Plasma hydroxychloroquine concentrations and efficacy in rheumatoid arthritis

Abstract

Plasma levels of hydroxychloroquine (HCQ) and its metabolites were measured, by high performance liquid chromatography, in 37 rheumatoid arthritis patients who could be clearly distinguished As responders (n = 28) or nonresponders (n = 9) to HCQ, 400 mglday. Efficacy in both groups was determined by the patients' erythrocyte sedimentation rates, joint counts, morning stiffness, globai assessments, Concurrent drug therapies, and grip strength. The response rate was 76%. Responders had a mean HCQ level of 213 ng/ml, versus 306 in nonresponders (P < 0.05). The mean level of HCQ plus total metabolites in respohders +as 363 ng/ml, versus 554 in nonresponders,(P < O.bI). We conclude that monitoring plasma kCQ levels is unlikely to be helpful in individualizing eeective drug dosage.The 4-aminoquinoline (4-AQ) compounds, chloroquine (CQ) and hydrox ychloroquine (HCQ), were introduced as aiitimalarials in 1943 have been used as antirheumatic compounds since 1951 (1). Their wide use has been inhibited by concern about irreversible ocular toxicity, which sometimes occurs. Many rheumatologists now believe that limitation of daily dosage and regular monitofing can prevent serious ocular hazards (1-4).By relating dosage to body weight, MacKenzie and Scherbel have estimated that 4.0 mg/kg/day of CQ or 6.4 mglkglday of HCQ offers high safety, while 5.4 mg/kg and 7.8 mg/kg cross the threshold into the toxic range (1). Even a dosage standardized for body weight, however, results in large inter-individual variation in blood levels of 4-AQ compounds. For example, a 5 mg/kg dosage of HCQ resulted in blood levels that ranged tenfold, from 0.1-1.0 pg/ml, in a pediatric population (4). For many drugs, clinical effects correlate better with blood concentration than With dosage (5); therefore, several researchers have attempted to correlate 4-AQ levels with their effects.Frisk-Holmberg and coworkers (3) found a strong correlation between serum concentration of CQ and incidence of all side effects. A safe concentration was 0.4 pg/ml, below which no side effects were observed. At concentrations >0.8 pg/ml, the incidence of side effects was 89%. Laaksonen et a1 (4) found that toxicity of any kind was rare in children who had serum concentrations of CQ <0.28 p g h l or HCQ CO.47 pg/ml. Wollheim and colleagues, however, found no correlation between therapeutic response and serum concentration of CQ in 15 rheumatoid arthritis (RA) patients after 3 months of treatment (6).Tht: above data thus suggest that monitoring of serum concentrations of the 4-AQ drugs may be helpful to avoid side effects, but not as an indicator of

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

“…This fact may provide an explanation for the different conclusions of the study reporting a positive relationship between blood hydroxy chloroquine concentrations and clinical outcomes (Tett et al 1993) and the studies reporting no relationship between plasma or serum hydroxychloroquine concentrations and effect (Laaksonen et al 1975;Miller et al 1987). In the former, cross-sectional study, patients with clinical measures indicating less active rheumatoid arthritis had statistically significantly higher blood concentrations of hydroxychloroquine than those with more active disease (Tett et al 1993).…”

Pharmacology of Chloroquine and Hydroxychloroquine

“…They are not comparable; plasma concentrations are the lowest, and whole blood concentrations are the greatest. Serum concentrations exceed plasma concentrations because platelets concentrate 4AQs, and upon coagulation of the blood the platelet contents are released into the serum [ 139 ]. Plasma levels of chloroquine effective against malaria are 10 [ 16 , 37 , 78 , 89 ].…”

Clinical Pharmacokinetics of Drugs Used in Juvenile Arthritis

“…Although Frisk-Holmberg et al (1979) suggested that chloroquine has a narrow therapeutic serum concentration range, no minimally effective concentration for 'antirheumatoid' activity for either agent has been accurately delineated (Maksymowych & Russell 1987). Miller et al (1987) found no relationship between plasma concentrations and the efficacy of hydroxy-chloroquine 400 mg/day. Their inference, however, is not conclusive: they used only 1 dose, rather than a wide dosage range, and also took blood samples at unspecified times.…”

“…There have never been any controlled trials involving chloroquine, and a randomised controlled clinical trial with hydroxy-chloroquine 3 to 6 mg/kg showed no statistical advantage over placebo ). However, Miller et al (1987) were able to divide their 37 adult rheumatoid arthritis patients into 28 responders and 9 nonresponders to hydroxy-chloroquine.…”