Drs Melles and Marmor claim that hydroxychloroquine is stored in fat and that actual body weight should be used to calculate maximal safe dosing in patients. In so doing, they incorrectly quote from cited literature, fail to cite contradictory literature, and change their minds from earlier publications without explaining why. Their reading of the literature is erroneous, and their advice to clinicians on safe dosing is dangerous for the short, obese patient.

Specifically, the quote from McChesney applies to chloroquine (C), not hydroxychloroquine (HC), and applies to rhesus monkeys, not rats. McChesney’s review cites work regarding 2 monkeys, but 1 (B) “was virtually devoid of fat,” making its data suspect. Reliable data were available for only 1 monkey (A). Its tissue distribution was 0.2 μg of chloroquine per gram of tissue for fat and 0.9 for muscle (ie, the concentration of drug in muscle was 4.5 times that in fat). In the cited work, the drug was not “stored to a similar level in all of these tissues,” contrary to the correspondents’ assertion.

Not cited by Drs Melles and Marmor, but of greater import, was an earlier study in 3 rhesus monkeys and 1 squirrel monkey given chloroquine and analyzed for tissue distribution at necropsy. The concentrations of chloroquine in fat were 0.3, 0.2, 0.3, and 0.5 μg of chloroquine per gram of tissue, respectively. The concentrations in muscle were 1.2, 0.8, 1.0, and 1.2, respectively. The average concentration of chloroquine in muscle was 3.2 times that in fat.

Other organs sequester far higher amounts of chloroquine than does fat. Pooling the data from all 5 monkeys above, the concentrations of chloroquine in liver, lung, and spleen were 38.9, 22.6, and 16.3 times the concentrations in fat. Until the letter of Drs Melles and Marmor, no one who has studied the pharmacology of the 4-aminoquinolines has questioned the consistent data across multiple species that these drugs are excluded from fat relative to muscle, viscera, and the eye. McChesney writes in the same article from which the correspondents’ incorrect quote was taken, “Tissue distributions are qualitatively similar for both drugs [C and HC] in albino rats—namely, bone, fat, and brain < muscle < eye < heart < kidney < liver < lung < spleen < adrenal,” contradicting the correspondents’ claim that he supports the view of similar distributions of 4-aminoquinolines across tissues.

Drs Melles and Marmor cite a paper reporting that blood concentrations of HC correlate with actual body weight (ABW) but not ideal body weight (IBW) in patients with cutaneous lupus erythematosus. Blood concentrations of HC have no known relationship to HC retinopathy, as the authors of the cited article state; the reference is irrelevant to the issue of HC retinopathy.

The most serious issue, and one that Drs Melles and Marmor miss in their letter and in their previous work, is that safe dosing of 4-aminoquinolines cannot be based on either IBW or ABW alone, as a consequence of their nonuniform distribution across fat and other tissues. Properly performed, the lesser of IBW and ABW should be used for calculating safe doses. For the commonly prescribed dose of HC, 400 mg/d, using IBW alone, is dangerous if the patient is asthenic. Using ABW alone is dangerous if the patient is short and obese. Marmor recognized the latter aspect in the past, when he wrote that “Chloroquine and HCQ are not retained in fatty tissues, so patients who are obese could be seriously overdosed if medicated on the basis of weight alone. Obese individuals should be dosed on the basis of height, which allows estimation of an asthenic or ‘ideal’ body weight.” The evidence in the literature supports this statement.

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Jan 5, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Reply

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