Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease
Abstract 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 mea...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-12-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12862 |
| _version_ | 1811293284715200512 |
|---|---|
| author | Seiichi Hayato Osamu Takenaka Sree Harsha Sreerama Reddy Ishani Landry Larisa Reyderman Akihiko Koyama Chad Swanson Sanae Yasuda Ziad Hussein |
| author_facet | Seiichi Hayato Osamu Takenaka Sree Harsha Sreerama Reddy Ishani Landry Larisa Reyderman Akihiko Koyama Chad Swanson Sanae Yasuda Ziad Hussein |
| author_sort | Seiichi Hayato |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T04:59:08Z |
| format | Article |
| id | doaj.art-a4225fc1516d43588fdf82ef59d7e7a2 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-13T04:59:08Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-a4225fc1516d43588fdf82ef59d7e7a22022-12-22T03:01:23ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062022-12-0111121578159110.1002/psp4.12862Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's diseaseSeiichi Hayato0Osamu Takenaka1Sree Harsha Sreerama Reddy2Ishani Landry3Larisa Reyderman4Akihiko Koyama5Chad Swanson6Sanae Yasuda7Ziad Hussein8Eisai Co., Ltd. Tokyo JapanEisai Co., Ltd. Tokyo JapanEisai Inc. Nutley New Jersey USAEisai Inc. Nutley New Jersey USAEisai Inc. Nutley New Jersey USAEisai Inc. Nutley New Jersey USAEisai Inc. Nutley New Jersey USAEisai Inc. Nutley New Jersey USAEisai Ltd. Hatfield UKAbstract 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.https://doi.org/10.1002/psp4.12862 |
| spellingShingle | Seiichi Hayato Osamu Takenaka Sree Harsha Sreerama Reddy Ishani Landry Larisa Reyderman Akihiko Koyama Chad Swanson Sanae Yasuda Ziad Hussein 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 |
| title | Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease |
| title_full | Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease |
| title_fullStr | Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease |
| title_full_unstemmed | Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease |
| title_short | Population pharmacokinetic‐pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease |
| title_sort | population pharmacokinetic pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early alzheimer s disease |
| url | https://doi.org/10.1002/psp4.12862 |
| work_keys_str_mv | AT seiichihayato populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT osamutakenaka populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT sreeharshasreeramareddy populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT ishanilandry populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT larisareyderman populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT akihikokoyama populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT chadswanson populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT sanaeyasuda populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease AT ziadhussein populationpharmacokineticpharmacodynamicanalysesofamyloidpositronemissiontomographyandplasmabiomarkersforlecanemabinsubjectswithearlyalzheimersdisease |