Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma.
Clinical
Drug conjugates
PK/PD Modeling
Pharmacodynamics
Pharmacokinetics
Journal
The AAPS journal
ISSN: 1550-7416
Titre abrégé: AAPS J
Pays: United States
ID NLM: 101223209
Informations de publication
Date de publication:
10 12 2021
10 12 2021
Historique:
received:
26
07
2021
accepted:
15
10
2021
entrez:
11
12
2021
pubmed:
12
12
2021
medline:
5
4
2022
Statut:
epublish
Résumé
We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure-response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores > 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p < 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p < 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469.
Identifiants
pubmed: 34893942
doi: 10.1208/s12248-021-00660-3
pii: 10.1208/s12248-021-00660-3
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Immunoconjugates
0
Benzodiazepines
12794-10-4
loncastuximab tesirine
7K5O7P6QIU
Banques de données
ClinicalTrials.gov
['NCT03589469', 'NCT02669017']
Types de publication
Clinical Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11Informations de copyright
© 2021. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.
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