Optimizing Hydroxychloroquine Dosing for Patients With COVID-19: An Integrative Modeling Approach...

Optimizing Hydroxychloroquine Dosing for Patients With COVID-19: An Integrative Modeling Approach

for Effective Drug Repurposing


External validation and simulations for optimal dose range

For PK/PD-viral kinetics simulations, a median baseline CT of 27.13 (2.5–97.5%; 15.00–34.35) was assumed (Figure 6a). First, we predicted the longitudinal viral loads of an external study of 80 patients receiving 200 mg t.i.d. of HCQ with azithromycin (Figure 6a). The model predicted the viral decline in the first week, however, it overpredicted later time points. After incorporating a time varying function to mimic a delayed immune effect, predictions aligned well with the data throughout treatment (Figure 6a). The simulations performed in order to obtain the predicted percentage of patients with positive PCR accounted for interindividual variability in the PK and growth rate kinetics. The data were not sufficient to identify variability in the drug effect and it was not included in our simulations.


Optimizing Hydroxychloroquine Dosing for Patients With COVID-19: An Integrative Modeling Approach for Effective Drug Repurposing

Sensitivity analysis

The viral load decline in the control arms was substantially different in the two reported clinical studies (Figure 7a).6, 21 We explored HCQ efficacy under different control arm scenarios. Different viral growth and death values were obtained when the model was fit to each study's control arm. This represents the intrinsic variability of disease progression, and, accordingly, resulted in different viral kinetics over time, suggesting large uncertainty and variability in the natural history of disease. Two dosing regimens (400 mg HCQ daily and 400 mg HCQ b.i.d.) were simulated and overlaid for comparison with the different natural history scenarios (Figure 7b). This sensitivity analysis revealed that the low-dose regimen might be indistinguishable from placebo under different control group scenarios. However, higher HCQ doses (≥ 400 mg b.i.d.) are likely to show efficacy in viral clearance regardless of the control arm.


Optimizing Hydroxychloroquine Dosing for Patients With COVID-19: An Integrative Modeling Approach for Effective Drug Repurposing

Discussion

For HCQ to maximally suppress SARS-CoV-2 replication in vivo, the HCQ dose may need to be optimized. To best define the effective HCQ concentrations for treatment of COVID-19, all available data from in vitro and clinical studies using HCQ for SARS-CoV-2 were pooled to quantify the relationship between HCQ PK and SARS-CoV-2 viral decline in patients with COVID-19. We predicted that higher HCQ daily doses (e.g., as high as 800 mg b.i.d.), were associated with rapid rates of viral decline and increased the percentage of PCR-negative patients but could result in increased risk of QTc prolongation. Regimens that give ~ 800 mg/day either loaded upfront or as 400 mg b.i.d., could be safely tolerated and would reduce the time with a detectable SARS-CoV-2 viral load, and, thus, improve treatment outcomes. Higher HCQ doses of up to 800 mg b.i.d. could result in even faster rates of viral decline but there is limited safety information for these high doses.

HCQ pharmacology is complex; HCQ distributes extensively into erythrocytes (whole blood to plasma ratio ~ 3.8, exhibits a long half-life (123 hours) and a large volume of distribution, all attributed to extensive tissue uptake, clearly important for treatment of COVID-19 systemic illness.22, 23 HCQ and CQ are diprotic weak bases (with PKa of 9.67 and 8.27 vs. 10.18 and 8.38 for HCQ and CQ, respectively).24 Interestingly, both drugs experience ion-trapping in which the drug becomes ionized in acidic environments like the lysosome (pH ~ 5.0). This causes an irreversible accumulation, explains the large volume of distribution, and potentially impacts the amount of free drug available in tissues.25, 26 HCQ is converted into at least three metabolites (desethylhydroxychloroquine, desethylchloroquine, and bidesethylhdroxychloroquine). Desethylhydroxychloroquine HCQ, the primary metabolite, is pharmacologically active for some nonviral illnesses, and formed by various cytochrome P450 isozymes. For our analysis, we focused on the parent HCQ, as potent in vitro activity against SARS-CoV-2 has only been described for the parent compound.3

For derivation of our dosing rationale, we have utilized HCQ levels in plasma, instead of the lungs. Lung accumulation has been observed for HCQ and CQ in animal PK studies and reported to be substantial (a partition coefficient of 281 (102.45)). The partition coefficient ratio enables quantification of the total drug concentration in the tissue, and by assuming the same fraction of unbound drug in plasma and tissue, one can further estimate unbound concentrations in the tissue. By using this approach, a wide range of doses, including doses as low as 10 mg, seem to be potentially therapeutic. The drug efficacy at the site of action is determined by the fraction of drug unbound in the tissue, which has not been studied for HCQ, and, thus, the amount of free drug in tissue remains unknown. Highly lipophilic drugs for other infectious diseases, like bedaquiline and clofazimine, accumulate in lungs as well, however, the accumulation correlates with binding to macromolecules in tissue, not necessarily to the free fraction.27, 28 Based on the physicochemical parameters of HCQ (log P of 3.85 and pKa of 9.67, 8.27), the fraction unbound in tissue is likely low.29 Therefore, in our study, we conservatively assume that the free fraction in plasma equilibrates between plasma and tissue and consider that to be the fraction of drug that can contribute to drug effect. Tissue binding studies using a rapid equilibrium dialysis assay with lung homogenate should be performed to define an accurate fraction unbound in the tissue.

