Factors associated with blood hydroxychloroquine level in lupus patients: renal function could be important

Lee, J Y; Luc, Stanley A; Greenblatt, David J.; Kalish, Robert A.; McAlindon, T.E.

doi:10.1177/0961203313476361

Cited by 28 publications

(30 citation statements)

References 7 publications

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“…Renal dysfunction has been identified as a cause for higher HCQ levels in patients with SLE and may increase the risk of retinopathy . This is contrary to our results in that there was no relationship between HCQ level and estimated GFR.…”

Section: Discussioncontrasting

confidence: 99%

Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis

Mok

Penn

Chan

et al. 2016

Arthritis Care & Research

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Objective. To study the relationship between serum hydroxychloroquine (HCQ) concentrations and flares of systemic lupus erythematosus (SLE) in a longitudinal cohort of patients. Methods. Patients who fulfilled ‡4 American College of Rheumatology classification criteria for SLE and had been treated with HCQ for >6 months were studied. Blood was assayed for HCQ levels by tandem mass spectrometry. Patients were serially assessed for disease activity, using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and flares (SELENA flares instrument). Comparison of the mean summated SLEDAI scores over time and rates of flares in groups with different HCQ levels was performed by the Kruskal-Wallis test. Results. A total of 276 SLE patients were studied (93% women, mean 6 SD age 41.0 6 13.8 years). The proportion of patients with HCQ levels <10 (total noncompliance), 10-500 (subtherapeutic), and >500 ng/ml (therapeutic) was 11%, 77%, and 12%, respectively. HCQ levels correlated significantly with the prescribed dose but not with body weight or renal function. The prescribed HCQ dose also correlated significantly with baseline SLEDAI scores, indicating that higher doses were used for more active manifestations. After a mean 6 SD observation period of 32.5 6 5.5 months, the mean summated SLEDAI score and the incidence of SLE flares was not statistically different among patients with different baseline HCQ levels. In a subgroup of 73 patients with serologic and clinical remission and having therapeutic HCQ levels, a trend of lower disease activity and fewer incidences of flares was observed. Conclusion. Noncompliance and subtherapeutic serum HCQ levels were seen frequently in these SLE patients, which was partly due to the low prescribed dose. In patients in remission, higher HCQ concentrations were associated with a trend showing fewer flares over time.

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Section: Discussioncontrasting

confidence: 99%

Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis

Mok

Penn

Chan

et al. 2016

Arthritis Care & Research

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“…It is reassuring that the [HCQ] and [DHCQ] were significantly related to HCQ dose per weight per day ( P < 0.0001). In addition, the concentrations measured in our study were similar to those found in other similar studies . Therefore, we are less concerned about potential bias stemming from self‐reported compliance with regard to our results.…”

