Pharmacokinetics of hydroxychloroquine in pediatric lupus

To control disease activity and prevent adverse outcomes, almost all patients with SLE are treated with hydroxychloroquine (HCQ), which prevents disease flare-ups, reduces cumulative organ damage, and improves survival
.
HCQ is metabolized into several metabolites, the main active metabolite being desethylhydroxychloroquine (DHCQ).

Despite widespread use in children, few population-based pharmacokinetic/pharmacodynamic (PK/PD) studies have been conducted to guide HCQ doses for pediatric SLE (pSLE), and children are prescribed the same weight-based doses
as adults.
However, weight-based administration may produce significantly different exposures
in children due to differences in drug metabolism enzyme maturity, renal function, and other physiological changes.
In children, the need for PK studies is emphasized to ensure that children obtain therapeutic HCQ and DHCQ concentrations
.

To overcome existing gaps in PK and exposure response data in children, a novel direct-to-home clinical trial was conducted in pSLE using electronic vial caps to improve adherence to HCQ
.
As a secondary result of the trial, plasma samples were collected to measure HCQ concentration and biomarkers of HCQ response, including inflammatory cytokines
.
Therefore, this analysis aims to determine population PK and exposure responses
for HCQ and DHCQ in pSLE.

Relationship between dose-normalized hydroxychloroquine (HCQ) concentration and body size:

Methods: An exploratory phase 2 direct-to-family trial
was conducted.
Children registered with the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry and diagnosed with pSLE are eligible
if they receive HCQ as standard care ≥ 3 months.
Collect biological samples
up to four visits over a 6-month period.
At each visit, plasma is obtained to measure the concentration
of HCQ and DHCQ as well as cytokines.
HCQ and DHCQ plasma PK data
were analyzed using population PK modeling methods.

Relationship between inflammatory biomarkers and hydroxychloroquine (HCQ) concentration:

Results: A total of 88 plasma concentrations were provided to 25 subjects for PK analysis
.
The linear fit between HCQ concentration and population weight was poor (R2=0.
03).

Both interferon (IFN)-α and IFN-γ decreased, and HCQ and DHCQ concentrations were higher
.
The volume of distribution of HCQ in the plasma of children is higher compared to the published values in adults (73 000 L versus 44 000 L), but the clearance in children is similar
to that in adults.

Final PK model parameter estimation:

In summary, the first population PK model
of HCQ and DHCQ in children was reported using data from a novel direct-to-family clinical trial.
Large between-individual variation in HCQ PK was observed and a poor correlation between weight-based HCQ doses and drug concentrations was found, suggesting the need to personalize the dose
using therapeutic drug monitoring.
In addition, the findings suggest that the current weight-based HCQ dosing paradigm may lead to suboptimal drug exposure, particularly in obese children
.
Therefore, more research on HCQ in pSLE is needed to determine optimal drug concentrations and doses to reduce disease activity and improve outcomes
.

References: Balevic SJ, Randell R, Weiner D, Beard C, Schanberg LE, Hornik CP, Cohen-Wolkowiez M, Gonzalez D; with the CARRA Registry investigators.
Pharmacokinetics of hydroxychloroquine in paediatric lupus: data from a novel, direct-to-family clinical trial.
Lupus Sci Med.
2022 Nov; 9(1):e000811.
doi: 10.
1136/lupus-2022-000811.
PMID: 36328395; PMCID: PMC9639143.