Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

Abstract

The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.

Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma

“…The rationale for the dosing scheme of 72 h pretreatment prior to the first dose of DOX followed by continuous daily dosing with HCQ was based on the reported long halflife and time to reach steady-state in humans, and the lack of any corresponding pharmacokinetic data in dogs. [19][20][21] Four dose cohorts, ranging from 5 mg/kg/d up to 12.5 mg/kg/d, were evaluated. This study identified maximum tolerated doses of HCQ in combination with DOX of 12.5 mg/kg/d, and 25 mg/m 2 , respectively.…”

“…Three HCQ metabolites have been identified, including N-desethylchloroquine, desethylhydroxychloroquine (DHCQ), and bidesethylchloroquine. 18,19 However, little is known about HCQ pharmacokinetics in dogs. HCQ has been used in canine discoid and cutaneous lupus erythematosus, similar to humans, at dosages of 5 to 10 mg/kg/d with some evidence of clinical efficacy, suggesting adequate blood and tissue concentrations for that specific indication.…”

Cardiomyopathy Caused by Longterm Treatment with Chloroquine: A Rare Disease, or a Rare Diagnosis?

“…These appear histologically as granulovacuolar cell mutations and ultrastructurally as lamellar inclusion bodies ("myeloid bodies") and as "curvilinear bodies" in cytoplasm (remnants of poorly digested membranes) 2,3 . Their pharmacokinetics are characterized by a long half-life and a high volume of distribution; they follow a multicompartment model with very slow distribution between plasma and tissue, leading to sustained organ sequestration and sometimes irreversible organ damage 4 .…”

“…The Journal of on May 7, 2018 -Published by www.jrheum.org Downloaded from lism of the substance 4 . Thus, the cardiac process may be asymptomatic for a long period.…”

Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response

“…SASP is variably absorbed, with estimates ranging from 10 to 30%, and undergoes extensive enterohepatic recycling. The metabolites of SASP have complex dispositional characteristics [10 ].…”