ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 8, August 2015, pp 2176–2184 DOI 10.1002/art.39194 C 2015, American College of Rheumatology V
Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus M. Jallouli,1 L. Galicier,2 N. Zahr,3 O. Auma^ıtre,4 C. France`s,5 V. Le Guern,1 F. Liote,6 A. Smail,7 N. Limal,8 L. Perard,9 H. Desmurs-Clavel,9 D. Le Thi Huong,10 B. Asli,2 J.-E. Kahn,11 J. Pourrat,12 L. Sailler,13 F. Ackermann,11 T. Papo,14 K. Sacre,14 O. Fain,15 J. Stirnemann,16 P. Cacoub,17 G. Leroux,10 J. Cohen-Bittan,18 J. Sellam,19 X. Mariette,20 B. Blanchet,21 J. S. Hulot,3 Z. Amoura,10 J. C. Piette,10 N. Costedoat-Chalumeau,1 and the Plaquenil Lupus Systemic Study Group Objective. Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/ pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment.
Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. Methods. We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus
ClinicalTrials.gov identifier: NCT0041336. Supported by the French Ministe`re de la Sante (Programme Hospitalier de Recherche Clinique, PHRC 2005 grant) and the Association France Lupus (AFL grant). The AP-HP Direction de la Recherche Clinique et du Developpement provided logistic and administrative support. Sanofi provided the hydroxychloroquine and placebo tablets for the Plaquenil Lupus Systemic (PLUS) study. 1 M. Jallouli, MD, V. Le Guern, MD, N. Costedoat-Chalumeau, MD, PhD: Universite Paris-Descartes, AP-HP, H^ opital Cochin, and Centre de Reference Maladies Auto-Immunes et Syst emiques Rares, 2 Paris, France; L. Galicier, MD, B. Asli, MD: Universite Paris Diderot, Sorbonne Paris Cit e, and AP-HP, H^ opital Saint Louis, Paris, France; 3 N. Zahr, PharmD, PhD, J. S. Hulot, MD, PhD: Universite Pierre et Marie Curie and AP-HP, H^ opital Pitie-Salp^etrie`re, Paris, France; 4 O. Auma^ıtre, MD, PhD: Universite de Clermont-Ferrand and Centre Hospitalier Universitaire (CHU) Clermont-Ferrand, H^ opital Gabriel Montpied, Clermont-Ferrand, France; 5C. France`s, MD: Universite Pierre et Marie Curie and AP-HP, H^ opital Tenon, Paris, France; 6 F. Liote, MD, PhD: Universite Paris Diderot, Sorbonne Paris Cite, and AP-HP, H^ opital Lariboisie`re, Paris, France; 7A. Smail, PhD: CHU Amiens, H^ opital Nord, Amiens, France; 8N. Limal, MD: AP-HP, H^ opital Henri Mondor, Creteil, France; 9L. Perard, MD, H. DesmursClavel, MD: Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Lyon, France; 10D. Le Thi Huong, MD, PhD, G. Leroux, MD, Z. Amoura, MD, MSc, J. C. Piette, MD: Universit e Pierre et Marie Curie, AP-HP, H^ opital Pitie-Salp^etrie`re, and Centre de Reference pour le Lupus Systemique et le Syndrome des Antiphospholipides, Paris, France; 11J.-E. Kahn, MD, PhD, F. Ackermann, MD: Universite Versailles St. Quentin en Yvelines and H^ opital Foch, Suresnes, France, and Universit e Paris-Sud and AP-HP, H^ opitaux Univer12 sitaires Paris-Sud, Le Kremlin Bic^ etre, France; J. Pourrat, MD: Universite Paul Sabatier and CHU Toulouse, H^ opital Rangueil, Toulouse, France; 13L. Sailler, MD, PhD: Universite Paul Sabatier and CHU Toulouse, H^ opital Purpan, Toulouse, France; 14T. Papo, MD, K. Sacre, MD, PhD: Universite Paris Diderot, Sorbonne Paris-Cit e,
