Population pharmacokinetic modelling and simulation
Two previous published population pharmacokinetic models have been
published for hydroxychloroquine (HCQ) in patients with RA [3] and
lupus erythematosus [4] using whole-blood HCQ concentrations. Four
additional models describe plasma concentrations or merged blood and
plasma concentrations [13-15]. Blood concentrations are known to be
more reproducible (because higher, with lesser analytical sensitivity
issues). We therefore used the model by Caramichael et al [3] for
subsequent simulation after independent validation. The authors
developed a one-compartment model with first-order elimination and
absorption and an absorption lag time. Nine of the patients received
oral dose and intravenous infusion for the bioavailability study.
Patients received Plaquenil® tablets, each tablet having 200 mg of
racemic HCQ sulfate equivalent to 155 mg of racemic HCQ base. The only
covariate retained in the model is the methotrexate, a drug most
commonly used in RA.
This model was externally validated using digitised blood concentrations
obtained from Morito et al. paper. In this study, HCQ was used to treat
patients with cutaneous lupus erythematosus [4]. The 90 patients
received one of these three dosing regimens of HCQ sulfate, depending on
their ideal body weight: 200 mg daily (n=20), 200 mg and 400 mg every
other day (n=55) or 400 mg daily (n=15). The steady-date blood
concentration data (3 samples/patient) were digitised from Figure 1 in
the paper by Morito et al [4], using MATLAB R2016b software (The
MathWorks Inc, Natick City, MA, USA). Monte Carlo simulations were
performed using NONMEM software, version 7.3 (Icon Development
Solutions, Ellicott City, MD, USA).
This model was also used for simulations of the serum concentrations
serum PK data including data from 20 patients from Gautret et al. study
[6] with a serum/whole blood correction ratio of 0.53 [16].
Gautret et al. study patients were confirmed COVID-19 and received 200
mg every 8 hours during 10 days. It is assumed that they were trough
concentrations, measured before the first dose of the indicated day.
NONMEM software was used for this purpose.
Subsequently, we used this model to perform simulations of blood
concentrations of HCQ base for different dosing protocols for treatment
of COVID-19. Table 1 includes the relevant information on the
simulations performed. The figures were generated using MATLAB software.