Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients

被引：89

作者：

Kim, Hanna ^{[1
,2
]}

Brooks, Kristina M. ^{[3
]}

Tang, Cheng Cai ^{[4
]}

Wakim, Paul ^{[5
]}

Blake, Mary ^{[6
]}

Brooks, Stephen R. ^{[7
]}

Sanchez, Gina A. Montealegre ^{[8
]}

de Jesus, Adriana A. ^{[8
]}

Huang, Yan ^{[8
]}

Tsai, Wanxia Li ^{[6
]}

Gadina, Massimo ^{[6
]}

Prakash, Apurva ^{[9
]}

Janes, Jonathan Marcus ^{[9
]}

Zhang, Xin ^{[9
]}

Macias, William L. ^{[9
]}

Kumar, Parag ^{[3
]}

Goldbach-Mansky, Raphaela ^{[8
]}

机构：

[1] NIAMS, Off Clin Director, NIH, Bethesda, MD USA

[2] NIAMS, Pediat Translat Res Branch, NIH, Bethesda, MD USA

[3] NIH, Clin Pharmacokinet Res Unit, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA

[4] Lilly NUS Ctr Clin Pharmacol, Singapore, Singapore

[5] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA

[6] NIAMS, Translat Immunol Sect, Off Sci & Technol, NIH, Bethesda, MD USA

[7] NIAMS, Biodata Min & Discovery Sect, Off Sci & Technol, NIH, Bethesda, MD USA

[8] NIAID, Translat Autoinflammatory Dis Studies, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[9] Eli Lilly & Co, Indianapolis, IN 46285 USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2018年 / 104卷 / 02期

基金：

美国国家卫生研究院;

关键词：

PROTEASOME SUBUNIT; I INTERFERONOPATHIES; RHEUMATOID-ARTHRITIS; GM-CSF; DISEASE; EFFICACY; SAFETY; LIPODYSTROPHY; PATHWAYS; ANAKINRA;

D O I：

10.1002/cpt.936

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.

引用

页码：364 / 373

页数：10

共 38 条

[1] PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome [J].

Agarwal, Anil K. ;

Xing, Chao ;

DeMartino, George N. ;

Mizrachi, Dario ;

Dolores Hernandez, Maria ;

Sousa, Ana Berta ;

Martinez de Villarreal, Laura ;

dos Santos, Heloisa G. ;

Garg, Abhimanyu .

AMERICAN JOURNAL OF HUMAN GENETICS, 2010, 87 (06) :866-872

[2]

Alcorn J, 2002, CLIN PHARMACOKINET, V41, P1077, DOI 10.2165/00003088-200241130-00005

[3] Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome [J].

Arima, Kazuhiko ;

Kinoshita, Akira ;

Mishima, Hiroyuki ;

Kanazawa, Nobuo ;

Kaneko, Takeumi ;

Mizushima, Tsunehiro ;

Ichinose, Kunihiro ;

Nakamura, Hideki ;

Tsujino, Akira ;

Kawakami, Atsushi ;

Matsunaka, Masahiro ;

Kasagi, Shimpei ;

Kawano, Seiji ;

Kumagai, Shunichi ;

Ohmura, Koichiro ;

Mimori, Tsuneyo ;

Hirano, Makito ;

Ueno, Satoshi ;

Tanaka, Keiko ;

Tanaka, Masami ;

Toyoshima, Itaru ;

Sugino, Hirotoshi ;

Yamakawa, Akio ;

Tanaka, Keiji ;

Niikawa, Norio ;

Furukawa, Fukumi ;

Murata, Shigeo ;

Eguchi, Katsumi ;

Ida, Hiroaki ;

Yoshiura, Koh-ichiro .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (36) :14914-14919

[4] Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production [J].

Brehm, Anja ;

Liu, Yin ;

Sheikh, Afzal ;

Marrero, Bernadette ;

Omoyinmi, Ebun ;

Zhou, Qing ;

Montealegre, Gina ;

Biancotto, Angelique ;

Reinhardt, Adam ;

de Jesus, Adriana Almeida ;

Pelletier, Martin ;

Tsai, Wanxia L. ;

Remmers, Elaine F. ;

Kardava, Lela ;

Hill, Suvimol ;

Kim, Hanna ;

Lachmann, Helen J. ;

Megarbane, Andre ;

Chae, Jae Jin ;

Brady, Jilian ;

Castillo, Rhina D. ;

Brown, Diane ;

Vera Casano, Angel ;

Gao, Ling ;

Chapelle, Dawn ;

Huang, Yan ;

Stone, Deborah ;

Chen, Yongqing ;

Sotzny, Franziska ;

Lee, Chyi-Chia Richard ;

Kastner, Daniel L. ;

Torrelo, Antonio ;

Zlotogorski, Abraham ;

Moir, Susan ;

Gadina, Massimo ;

McCoy, Phil ;

Wesley, Robert ;

Rother, Kristina ;

Hildebrand, Peter W. ;

Brogan, Paul ;

Krueger, Elke ;

Aksentijevich, Ivona ;

Goldbach-Mansky, Raphaela .

JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (11) :4196-4211

[5] Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group [J].

Brouwer, K. L. R. ;

Aleksunes, L. M. ;

Brandys, B. ;

Giacoia, G. P. ;

Knipp, G. ;

Lukacova, V. ;

Meibohm, B. ;

Nigam, S. K. ;

Rieder, M. ;

de Wildt, S. N. .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2015, 98 (03) :266-287

[6]

Center for Drug Evaluation and Research (CDER), 2014, FDA GEN CLIN PHARM C

[7] Aicardi-Goutieres syndrome and the type I interferonopathies [J].

Crow, Yanick J. ;

Manel, Nicolas .

NATURE REVIEWS IMMUNOLOGY, 2015, 15 (07) :429-440

[8] Type I interferonopathies: a novel set of inborn errors of immunity [J].

Crow, Yanick J. .

YEAR IN HUMAN AND MEDICAL GENETICS: INBORN ERRORS OF IMMUNITY I, 2011, 1238 :91-98

[9] Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling [J].

de Jesus, Adriana Almeida ;

Canna, Scott W. ;

Liu, Yin ;

Goldbach-Mansky, Raphaela .

ANNUAL REVIEW OF IMMUNOLOGY VOL 33, 2015, 33 :823-874

[10] Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050 [J].

Fridman, Jordan S. ;

Scherle, Peggy A. ;

Collins, Robert ;

Burn, Timothy C. ;

Li, Yanlong ;

Li, Jun ;

Covington, Maryanne B. ;

Thomas, Beth ;

Collier, Paul ;

Favata, Margaret F. ;

Wen, Xiaoming ;

Shi, Jack ;

McGee, Ryan ;

Haley, Patrick J. ;

Shepard, Stacey ;

Rodgers, James D. ;

Yeleswaram, Swamy ;

Hollis, Greg ;

Newton, Robert C. ;

Metcalf, Brian ;

Friedman, Steven M. ;

Vaddi, Kris .

JOURNAL OF IMMUNOLOGY, 2010, 184 (09) :5298-5307

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