Cytochrome P450 Polymorphisms on Blood Hydroxychloroquine Levels in Patients with Systemic Lupus Erythematosus

Ji Yeon Lee¹, Min Kyung Chung², Ji Hun Kim², Jung Hee Koh³, Seung Min Jung⁴, Jennifer Lee², Seung-Ki Kwok⁵, Ji Hyeon Ju⁶, Kyung-Su Park⁷ and Sung-Hwan Park², ¹Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, South Korea, ²Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea, ³Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea, ⁴Division of Rheumatology, Department of Internal Medicine, school of medicine, The catholic university of Korea, Seoul, South Korea, ⁵[email protected], Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea, ⁶Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea, ⁷Division of Rheumatology, Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: drug treatment, hydroxychloroquine and polymorphism, Lupus

Session Information

Date: Tuesday, November 10, 2015

Session Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment Poster Session III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

Hydroxychloroquine (HCQ) is a safe and effective treatment for systemic lupus erythematosus (SLE), and its blood concentration is known to be closely related to the treatment response [1, 2]. However, blood HCQ concentration has been found to be widely variable in patients taking the medication at same dose and frequency [1-4], and the reason is not well understood. We sought to evaluate the association of genetic polymorphisms in Cytochrome P450 (CYP) 2D6, 3A5, 3A4 and blood concentration of HCQ and its metabolite, N-desethylhydroxychloroquine (DHCQ), in patients with SLE.

Methods: Patients meeting the 1997-updated 1982 revised SLE criteria or the SLICC classification criteria who have been taking HCQ > 3 months were recruited and were genotyped for four SNPs 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: Total 194 patients were included in the analysis. The mean patient age was 39.2 ±0.83 years, 93.8% were female, and the average daily HCQ dose per weight was 4.48mg/kg/day. The mean time between the last HCQ dose and the blood draw was 15.58 ±0.86 hours. The mean SLEDAI score was 3.44±0.2. The mean [HCQ] and [DHCQ] were 575.05±26.33 ng/ml and 449.83±21.78 ng/ml, respectively. The allele frequencies of the 2 SNPs in CYP2D6*10 were relatively frequent among our participants. However, the other SNPs in the CYP3A4 and CYP3A5 isoforms were infrequent. CYP2D6*10 polymorphisms (rs1065852 and rs1135840) were significantly associated with the ratio of [DHCQ]/[HCQ] when adjusted for age, sex, dose per weight and SLEDAI score (p=0.03 and p<0.01, respectively)(Table). The ratio of [DHCQ]/[HCQ] was the highest in patients with G/G type of CYP2D6*10 (rs1065852) polymorphism and the lowest in those with A/A type (p=0.03). Similarly, the ratio was the highest in patients with C/C type of CYP2D6*10 (rs1135840) polymorphism and the lowest in those with G/G type (p<0.01). CYP2D6*10 (rs1065852) polymorphism was significantly related to [DHCQ] (p=0.01). However, polymorphism of CYP3A5*3 and CYP3A4*18B did not show any significant association with [HCQ], [DHCQ] or the ratio which could be due to small allele frequencies.

Table. Associations between CYP genotypes and HCQ concentration

	[HCQ]*	[DHCQ]*	Ratio
*rs1065852(CYP2D610**)
A/A	424.6(352.3,511.7)	280.6(230.6,341.4)	0.72±0.05
A/G	524.9(457.5,602.3)	405.4(350.8,468.4)	0.83±0.03
G/G	409.5(340.1,493.2)	340.7(280.2,414.2)	0.89±0.04
p value	0.06	0.01	0.03
*rs1135840(CYP2D610**)
C/C	403(309.2,525.3)	349.4(264.5,461.7)	0.94±0.06
C/G	481.9(413.1,562.2)	391.6(333,460.4)	0.86±0.03
G/G	453.3(389.4,527.7)	305.9(260.7,358.8)	0.73±0.03
p value	0.51	0.11	<0.01
*rs776746(CYP3A53**)
C/C	402.9(309,524.8)	330.5(288.3,378.9)	0.79±0.03
T/C	481.9(412.8,562.1)	380.5(320.3,452)	0.87±0.04
T/T	453.3(389.2,527.6)	255.2(140.2,464.5)	0.74±0.13
p value	0.68	0.27	0.21
rs28371759 *(CYP3A418B)**
A/G	317.1(158.2,635.7)	304.4(145.7,636.2)	0.99±0.16
A/A	461.8(416.3,512.3)	351.9(315.2,392.8)	0.82±0.02
p value	0.29	0.70	0.32

Adjusted for age, sex, SLEDAI score, dose per weight per day

*Log transformed

Ratio: [DHCQ]/[HCQ]

Conclusion: Our study showed that the ratio of HCQ and its metabolite, DHCQ, was related to CYP2D6 polymorphisms in Korean lupus patients taking oral HCQ. CYP polymorphisms may explain why there is wide variation in blood HCQ concentration levels. Therefore, it is important to consider the role of an individual’s CYP polymorphisms when one prescribes oral HCQ.

Disclosure: J. Y. Lee, None; M. K. Chung, None; J. H. Kim, None; J. H. Koh, None; S. M. Jung, None; J. Lee, None; S. K. Kwok, None; J. H. Ju, None; K. S. Park, None; S. H. Park, None.

To cite this abstract in AMA style:

Lee JY, Chung MK, Kim JH, Koh JH, Jung SM, Lee J, Kwok SK, Ju JH, Park KS, Park SH. Cytochrome P450 Polymorphisms on Blood Hydroxychloroquine Levels in Patients with Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/cytochrome-p450-polymorphisms-on-blood-hydroxychloroquine-levels-in-patients-with-systemic-lupus-erythematosus/. Accessed January 21, 2022.

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