Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies

被引:578
作者
Keizer, Ron J. [1 ]
Huitema, Alwin D. R. [1 ,2 ]
Schellens, Jan H. M. [2 ,3 ]
Beijnen, Jos H. [1 ,2 ,3 ]
机构
[1] Slotervaart Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands
[2] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Clin Pharmacol, Amsterdam, Netherlands
[3] Univ Utrecht, Fac Sci, Dept Pharmaceut Sci, Div Drug Toxicol,Sect Biomed Anal, Utrecht, Netherlands
关键词
ANTITUMOR NECROSIS FACTOR; RHEUMATOID-ARTHRITIS PATIENTS; CHRONIC LYMPHOCYTIC-LEUKEMIA; I-RELATED RECEPTOR; EVERY; WEEKS; POPULATION PHARMACOKINETICS; ANTI-CD11A ANTIBODY; PHASE-II; 1ST-LINE TREATMENT; IMMUNOGLOBULIN-G;
D O I
10.2165/11531280-000000000-00000
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
引用
收藏
页码:493 / 507
页数:15
相关论文
共 129 条
[1]
*ABB LAB LTD, 2010, HUM PEN SYR SUMM PRO
[2]
*ABB LAB LTD, 2010, SYN SUMM PROD CHAR
[3]
*AL PHARM UK LTD, 2009, SOL SUMM PROD CHAR W
[4]
Production technologies for monoclonal antibodies and their fragments [J].
Andersen, DC ;
Reilly, DE .
CURRENT OPINION IN BIOTECHNOLOGY, 2004, 15 (05) :456-462
[5]
[Anonymous], 2009, IL CAN INJ SUBC US U
[6]
Safety and efficacy of trastuzumab every 3 weeks combined with cytotoxic chemotherapy in patients with HER2-positive recurrent breast cancer: Findings from a case series [J].
Ardavanis, A ;
Tryfonopoulos, D ;
Orfanos, G ;
Karamouzis, M ;
Scorilas, A ;
Alexopoulos, A ;
Rigatos, G .
ONKOLOGIE, 2005, 28 (11) :558-564
[7]
Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study [J].
Bartelds, G. M. ;
Wijbrandts, C. A. ;
Nurmohamed, M. T. ;
Stapel, S. ;
Lems, W. F. ;
Aarden, L. ;
Dijkmans, B. A. C. ;
Tak, P. P. ;
Wolbink, G. J. .
ANNALS OF THE RHEUMATIC DISEASES, 2010, 69 (05) :817-821
[8]
Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule [J].
Baselga, J ;
Carbonell, X ;
Castañeda-Soto, NJ ;
Clemens, M ;
Green, M ;
Harvey, V ;
Morales, S ;
Barton, C ;
Ghahramani, P .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (10) :2162-2171
[9]
Early development of therapeutic biologics - Pharmacokinetics [J].
Baumann, A .
CURRENT DRUG METABOLISM, 2006, 7 (01) :15-21
[10]
TRANSPORT OF FLUID AND MACROMOLECULES IN TUMORS .4. A MICROSCOPIC MODEL OF THE PERIVASCULAR DISTRIBUTION [J].
BAXTER, LT ;
JAIN, RK .
MICROVASCULAR RESEARCH, 1991, 41 (02) :252-272