Determinants of Blood Hydroxychloroquine Concentration Variations in Systemic Lupus Erythematosus Patients

Moez Jallouli¹, Lionel Galicier², Olivier Aumaître³, Camille Francès⁴, Véronique Le-Guern⁵, F. Lioté⁶, Amar Smail⁷, Nicolas Limal⁸, L. Perard⁹, H. Desmurs-Clavel¹⁰, Du Boutin¹¹, B. Asli¹², Jean Emmanuel Kahn¹³, Jacques Pourrat¹⁴, Laurent Sailler¹⁵, F. Ackermann^1,13, T. Papo¹⁶, Karim Sacre¹⁷, O. Fain¹⁸, J. Stirnemann¹⁸, Patrice Cacoub¹⁹, Gaëlle Leroux²⁰, Judith Cohen-Bittan²¹, Js Hulot²², Zahir Amoura²³, Jean-Charles Piette²⁴ and Nathalie Costedoat-Chalumeau²⁵, ¹Department of Internal Medicine 2. Referal center for SLE/APS, CHU Pitié-Salpêtrière, Paris, France, ²Internal Medicine, Hopital St Louis, AP-HP, Paris, France, ³Division of internal Medicine, Centre Hospitalier Universitaire, Hôpital Gabriel Montpied, Clermont–Ferrand, Clermont–Ferrand, France, ⁴service de dermatologie allergologie, Hôpital Tenon, Paris Cedex 20, France, ⁵service de médecine interne, Department of Internal Medicine, Referral Center for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, France, ⁶service de rhumatologie, Hôpital Lariboisière, Université Paris-Diderot, Sorbonne Paris-Cité, Paris, France, ⁷Internal Medicine Department, CHU Amiens Nord, Amiens, France, ⁸Department of Internal Medicine, Hôpital Henri Mondor, APHP, Creteil, France, ⁹service de médecine interne, Hospices Civils de Lyon, groupement Hospitalier Edouard Herriot, Lyon, France, ¹⁰service de médecine interne, Hospice civils de Lyon, Lyon, France, ¹¹Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hopital Pitié-Salpétrière, Paris, France, ¹²Departement of clinical immunology, Hopital Saint Louis, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, ¹³internal medicine, Hopital Foch, Suresnes, France, ¹⁴nephrolohy, CHU Toulouse, Hopital Rangueil, University of Paul Sabatier, Toulouse, France, ¹⁵Service de Médecine Interne, S, CHU Toulouse, Hopital Purpan, University of Paul Sabatier, Toulouse, France, ¹⁶Internal Medicine, Hopital Bichat Claude Bernard, University of Paris Diderot, Sorbonne Paris cité, Paris, FL, France, ¹⁷Internal Medicine, University Paris-7, INSERM U699, APHP, Bichat Hospital, Paris, France, ¹⁸Internal Medicine, Hopital Jean Verdier, University Paris Nord, Sorbonne Paris Cité, Paris, France, ¹⁹Department of Internal Medicine 2., CHU Pitié-Salpêtrière, Paris, France, ²⁰Department of Internal Medicine 1, CHU Pitié-Salpêtrière, Paris, France, ²¹Service de medecine gériatrique, CHU Pitié-Salpêtrière, Paris, France, ²²Pharmacology, CHU Pitié-Salpêtrière, UPMC, University Paris 6, Paris, France, ²³Internal medicine 2, French National Reference Center for Systemic Lupus and Antiphospholipid Syndrome, Pitié-Salpêtrière Hospital (AP-HP), Paris, France, ²⁴Department of Internal Medicine 1., CHU Pitié-Salpêtrière, Paris, France, ²⁵Internal Medicine, Department of Internal Medicine, Referral Center for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: hydroxychloroquine and systemic lupus erythematosus (SLE)

Session Information

Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment: Biomarkers in Systemic Lupus Erythematosus

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Hydroxychloroquine (HCQ) is now recognized as an important treatment of systemic lupus erythematosus (SLE). Blood HCQ levels ([HCQ]) can be quantified by high performance liquid chromatography (HPLC). [HCQ] varies widely between individual: a pharmacokinetic/pharmacodynamic (PK/PD) relation has been found in different situations, and very low [HCQ] is a simple marker of non-adherence to treatment (2). Accordingly, the interest in the [HCQ] measurement has recently grown, but little is known regarding the determinants of variation of [HCQ].

Methods:

Retrospective analyses of our databases including the PLUS study (1) to determine the relationship between [HCQ] and different factors, including the daily dosage regimen, the weight and height, the renal function, the drug interactions, the smoking status and the ethnicity. Non-adherent patients ([HCQ] <200 ng/ml) were excluded.

Results

To have homogeneous pharmacological data, we restricted the analyses to the 509 patients treated with 400 mg/day. There was no correlation between [HCQ] and ethnicity or between [HCQ] and smoking. The median [HCQ] was 913 ng/ml [range: 213-2067], 951 [541-1701], and 916 [208-3316] in the patients who received enzyme inhibitors, enzyme inducers or none of these two groups of drugs respectively (p=0.7). Similarly, we did not find any significant differences in [HCQ] whereas the patient received or not antiacids.

In multivariate analysis, higher BMI (p=0.008), absence of treatment with corticosteroids (p=0.04), higher delay between the last tablet intake and the dosage of [HCQ] (p=0.017), lower platelet (p<0.001) and neutrophil (p<0.001) counts, and higher estimated creatinine clearance (p<001) were significantly associated with lower [HCQ].

Since patients with serum creatinine clearance lower than 60 ml/min were excluded from the PLUS study, we also studied 22 SLE patients with chronic renal insufficiency who were also treated with 400 mg/d of HCQ. Their median serum creatinine clearance was 52 ml/min [23-58]. Their median [HCQ] was significantly higher than those of the 509 patients from the PLUS study: 1338ng/ml [504-2229] versus 917 [208-3316] (p<0.001).

Finally, we studied 2 patients on long-term dialysis. Their [HCQ] did not change significantly after the dialysis and [HCQ] in the dialysis bath was undetectable for both patients (<50 ng/ml).

Conclusion

We report for the first time a comprehensive analyze of determinants of [HCQ]. Since this blood measurement is increasingly used, such data might be useful for clinicians.

(1) Ann Rheum Dis 2007;66:821-4.

(2) Ann Rheum Dis. 2013;72:1786-92

Disclosure:

M. Jallouli,
None;

L. Galicier,
None;

O. Aumaître,
None;

C. Francès,
None;

V. Le-Guern,
None;

F. Lioté,
None;

A. Smail,
None;

N. Limal,
None;

L. Perard,
None;

H. Desmurs-Clavel,
None;

D. Boutin,
None;

B. Asli,
None;

J. E. Kahn,
None;

J. Pourrat,
None;

L. Sailler,
None;

F. Ackermann,
None;

T. Papo,
None;

K. Sacre,
None;

O. Fain,
None;

J. Stirnemann,
None;

P. Cacoub,
None;

G. Leroux,
None;

J. Cohen-Bittan,
None;

J. Hulot,
None;

Z. Amoura,
None;

J. C. Piette,
None;

N. Costedoat-Chalumeau,
None.

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