Hydroxychloroquine

Antimalarial agents like chloroquine and hydroxychloroquine have several pharmacological actions which may be involved in their therapeutic effect in the treatment of rheumatic disease, but the role of each is not known. These include interaction with sulphydryl groups, interference with enzyme activity (including phospholipase, NADH-cytochrome C reductase, cholinesterase, proteases and hydrolases), DNA binding, stabilisation of lysosomal membranes, inhibition of prostaglandin formation, inhibition of polymorphonuclear cell chemotaxis and phagocytosis, possible interference with interleukin 1 production from monocytes and inhibition of neutrophil superoxide release.

Absorption

Following oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In one study, mean peak plasma hydroxychloroquine concentrations following a single dose of 400mg in healthy subjects ranged from 53-208ng/ml with a mean of 105ng/ml. The mean time to peak plasma concentration was 1.83 hours.

Distribution

The parent compound and metabolites are widely distributed in the body.

Metabolism

The metabolism of Hydroxychloroquine is similar to that of Chloroquine.

Elimination

The mean plasma elimination half-life varied, depending on the post-administration period, as follows; 5.9 hours (at C max- 10 hours), 26.1 hours (at 10-48 hours) and 229 hours (at 48-504 hours). Elimination is mainly via the urine, where 3% of the administered dose was recovered over 24 hours in one study.

Only limited preclinical data are available for hydroxychloroquine, therefore chloroquine data are considered due to the similarity of structure and pharmacological properties between the two products.

Genotoxicity

There are limited data on hydroxychloroquine genotoxicity. Chloroquine is reported in the literature to elicit both gene mutations and chromosomal/DNA breaks in some in vitro systems in others and in in vivo studies using rodents when dosed via the intraperitoneal route. Chromosomal effects were not observed in vivo when chloroquine was administered orally.

Carcinogenicity

There are no data on hydroxychloroquine carcinogenicity.

In a limited 2-years study in rats with chloroquine, no increase in neoplastic or proliferative changes was observed.

Development and reproductive toxicity

There are limited data on hydroxychloroquine teratogenicity. Chloroquine is teratogenic in rats after administration at very high, supratherapeutic doses, i.e. between 250–1500 mg/kg/day, showing a fetal mortality rate of 25% and ocular malformations (anophthalmia and microophthalmia) in 45% of foetuses in the 1000 mg/kg/day group. Auto-radiographic studies have shown that when administered at the start or the end of gestation, chloroquine accumulates in the eyes and ears of fetuses.

A study in male rats after 30 days of oral treatment at 5 mg/day of chloroquine showed a decrease in testosterone levels, weight of testes, epididymis, seminal vesicles and prostate. The fertility rate was also decreased in another rat study after 14 days of intraperitoneal treatment at 10mg/kg/day.