Population pharmacokinetics of unbound and total dolutegravir concentrations in children aged 12 years and older: a PK substudy of the SMILE trial.
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
03 04 2023
03 04 2023
Historique:
received:
15
10
2022
accepted:
02
02
2023
medline:
4
4
2023
pubmed:
5
3
2023
entrez:
4
3
2023
Statut:
ppublish
Résumé
SMILE, a multicentre randomized trial, compared the efficacy and safety of switching virologically suppressed children and adolescents with HIV to a once-daily dual regimen of dolutegravir plus ritonavir-boosted darunavir versus continuing standard ART. Within a nested pharmacokinetic (PK) substudy, we performed a population PK analysis to describe total and unbound dolutegravir plasma concentrations in children and adolescents receiving this dual therapy. Sparse blood samples were obtained during follow-up for dolutegravir quantification. A population PK model was developed to simultaneously describe total and unbound dolutegravir concentrations. Simulations were performed and were compared with the protein-adjusted 90% inhibitory concentration (IC90) and the in vitro IC50, respectively. Dolutegravir exposures in children aged ≥12 years were also compared with values in treatment-experienced adults. Four hundred and fifty-five samples from 153 participants aged between 12 and 18 years were collected for this PK analysis. A one-compartment model with first-order absorption and elimination best described unbound dolutegravir concentrations. The relationship between unbound and total dolutegravir concentrations was best characterized by a non-linear model. Unbound dolutegravir apparent clearance was significantly influenced by total bilirubin concentrations and by Asian ethnicity. All children and adolescents had trough concentrations well above the protein-adjusted IC90 and the in vitro IC50 values. Dolutegravir concentrations and exposures were also similar to those obtained in adults receiving dolutegravir 50 mg once daily. A once-daily 50 mg dolutegravir dose for children and adolescents produces adequate total and unbound concentrations when used as part of dual therapy with ritonavir-boosted darunavir.
Sections du résumé
BACKGROUND
SMILE, a multicentre randomized trial, compared the efficacy and safety of switching virologically suppressed children and adolescents with HIV to a once-daily dual regimen of dolutegravir plus ritonavir-boosted darunavir versus continuing standard ART. Within a nested pharmacokinetic (PK) substudy, we performed a population PK analysis to describe total and unbound dolutegravir plasma concentrations in children and adolescents receiving this dual therapy.
METHODS
Sparse blood samples were obtained during follow-up for dolutegravir quantification. A population PK model was developed to simultaneously describe total and unbound dolutegravir concentrations. Simulations were performed and were compared with the protein-adjusted 90% inhibitory concentration (IC90) and the in vitro IC50, respectively. Dolutegravir exposures in children aged ≥12 years were also compared with values in treatment-experienced adults.
RESULTS
Four hundred and fifty-five samples from 153 participants aged between 12 and 18 years were collected for this PK analysis. A one-compartment model with first-order absorption and elimination best described unbound dolutegravir concentrations. The relationship between unbound and total dolutegravir concentrations was best characterized by a non-linear model. Unbound dolutegravir apparent clearance was significantly influenced by total bilirubin concentrations and by Asian ethnicity. All children and adolescents had trough concentrations well above the protein-adjusted IC90 and the in vitro IC50 values. Dolutegravir concentrations and exposures were also similar to those obtained in adults receiving dolutegravir 50 mg once daily.
CONCLUSIONS
A once-daily 50 mg dolutegravir dose for children and adolescents produces adequate total and unbound concentrations when used as part of dual therapy with ritonavir-boosted darunavir.
Identifiants
pubmed: 36869720
pii: 7069107
doi: 10.1093/jac/dkad043
doi:
Substances chimiques
Darunavir
YO603Y8113
Ritonavir
O3J8G9O825
dolutegravir
DKO1W9H7M1
Heterocyclic Compounds, 3-Ring
0
Oxazines
0
Pyridones
0
Anti-HIV Agents
0
Types de publication
Randomized Controlled Trial
Multicenter Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1041-1049Investigateurs
R Bologna
(R)
V Reliquet
(V)
N Elenga
(N)
N Pavia-Ruz
(N)
L Marques
(L)
M F Candeias
(MF)
A Violari
(A)
M Cotton
(M)
P Rojo Conejo
(P)
M J Mellado Peña
(MJ)
C Fortuny Guasch
(C)
M Navarro Gómez
(M)
M A Muñoz Fernandez
(MA)
S Martin
(S)
J T Ramos Amador
(JT)
C Kalhert
(C)
P Paioni
(P)
A Duppenthaler
(A)
C Ngampiyaskul
(C)
N Chanto
(N)
P Ounchanum
(P)
S Kanjanavanit
(S)
U Srirompotong
(U)
S Srirojana
(S)
P Amuge
(P)
V Musiime
(V)
I Raus
(I)
J Kenny
(J)
S Vergnano
(S)
D Nayagam
(D)
S Welch
(S)
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.