This article describes the population pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses for amyloid plaques, as measured using positron emission tomography (PET), and biomarkers of amyloid pathology as evidenced by Aβ42/40 ratio and plasma p-tau181 following i.v. administration of lecanemab in subjects with early Alzheimer's disease. Lecanemab PKs were well-characterized with a two-compartment model with first-order elimination. Final PK model contained covariate effects of anti-drug antibody positive status, sex, body weight, and albumin on clearance. The time course of amyloid PET standard uptake ratio (SUVr), plasma Aβ42/40 ratio, and p-tau181 were described using indirect response models with lecanemab exposure as a maximum effect function stimulating the reduction of SUVr, and as a linear function increasing Aβ42/40 ratio and decreasing p-tau181 formation rates. PK/PD simulations show that 10 mg/kg biweekly dosing results in larger and faster decrease in SUVr and p-tau181 and increase in Aβ42/40 ratio as compared to 10 mg/kg monthly dose. Furthermore, the PK/PD simulations showed that after treatment discontinuation the brain amyloid re-accumulation to baseline levels is slow with a recovery half-life of ~4 years, whereas plasma Aβ42/40 ratio and p-tau181 return to baseline levels faster than amyloid. Given the relationship between changes in amyloid PET SUVr and soluble biomarkers, the developed PK/PD models can be used to inform lecanemab dose regimens in future clinical studies.
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APA 7th
Hayato, S., Takenaka, O., Sreerama Reddy, S. H., Landry, I., Reyderman, L., Koyama, A., et al. (2022). Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease. CPT: pharmacometrics & systems pharmacology. https://doi.org/10.1002/psp4.12862
Vancouver
Hayato S, Takenaka O, Sreerama Reddy SH, Landry I, Reyderman L, Koyama A, et al. Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease. CPT: pharmacometrics & systems pharmacology. 2022. doi:10.1002/psp4.12862. PMID: 36165093.
BibTeX
@article{hayato2022-36165093,
author = {Hayato, S. and Takenaka, O. and Sreerama Reddy, S. H. and Landry, I. and Reyderman, L. and Koyama, A. and Swanson, C. and Yasuda, S. and others},
title = {{Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease}},
journal = {CPT: pharmacometrics \& systems pharmacology},
year = {2022},
doi = {10.1002/psp4.12862},
pmid = {36165093},
url = {https://doi.org/10.1002/psp4.12862}
}
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Key findings
- PK/PD simulations show that 10 mg/kg biweekly dosing results in larger and faster decrease in SUVr and p-tau181 and increase in Aβ42/40 ratio as compared to 10 mg/kg monthly dose.
- Furthermore, the PK/PD simulations showed that after treatment discontinuation the brain amyloid re-accumulation to baseline levels is slow with a recovery half-life of ~4 years, whereas plasma Aβ42/40 ratio and p-tau181 return to baseline levels faster than amyloid.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (CPT: pharmacometrics & systems pharmacology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36165093) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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