Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants.
Antivir Ther
; 28(1): 13596535231151626, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36691849
ABSTRACT
BACKGROUND:
JNJ-4964 is a TLR7 agonist, which, via a type I interferon (IFN)-dependent mechanism, may enhance host immunity suppressed by persistent exposure to hepatitis B antigens in chronic hepatitis B.METHODS:
PK and PD data were pooled from 2 studies involving 90 participants (n = 74 JNJ-4964, dose range 0.2-1.8 mg; n = 16 placebo) in a fasted state. Food effects on PK were studied in 24 participants (1.2 or 1.25 mg). A population PK model and PK/PD models were developed to characterize the effect of JNJ-4964 plasma levels on the time course of IFN-α, IFN-γ-inducible protein 10 (IP-10 or CXCL10), IFN-stimulated gene 15 (ISG15), neopterin and lymphocytes following single and weekly dosing in healthy adults. Covariate effects, circadian rhythms and negative feedback were incorporated in the models.RESULTS:
A 3-compartment linear PK model with transit absorption adequately described JNJ-4964 PK. Bioavailability was 44.2% in fed state relative to fasted conditions. Indirect response models with maximum effect (Emax) stimulation on production rate constant (kin) described IFN-α, IP-10, ISG15 and neopterin, while a precursor-dependent indirect response model with inhibitory effect described the transient lymphocyte reduction. Emax, EC50 and γ (steepness) estimates varied according to PD markers, with EC50 displaying substantial between-subject variability. Female and Asian race exhibited lower EC50, suggesting higher responsiveness.CONCLUSIONS:
PK/PD models well characterized the time course of immune system markers in healthy adults. Our results supported sex and race as covariates on JNJ-4964 responsiveness, as well as circadian rhythms and negative feedback as homeostatic mechanisms that are relevant in TLR7-induced type I IFN responses.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Receptor 7 Toll-Like
/
Quimiocina CXCL10
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article