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

Abstract

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).

Hydroxychloroquine Blood Levels Predict Hydroxychloroquine Retinopathy

“…It should not be surprising that blood levels vary. Genetic polymorphisms are known to affect HCQ levels (31)(32)(33). However, the demonstrated nonadherence of patients receiving HCQ (30) and changes in adherence over time (37) are the major reasons for variations in blood levels.…”

Possible Consequences of a Shortage of Hydroxychloroquine for Patients with Systemic Lupus Erythematosus amid the COVID-19 Pandemic

“…Indeed, in Italy, where all hospitalized patients with COVID-19 are treated with HCQ and the resultant shortage at outpatient pharmacies is widespread, patients with SLE are advised to reduce their doses to maintain some degree of coverage (personal communication). Optimal doses of HCQ are not known 33 , and many factors affect individual variations in blood concentration 34,35,36 . However, there is a clear correlation between daily dose, blood concentration, and increased disease activity with risk of flare.…”

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

“…The volume of distribution is very large due to extensive sequestration of the drug by tissues . From 21–70% of HCQ is excreted without metabolism, while the rest is mostly metabolized via cytochrome P450 2D6 (the main isoform involved in a population of Korean lupus patients), 3A4, 3A5, and 2C8 isoforms . Approximately half of unchanged HCQ and metabolites are excreted through the kidneys …”

“…4,8 From 21-70% of HCQ is excreted without metabolism, while the rest is mostly metabolized via cytochrome P450 2D6 (the main isoform involved in a population of Korean lupus patients), 9 3A4, 3A5, and 2C8 isoforms. 9 Approximately half of unchanged HCQ and metabolites are excreted through the kidneys. 4,10 Hydroxychloroquine and desethylchloroquine (DCQ), its main metabolite, can be quantified by high-performance liquid chromatography (HPLC).…”