and AP-HP, H^ opital Bichat Claude-Bernard, Paris, France; 15O. Fain, MD: Universite Pierre et Marie Curie, Inflammation Immunopathology Biotherapy Department, and AP-HP, H^ opital St. Antoine, Paris, France; 16J. Stirnemann, MD, PhD: Geneva University Hospital, es, UniGeneva, Switzerland; 17P. Cacoub, MD: Sorbonne Universit versite Pierre et Marie Curie, UMR 7211, and Inflammation Immunopathology Biotherapy Department, AP-HP, H^ opital Piti eSalp^etrie`re, Centre de R ef erence pour le Lupus Systemique et le Syndrome des Antiphospholipides, INSERM UMRS 959, and CNRS, FRE3632, Paris, France; 18J. Cohen-Bittan, MD: AP-HP, H^ opital Piti e-Salp^ etrie`re, Paris, France; 19J. Sellam, MD, PhD: AP-HP, Universit e Pierre et Marie Curie, Inflammation Immunopathology Biotherapy Department, and INSERM UMRS 938, Paris, France; 20 X. Mariette, PhD: Universite Paris-Sud, INSERM U1012, and APHP, H^ opitaux Universitaires Paris-Sud, Le Kremlin-Bic^etre, France; 21 B. Blanchet, PharmD, PhD: AP-HP, H^ opital Cochin, Paris, France. Dr. Galicier has received consulting fees, speaking fees, and/ or honoraria from Amgen, Roche, Janssen, and GlaxoSmithKline (less than $10,000 each). Dr. Papo has received consulting fees, speaking fees, and/or honoraria from Ferring (less than $10,000 each). Dr. Cacoub has received consulting fees, speaking fees, and/or honoraria from AbbVie, AstraZeneca, Bristol-Myers Squibb, Gilead, Glaxo SmithKline, Janssen, Merck Sharp & Dohme, Roche, Servier, and Vifor (less than $10,000 each). Dr. Sellam has received consulting fees, speaking fees, and/or honoraria from Roche, Bristol-Myers Squibb, MSD, UCB, Pfizer, Chugai, and AbbVie (less than $10,000 each). Address correspondence to N. Costedoat-Chalumeau, MD, PhD, Universite Paris-Descartes, AP-HP, H^ opital Cochin, Centre de R eference Maladies Auto-Immunes et Syst emiques Rares, Service de M edecine Interne, 27 Rue du Faubourg St. Jacques, 75014 Paris, France. E-mail: [email protected]. Submitted for publication November 11, 2014; accepted in revised form May 5, 2015. 2176
DETERMINANTS OF HCQ BLOOD CONCENTRATION IN SLE
2177
Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration
Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus M. Jallouli,1 L. Galicier,2 N. Zahr,3 O. Auma^ıtre,4 C. France`s,5 V. Le Guern,1 F. Liote,6 A. Smail,7 N. Limal,8 L. Perard,9 H. Desmurs-Clavel,9 D. Le Thi Huong,10 B. Asli,2 J.-E. Kahn,11 J. Pourrat,12 L. Sailler,13 F. Ackermann,11 T. Papo,14 K. Sacre,14 O. Fain,15 J. Stirnemann,16 P. Cacoub,17 G. Leroux,10 J. Cohen-Bittan,18 J. Sellam,19 X. Mariette,20 B. Blanchet,21 J. S. Hulot,3 Z. Amoura,10 J. C. Piette,10 N. Costedoat-Chalumeau,1 and the Plaquenil Lupus Systemic Study Group Objective. Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/ pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment.
Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. Methods. We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus
ClinicalTrials.gov identifier: NCT0041336. Supported by the French Ministe`re de la Sante (Programme Hospitalier de Recherche Clinique, PHRC 2005 grant) and the Association France Lupus (AFL grant). The AP-HP Direction de la Recherche Clinique et du Developpement provided logistic and administrative support. Sanofi provided the hydroxychloroquine and placebo tablets for the Plaquenil Lupus Systemic (PLUS) study. 1 M. Jallouli, MD, V. Le Guern, MD, N. Costedoat-Chalumeau, MD, PhD: Universite Paris-Descartes, AP-HP, H^ opital Cochin, and Centre de Reference Maladies Auto-Immunes et Syst emiques Rares, 2 Paris, France; L. Galicier, MD, B. Asli, MD: Universite Paris Diderot, Sorbonne Paris Cit e, and AP-HP, H^ opital Saint Louis, Paris, France; 3 N. Zahr, PharmD, PhD, J. S. Hulot, MD, PhD: Universite Pierre et Marie Curie and AP-HP, H^ opital Pitie-Salp^etrie`re, Paris, France; 4 O. Auma^ıtre, MD, PhD: Universite de Clermont-Ferrand and Centre Hospitalier Universitaire (CHU) Clermont-Ferrand, H^ opital Gabriel Montpied, Clermont-Ferrand, France; 5C. France`s, MD: Universite Pierre et Marie Curie and AP-HP, H^ opital Tenon, Paris, France; 6 F. Liote, MD, PhD: Universite Paris Diderot, Sorbonne Paris Cite, and AP-HP, H^ opital Lariboisie`re, Paris, France; 7A. Smail, PhD: CHU Amiens, H^ opital Nord, Amiens, France; 8N. Limal, MD: AP-HP, H^ opital Henri Mondor, Creteil, France; 9L. Perard, MD, H. DesmursClavel, MD: Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Lyon, France; 10D. Le Thi Huong, MD, PhD, G. Leroux, MD, Z. Amoura, MD, MSc, J. C. Piette, MD: Universit e Pierre et Marie Curie, AP-HP, H^ opital Pitie-Salp^etrie`re, and Centre de Reference pour le Lupus Systemique et le Syndrome des Antiphospholipides, Paris, France; 11J.-E. Kahn, MD, PhD, F. Ackermann, MD: Universite Versailles St. Quentin en Yvelines and H^ opital Foch, Suresnes, France, and Universit e Paris-Sud and AP-HP, H^ opitaux Univer12 sitaires Paris-Sud, Le Kremlin Bic^ etre, France; J. Pourrat, MD: Universite Paul Sabatier and CHU Toulouse, H^ opital Rangueil, Toulouse, France; 13L. Sailler, MD, PhD: Universite Paul Sabatier and CHU Toulouse, H^ opital Purpan, Toulouse, France; 14T. Papo, MD, K. Sacre, MD, PhD: Universite Paris Diderot, Sorbonne Paris-Cit e,
and AP-HP, H^ opital Bichat Claude-Bernard, Paris, France; 15O. Fain, MD: Universite Pierre et Marie Curie, Inflammation Immunopathology Biotherapy Department, and AP-HP, H^ opital St. Antoine, Paris, France; 16J. Stirnemann, MD, PhD: Geneva University Hospital, es, UniGeneva, Switzerland; 17P. Cacoub, MD: Sorbonne Universit versite Pierre et Marie Curie, UMR 7211, and Inflammation Immunopathology Biotherapy Department, AP-HP, H^ opital Piti eSalp^etrie`re, Centre de R ef erence pour le Lupus Systemique et le Syndrome des Antiphospholipides, INSERM UMRS 959, and CNRS, FRE3632, Paris, France; 18J. Cohen-Bittan, MD: AP-HP, H^ opital Piti e-Salp^ etrie`re, Paris, France; 19J. Sellam, MD, PhD: AP-HP, Universit e Pierre et Marie Curie, Inflammation Immunopathology Biotherapy Department, and INSERM UMRS 938, Paris, France; 20 X. Mariette, PhD: Universite Paris-Sud, INSERM U1012, and APHP, H^ opitaux Universitaires Paris-Sud, Le Kremlin-Bic^etre, France; 21 B. Blanchet, PharmD, PhD: AP-HP, H^ opital Cochin, Paris, France. Dr. Galicier has received consulting fees, speaking fees, and/ or honoraria from Amgen, Roche, Janssen, and GlaxoSmithKline (less than $10,000 each). Dr. Papo has received consulting fees, speaking fees, and/or honoraria from Ferring (less than $10,000 each). Dr. Cacoub has received consulting fees, speaking fees, and/or honoraria from AbbVie, AstraZeneca, Bristol-Myers Squibb, Gilead, Glaxo SmithKline, Janssen, Merck Sharp & Dohme, Roche, Servier, and Vifor (less than $10,000 each). Dr. Sellam has received consulting fees, speaking fees, and/or honoraria from Roche, Bristol-Myers Squibb, MSD, UCB, Pfizer, Chugai, and AbbVie (less than $10,000 each). Address correspondence to N. Costedoat-Chalumeau, MD, PhD, Universite Paris-Descartes, AP-HP, H^ opital Cochin, Centre de R eference Maladies Auto-Immunes et Syst emiques Rares, Service de M edecine Interne, 27 Rue du Faubourg St. Jacques, 75014 Paris, France. E-mail: [email protected]. Submitted for publication November 11, 2014; accepted in revised form May 5, 2015. 2176
DETERMINANTS OF HCQ BLOOD CONCENTRATION IN SLE
2177
Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration
