PK of HCQ:
There is no information available to indicate that HCQ concentrations will be different in patients who already have COVID19 infection. The pharmacokinetics of HCQ has been studied in many populations including healthy subjects, patients with lupus, and patients with malaria. Because of varied analytical methods, martcies, dosages, and population, there is a large variation in reported HCQ concentrations that makes comparison between populations less meaningful.
In the package insert, the PK is described as follows. Following a single 200 mg oral dose of PLAQUENIL to healthy males, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with a half-life of about 22 days (half life after chronic administration ranges from 30 to 40 days). In the one paper by Gautret et al, 2020, mean HCQ serum concentrations in patients with COVID19 were 0.46 mcg/mL. As this is sparse untimed sample collected in each patient on day 2, 4 or 6 of treatment, no additional rationalization is possible. However, Garcia-Cremades et al, 2020, used these data to reconstruct individual PK profiles of HCQ in the treatment group and could be used as a reference.
It is known that HCQ distributes into erythrocytes with a whole blood to plasma ratio ~ 4, exhibits a long half-life (123 h) and a large volume of distribution, indicating extensive tissue uptake (Garcia-Cremades et al., 2020). HCQ is a diprotic weak base that is prone to ion-trapping inside favorable acidic environments leading to significant tissue residence. While metabolites appear important in pharmacological activity, to date in vitro activity against SARSCoV-2 has only been described for the parent compound (Yao et al., 2020). If the pathophysiological factors were to be altered between pre and post-covid19 infected states, then it is possible that HCQ concentrations may be different although this has not been studied.
Renal clearance accounts for half of the total systemic clearance of chloroquine, but little is known about that of HCQ. Jallouli et al, 2015, found a significant association of impaired renal function with high blood HCQ concentrations. Caution and appropriate monitoring may be recommended in such populations (Jallouli et al., 2015; Lee at al., 2013). As per HCQ’s package insert revised in 2019, caution is needed in patients with renal impairment. Please refer to text below:
Renal: Observe caution in patients with renal disease, in whom a reduction in dosage may be necessary, as well as in those taking medicines known to affect this organ. During treatment and after discontinuation, monitoring for adverse reactions may be warranted in patients with severe renal impairment or end-stage renal disease (ESRD), given the long half-life of hydroxychloroquine (see WARNINGS AND PRECAUTIONS, Cardiovascular, DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).
Garcia-Cremades M et al. Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing. Clin Pharmacol Ther. doi: 10.1002/CPT.185, 2020.
Gautret P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949.
Jallouli M et al. Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus. Arthritis and Rheumatol. 67 (8):2176–2184, 2015.
Lee JY, Luc S, Greenblatt DJ, Kalish R, McAlindon TE. Factors associated with blood hydroxychloroquine level in lupus patients: renal function could be important. Lupus 2013;22: 541–2.
PLAQUENIL® Package insert, 2019 revision.
Yao, X. et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020.
- This reply was modified 1 year ago by kdev.