Section: Discussionsupporting

confidence: 88%

Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus

Lee

Vinayagamoorthy

Han

et al. 2015

Arthritis & Rheumatology

125

102

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Objective. To evaluate associations of genetic polymorphisms in cytochrome P450 (CYP) isoforms 2D6, 3A5, and 3A4 with blood concentrations of hydroxychloroquine (HCQ) and its metabolite, N-desethyl HCQ (DHCQ), in patients with systemic lupus erythematosus (SLE).Methods. SLE patients taking HCQ for >3 months were recruited and were genotyped for 4 single-nucleotide polymorphisms in CYP2D6*10, CYP3A5*3, and CYP3A4* 18B. Blood HCQ and DHCQ concentrations ([HCQ] and [DHCQ]) were measured and their association with corresponding genotypes was investigated.Results. A total of 194 patients were included in the analysis. CYP2D6*10 polymorphisms (rs1065852 and rs1135840) were significantly associated with the [DHCQ]:[HCQ] ratio after adjustment for age, sex, dose per weight per day, and SLE Disease Activity Index score (P 5 0.03 and P < 0.01, respectively). In adjusted models, the [DHCQ]:[HCQ] ratio was highest in patients with the G/G genotype of the CYP2D6*10 (rs1065852) polymorphism and lowest in those with the A/A genotype (P 5 0.03). Similarly, the [DHCQ]:[HCQ] ratio was highest in patients with the C/C genotype of the CYP2D6*10 (rs1135840) polymorphism and lowest in those with the G/G genotype (P < 0.01). The CYP2D6*10 (rs1065852) polymorphism was significantly related to the [DHCQ] (P 5 0.01). However, the polymorphisms of CYP3A5*3 and CYP3A4*18B did not show any significant association with the Hydroxychloroquine (HCQ) is an antimalarial drug that is proven to be a safe and effective treatment for systemic lupus erythematosus (SLE) (1). Despite its wide application, only a few studies have previously measured blood HCQ levels in patients taking the drug in the long term. Interestingly, blood HCQ levels vary widely between patients, even those taking the same dose at the same frequency (2-7). This interpersonal variation is not well understood. However, the blood HCQ concentration is closely related to the treatment response in autoimmune diseases such as SLE (4,5,8,9). Therefore, identifying factors related to variations in blood levels is critical to maximize the benefit of HCQ in SLE patients.Cytochrome P450 (CYP) enzymes play major roles in drug metabolism. Certain single-nucleotide polymorphisms (SNPs) in CYP genes may have a large impact on CYP enzyme activity. HCQ is metabolized to N-desethyl HCQ (DHCQ) in the liver through the Ndesethylation pathway (10,11). This reaction is mediated by CYP 2D6, 3A4, 3A5, and 2C8 isoforms (11-13).

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“…Evaluating nonadherence is difficult: methods vary widely and do not capture the same patterns of nonadherence. 2,16,18,20,[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Studies using self-administered questionnaires report that 17-30% 2,40 of patients take less than 80% of their treatment. Consistently, only 23.4% of our patients admitted HCQ adherence below 80% with the MASRI.…”

Section: Discussionmentioning

confidence: 99%

“…Although the large French multicenter randomized prospective study PLUS did not confirm the interest of adapting daily HCQ dosage to its blood level in terms of efficacy, it did confirm the correlation between HCQ levels and efficacy . Possibly most important, since the blood half‐life of HCQ is at least 5 days, and the terminal half‐life of HCQ is 43 days, very low blood HCQ levels objectively indicate severe nonadherence (i.e., identify patients who have not taken HCQ for a significant period and not those who miss a few tablets) …”

mentioning

confidence: 95%

“…15 Possibly most important, since the blood halflife of HCQ is at least 5 days, and the terminal half-life of HCQ is 43 days, 8 very low blood HCQ levels objectively indicate severe nonadherence (i.e., identify patients who have not taken HCQ for a significant period and not those who miss a few tablets). 2,[16][17][18][19][20][21][22][23][24] Here we studied the frequency and determinants of nonadherence in SLE flaring patients treated with HCQ by assessing nonadherence by two different methods: blood drug assays (HCQ and DCQ levels), and patient questionnaires (Medication Adherence Self-Report Inventory scale (MASRI)). We correlated the results of these two methods with physician evaluations of nonadherence.…”

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confidence: 99%

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A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self‐Administered Questionnaires

Costédoat-Chalumeau

Houssiau

Izmirly

et al. 2018

Clin Pharma and Therapeutics

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Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by high-performance liquid chromatography. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ < 200 ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI < 80%). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, nonuse of steroids, higher body mass index, and unemployment were associated with nonadherence by drug level. Questionnaires classified 23.4% of patients as nonadherent. Correlations between adherence measured by questionnaires, drug level, and physician assessment were moderate. Both methods probably measured two different patterns of nonadherence: self-administered questionnaires mostly captured relatively infrequently missed tablets, while drug levels identified severe nonadherence (i.e., interruption or erratic tablet intake). The frequency with which physicians miss nonadherence, together with underreporting by patients, suggests that therapeutic drug monitoring is useful in this setting. (Trial registration: ClinicalTrials.gov: NCT01509989.).

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Factors associated with blood hydroxychloroquine level in lupus patients: renal function could be important

Cited by 28 publications

References 7 publications

Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis

Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis

Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus

A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self‐Administered Questionnaires

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