Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants

被引：20

作者：

Emoto, C. ^{[1
,2
]}

Fukuda, T. ^{[1
,2
]}

Mizuno, T. ^{[1
]}

Schniedewind, B. ^{[3
]}

Christians, Uwe ^{[3
]}

Adams, D. M. ^{[2
,4
]}

Vinks, A. A. ^{[1
,2
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45220 USA

[3] Univ Colorado, Anschutz Med Ctr, Integrated Solut Clin Res & Dev iC42, Aurora, CO USA

[4] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA

来源：

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY | 2016年 / 5卷 / 08期

关键词：

D O I：

10.1002/psp4.12096

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age-dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age-dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age-dependent change in CYP3A activity. The increasing pattern over time of allometrically size-normalized sirolimus CL estimates vs. age was well described by a sigmoidal E-max model. This age-dependent increase was also observed within each individual patient over a 4-year study period. CYP3A-dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity.

引用

页码：411 / 417

页数：7

共 36 条

[31] Developmental expression of the major human hepatic CYP3A enzymes [J].

Stevens, JC ;

Hines, RN ;

Gu, CG ;

Koukouritaki, SB ;

Manro, JR ;

Tandler, PJ ;

Zaya, MJ .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 307 (02) :573-582

[32]

Streit F, 1996, CLIN CHEM, V42, P1417

[33] Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer [J].

Wu, K. ;

Cohen, E. E. W. ;

House, L. K. ;

Ramirez, J. ;

Zhang, W. ;

Ratain, M. J. ;

Bies, R. R. .

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, 2012, 1 (12)

[34] Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation [J].

Zanger, Ulrich M. ;

Schwab, Matthias .

PHARMACOLOGY & THERAPEUTICS, 2013, 138 (01) :103-141

[35] Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review [J].

Zhao, P. ;

Zhang, L. ;

Grillo, J. A. ;

Liu, Q. ;

Bullock, J. M. ;

Moon, Y. J. ;

Song, P. ;

Brar, S. S. ;

Madabushi, R. ;

Wu, T. C. ;

Booth, B. P. ;

Rahman, N. A. ;

Reynolds, K. S. ;

Berglund, E. Gil ;

Lesko, L. J. ;

Huang, S-M .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2011, 89 (02) :259-267

[36] Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration [J].

Zimmerman, JJ ;

Kahan, BD .

JOURNAL OF CLINICAL PHARMACOLOGY, 1997, 37 (05) :405-415

← 1 2 3 4 →