Hydroxychloroquine - How It Works
Clinical pharmacology details from the US FDA-approved label: how Hydroxychloroquine works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Malaria Hydroxychloroquine is a 4-aminoquinoline antimalarial [see Microbiology ] and antirheumatic agent. Rheumatoid Arthritis, Systemic Lupus Erythematosus and Chronic Discoid Lupus Erythematosus The mechanisms underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine sulfate tablets in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus are not fully known.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Malaria Hydroxychloroquine is a 4-aminoquinoline antimalarial [see Microbiology ] and antirheumatic agent.
Rheumatoid Arthritis, Systemic Lupus Erythematosus and Chronic Discoid Lupus Erythematosus The mechanisms underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine sulfate tablets in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus are not fully known.
12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of hydroxychloroquine have not been fully characterized.
12.3 Pharmacokinetics Following oral administration, the whole blood concentration of hydroxychloroquine at steady state is dose proportional over a dose range from 200 mg daily to 400 mg daily of hydroxychloroquine sulfate tablets in rheumatoid arthritis and lupus patients.
Absorption Following a single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy male volunteers, whole blood hydroxychloroquine Cmax was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours).
Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine.
Mean absolute oral bioavailability is 79% (SD: 12%) in fasting conditions.
Peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following a single dose of 155 mg intravenous infusion and from 2290 ng/mL to 4211 ng/mL (mean 3312 ng/mL) following a single dose of 310 mg intravenous infusion in healthy subjects.
Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg, indicating linear kinetics.
In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e.
30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity.
Distribution Hydroxychloroquine sulfate tablets are extensively distributed to tissues and has a large volume of distribution.
Approximately 50% of hydroxychloroquine is bound to plasma proteins.
Metabolism Significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) were found in plasma and blood, with DHCQ being the major metabolite.
In vitro, hydroxychloroquine is metabolized mainly by CYP2C8, CYP3A4 and CYP2D6 as well as by FMO-1 and MAO-A Elimination / Excretion Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate tablets for at least 6 months was similar to that in single dose studies in healthy volunteers, suggesting that no change in clearance occurred with chronic dosing.
Renal clearance of unchanged hydroxychloroquine was approximately 16% to 30% of the dose after oral and IV administration.
Results following a single oral dose of a 200 mg tablet demonstrated a half-life of hydroxychloroquine about 40 days in whole blood.
Following chronic oral administration of hydroxychloroquine, the absorption half-life of hydroxychloroquine was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days in whole blood.
The effective half-life of hydroxychloroquine is likely to be shorter and steady state is achieved by 6 weeks following 400 mg daily oral administration in rheumatoid arthritis patients.
Drug Interaction Studies In vitro study suggested that hydroxychloroquine has a potential to inhibit CYP2D6, CYP3A4, P-glycoproteins (P-gp), MATE1 and MATE2-K.
Pharmacokinetics
12.3 Pharmacokinetics Following oral administration, the whole blood concentration of hydroxychloroquine at steady state is dose proportional over a dose range from 200 mg daily to 400 mg daily of hydroxychloroquine sulfate tablets in rheumatoid arthritis and lupus patients. Absorption Following a single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy male volunteers, whole blood hydroxychloroquine Cmax was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. Mean absolute oral bioavailability is 79% (SD: 12%) in fasting conditions. Peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following a single dose of 155 mg intravenous infusion and from 2290 ng/mL to 4211 ng/mL (mean 3312 ng/mL) following a single dose of 310 mg intravenous infusion in healthy subjects. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg, indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Distribution Hydroxychloroquine sulfate tablets are extensively distributed to tissues and has a large volume of distribution. Approximately 50% of hydroxychloro