Using a mechanistic PK/PD modeling approach, we were able to quantify a relationship between HCQ concentration and SARS-CoV-2 viral decline. However, we were not able to differentiate if azithromycin offered any additional benefit. The group receiving HCQ and azithromycin had the lowest baseline viral load and showed a similar rate of viral decline compared with the HCQ group.6 Therefore, it remains unclear if azithromycin offers any additional benefit.

Clinically significant QTc prolongation associated with HCQ have been reported.30-32 Only two small observational studies have reported associations between HCQ doses of 200–400 mg daily and QTc prolongation32, 33 and a concentration-dependent QTc relationship is not available. As a result, we used CQ as a model to predict QTc prolongation risk.19 HCQ and CQ have an identical structure with the substitution of a hydroxyl group for HCQ, and both have been found in vitro to inhibit the inward rectifier K+ channels.34, 35 This has been associated with QTc prolongation, and docking studies suggest nitrogen in the alkylamine and quinoline ring found in both compounds are responsible for binding with potassium channels.36 Although a dedicated study is needed, the hydroxyl group in HCQ is unlikely to affect rectifier K+ channels binding as the pKa for the alkylamine nitrogen is similar to that of chloroquine's.37 In vitro data from CQ identified an hERG IC50 of 2,500 nM.38 We leveraged a recent study of high-dose CQ for malaria treatment to predict potential risk of QTc prolongation with HCQ.19 In support of our findings, a maximum dose of 1,200 mg daily for 2–6 weeks has been well-tolerated without reported cardiac toxicity.39, 40 Based on this evidence, and the PK-QTc relationship for CQ presented here, we expect a HCQ course of 400–600 mg b.i.d. for 10 days or less is unlikely to be associated with clinically significant cardiac toxicity in patients without a known risk factor for QTc prolongation.41 As data for HCQ and QTc prolongation are limited, we recommend the highest doses of HCQ be reserved for study in dose escalation studies.

Additional toxicities associated with HCQ include retinopathy and gastrointestinal adverse events.39, 42 The mechanism of irreversible retinal damage associated with HCQ is unknown, but it has been associated with HCQ doses > 5 mg/kg and in patients who receive HCQ for > 5 years.42 Retinopathy associated with use < 1 month of HCQ has not been reported, and this side effect is less likely in the acute setting.30, 43 Gastrointestinal toxicity with HCQ is concentration-related and could be a limiting factor to dosage of HCQ but doses up to 1,200 mg have been reported to be well-tolerated without adverse events in patients with cancer and rheumatologic disease in other studies.39, 40

There were a few limitations to this study. First, clinical HCQ data are limited to nonrandomized studies, and a clear model for the natural rate of viral decline is not well defined. To explore this effect, we compared viral kinetic trends on treatment to the extracted baseline data from Cao et al. (n = 100 hospitalized patients who received supportive care).21 Second, the translational viral replication was obtained from SARS-CoV-1 data. SARS-CoV-1 and SARS-CoV-2 share an estimated 79.6% sequence homology.44 Third, we imputed the PK profiles for HCQ using population PK parameters derived from a pool of both healthy and malaria-infected patients. Fourth, we were not able to predict how concomitant HCQ and azithromycin may impact the risk of QTc prolongation or anticipate how underlying risk factors for QTc prolongation could impact the PK-QTc relationship due to the lack of available data. Closely monitored clinical trials will be needed to confirm that high-dose HCQ is safe with or without azithromycin. Finally, our model used plasma HCQ concentrations to predict nasopharyngeal viral loads, which may not fully correlate with clinical improvement or viral load measured at different sites, however, it has generally been accepted that viral decline is a desirable marker leading to clinical improvement.45-50 In addition, all relevant assumptions made during the analysis are summarized in Supplementary Table S4.

Treatment options for COVID-19 can most effectively be advanced by utilizing all available data and pharmacologically driven drug repurposing. Suboptimal dosing can result in wasted time and resources. Even more problematic is the potential to declare a drug ineffective because of misdosing. Using PK-exposure modeling, we predict that higher doses of HCQ will be needed to achieve cure within 7 days for all patients. Given the observed prolonged viral shedding in patients with COVID-19, these data support the possibility that early treatment with high-dose HCQ could reduce transmissibility and potentially reduce the risk of late clinical decompensation. However, given the possibility of QTc prolongation with high-dose regimens, rigorous trials must precede widespread clinical usage. We predict that higher HCQ doses, (> 400 mg b.i.d.) are most efficacious for viral suppression and should be further examined in clinical trials to evaluate safety and efficacy.

Acknowledgment The investigators thank the Savic laboratory for all their help and support during this project. We would also like to thank Tia Tummino for her help addressing reviewer comments.

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