Bioavailability and clearance of HQ seems to be unaffected by methotrexate. Conversely, mixed effects have been observed for methotrexate pharmacokinetics (increased AUC, decreased Cmax).
Population Pharmacokinetics of Hydroxychloroquine in Patients With Rheumatoid Arthritis
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Study Design
This study aimed to develop a population PK model including an estimation of the oral bioavailability of HCQ. In addition, the effects of the coadministration of methotrexate on the PK of HCQ were examined. Hydroxychloroquine blood concentration data were combined from previous pharmacokinetic studies in patients with rheumatoid arthritis. A total of 123 patients were studied, giving the data cohort from four previously published studies. Two groups of patients were included: 74 received hydroxychloroquine (HCQ) alone, and 49 received HCQ and methotrexate (MTX). All data analyses were carried out using the NONMEM program.
Study Results
A one-compartment PK model was supported, rather than a three-compartment model as previously published, probably because of the clustering of concentrations taken at the end of a dosing interval. The population estimate of bioavailability of 0.75 (0.07), n 9, was consistent with literature values. The parameter values from the final model were: Cl 9.9 /- 0.4 L/h, V 605 /- 91 L, ka 0.77 /- 0.22 hours(-1), t(tag) 0.44 /- 0.02 hours. Clearance was not affected by the presence of MTX, and, hence, steady-state drug concentrations and maintenance dosage requirements were similar.
Study Conclusions
A population PK model was successfully developed for HCQ.
References
Carmichael SJ. Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis. Ther Drug Monit. 2003; 6: 671-81.
Combination Therapy With Methotrexate and Hydroxychloroquine for Rheumatoid Arthritis Increases Exposure to Methotrexate
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Study Design
In a randomized crossover study, 10 healthy subjects received, on each of 5 dosing occasions, MTX alone as tablets or intravenous solution, HCQ alone as a tablet or oral solution, or a coadministered dose of MTX tablets with an HCQ tablet. The area under the concentration-time curve (AUC) was determined for each subject, on each dosing occasion, for each compound.
Study Results
The mean AUC for MTX was increased (p 0.005) and the maximum MTX concentration (Cmax) decreased (p 0.025) when MTX was coadministered with HCQ, compared to MTX administered alone. The time to reach Cmax for MTX administration, tmax, was also increased during the coadministration with HCQ (p 0.072). The AUC of HCQ showed no significant difference (p 0.957) between any of the dosing occasions.
Study Conclusions
hese results may explain the increased potency of the MTX-HCQ combination over MTX as a single agent and also the sustained effects of MTX when administered with HCQ. In addition, the reduced Cmax of MTX observed during the coadministration may explain diminution of acute liver adverse effects. Extra vigilance for MTX adverse effects during combination therapy with HCQ is recommended, especially if renal function is known to be decreased.
References
Carmichael SJ. Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol. 2002; 10: 2077-83.
Population Pharmacokinetics of Hydroxychloroquine in Patients With Rheumatoid Arthritis
^
Study Design
This study aimed to develop a population PK model including an estimation of the oral bioavailability of HCQ. In addition, the effects of the coadministration of methotrexate on the PK of HCQ were examined. Hydroxychloroquine blood concentration data were combined from previous pharmacokinetic studies in patients with rheumatoid arthritis. A total of 123 patients were studied, giving the data cohort from four previously published studies. Two groups of patients were included: 74 received hydroxychloroquine (HCQ) alone, and 49 received HCQ and methotrexate (MTX). All data analyses were carried out using the NONMEM program.
Study Results
A one-compartment PK model was supported, rather than a three-compartment model as previously published, probably because of the clustering of concentrations taken at the end of a dosing interval. The population estimate of bioavailability of 0.75 (0.07), n 9, was consistent with literature values. The parameter values from the final model were: Cl 9.9 /- 0.4 L/h, V 605 /- 91 L, ka 0.77 /- 0.22 hours(-1), t(tag) 0.44 /- 0.02 hours. Clearance was not affected by the presence of MTX, and, hence, steady-state drug concentrations and maintenance dosage requirements were similar.
Study Conclusions
A population PK model was successfully developed for HCQ.
References
Carmichael SJ. Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol. 2002; 10: 2077-83.
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