4 Discussion
HCQ is approved and used worldwide for treatment of malaria, and RA (SLE
and CLE). The approved doses are higher in magnitude and of shorter
duration in malaria (1200mg on day 1 followed by 400mg daily over 10
days ) as compared to RA (loading dose of 400-800mg BID followed by
maintenance dose of 200mg BID chronically with sometimes therapeutic
drug monitoring targeting trough plasma concentrations of 0.6-1mg/L
[4]). Several PK models are available in the literature for HCQ in
these indications. [1, 2, 9] Our choice to use the PK model by
Carmichael et al was motivated by the fact that it was developed to
describe a relatively large cohort of blood concentrations (known to be
less variable). The estimated apparent clearance values were quite
consistent across previously published popPK models: 10-11L/h when whole
blood concentrations were analysed [3,4] vs 51-68L/h when plasma
concentrations were analysed [13-15]. The predictive performances of
Caramichael model were confirmed on external data including data in CLE
patients and in COVID-19 patients with overall satisfactory fitting of
digitized concentrations. It is therefore judged adequate be used to
explore the differential/relative impact of alternative dosing regimens
in COVID-19 patients in the absence of a refined popPK model developed
using COVID-19 patient data. It should however be noted that this model
still carries an high unexplained variability component on the volume of
distribution and clearance parameters: there is therefore a need for
refinement of this model and better characterisation of PK in COVID-19
patients, including by adequate description of covariate effects.
Potential covariates include bodyweight, CYP2D6 modulators and
underlying renal impairment.
In the absence of a high loading dose, the results of the dosing
simulations scenarios show that the drug progressively accumulates over
the dosing periods of 5 or 10 days: safety monitoring can therefore be
needed all the dosing time along and even after. This is confirmed by
case reports of patients experiencing adverse drug reactions such as QT
prolongations even after drug withdrawal. The appropriate
characterization of the loading and maintenance doses needed is
therefore important not only for drug efficacy but also for drug safety.
The use of high loading doses need to be justified in view of the hazard
for serious adverse events. There is still uncertainty on the
target/relevant systemic concentrations for drug efficacy and safety.
This is an important gap to be filled in the current situation because
systemic concentrations are more accessible for monitoring than could be
lung concentrations. There is an unmet need for adequately conducted
clinical PK and exposure-response studies.
Yao and al [5] have shown in their recent publication that in vitro
EC50 for prophylactic and treatment antiviral effects on SARS COV2 were
0.72 and 5.74 µM, respectively. Based on a PBPK modelling approach they
have proposed dosing regimens that allow reaching empirically determined
ratios between free lung concentrations and the in vitro EC50.
However, in addition to the fact that this model was not validated using
clinical data in COVID-19 patients, the recommended doses should still
be cautiously considered because the relevant target ratios between lung
or systemic concentrations and in vitro active levels are still to be
established as well as the ranges for effective whole blood and plasma
total concentrations. A more recent paper [12] was published in this
sense using a model-based approach and PK/PD modelling of viral load and
QT prolongation. However, it should be noted that this was a
retrospective analysis of either aggregated or limited previously
published data generated in different settings and for different
purposes. Several unverified assumptions were therefore needed for the
PK/viral load and the PK/QT modelling. Of note, the assumed/modelled QT
prolonging effects were those of choloroquine and not
hydroxychloroquine. Moreover, The overall unexplained variability was
very high and covariate modelling was not implemented. Research is still
needed to determine target HCQ level for in vivo (human) antiviral
effect in COVID-19 and the link with clinically relevant outcome such as
patient cure and survival for the different disease stages. Given the
known multiphasic features of the COVID-19 disease and the importance of
the inflammatory component of the disease, it is still unclear how
relevant are viral load clearance by antiviral drugs for the patient
clinical outcome in early vs later stages of the disease.
While it is not possible to identify the optimal dose in the absence of
properly conducted dose-exposure-response analyses using relevant data
in the target indication, the currently available clinical efficacy and
safety data in different doses used in COVID-19 patients can already
provide some useful information on the dose requirement when interpreted
in link with the related PK information. High rates of positive clinical
outcomes have been reported with doses of 600mg to 800mg daily on day 1
followed by 400 to 600mg daily for a total treatment duration of 5 to 10
days [6-10], also confirmed in the cohort of 172 patients treated at
Saint Pierre hospital (see Table 2 and Figure 3). While these studies
were all either single arm (no placebo arm), uncontrolled or of limited
size, and therefore precluding the robust identification of the actual
drug effect size, the important learning from these data is that higher
doses might not needed for an important proportion of the patients. The
determinants of positive patient outcomes are still to be identified,
and HCQ dose optimization can certainly be one of them. Additionally, as
extensively discussed in the recent literature, disease stage, patient
age, and comorbidities might also play key roles[17-19]
As regards safety, the overall safety profile seems quite good when the
drug is given at dose of 400mg - 800 mg on day 1 followed by 400 – 600
mg daily during 5 to 10 days, under close clinical monitoring. Available
concerning cases reported in EV or in the literature are consistent with
the known safety concerns with HCQ which are potentiated by either PK
overexposure due to pharmacokinetic drug-drug interactions and/or renal
impairment or PD drug-drug interactions due to additive toxicities with
co-medications. Aggravation of the toxicity due to comorbidities or
underlying renal or liver diseases related to COVID-19 pathophysiology
cannot be excluded either [17-19] (also see Table 3). It is
therefore essential that patient treated with HCQ are closely monitored
for these risk factors, and that appropriate risk minimisation measures
are implemented as needed.
It should however be noted that the clinical safety data from EV should
be cautiously interpreted due to the potential bias related to
spontaneous underreporting.