background conclusions low weight, cyp3a5*1 allele, low gamma glutamyl transpeptidase and low...

Background Conclusions •low weight, CYP3A5*1 allele, low gamma glutamyl transpeptidase and low hematocrit are associated with a higher tacrolimus clearance in children > 1 year following kidney transplantation • no association between tacrolimus pharmacokinetics and age • no association between tacrolimus pharmacokinetics and concomitant medications in our model • to develop a population model for tacrolimus exposure in pediatric renal transplant recipients at least 1 year after transplantation • to identify co-variates contributing to the variability in tacrolimus pharmacokinetics • to develop individualized dosage recommendations POPULATION PHARMACOKINETICS OF TACROLIMUS IN STABLE PAEDIATRIC RENAL TRANSPLANT RECIPIENTS TRANSLATED INTO CLINICAL PRACTICE Agnieszka Prytuła (1) Karlien Cransberg (2) Antonia Bouts (3) Saskia de Wildt (2) Ron van Schaik (4) Ron Mathôt (5) (1) Ghent University Hospital (2) Erasmus MC - Sophia Children’s Hospital, Rotterdam (3) Emma Children’s Hospital, Amsterdam (4) Erasmus MC, Rotterdam (5) Academic Medical Center, Amsterdam Tacrolimus clearance in de novo pediatric kidney recipients is related to: • body weight • hematocrit • CYP3A5 polymorphism Zhao et al. Clinical Pharm & Ther 2009 What changes > 1 year after transplantation ? - corticosteroids - antiviral prophylaxis + antihypertensive medications Objectives Patients and Methods Results Study design: • retrospective cohort study; 54 patients included • renal transplantation April 1993- June 2011 • genetic analysis: CYP3A5*3 and ABCB1 C3435T polymorphism Inclusion criteria • AUC at least 1 year after renal transplantation • functioning allograft with eGFR> 30 ml/min/1.73m² at baseline • on twice-daily tacrolimus formulation Prograft® Pharmacokinetic analysis • non-linear mixed-effects modelling (NONMEM) • structural model (oral clearance, inter- compartment clearance, volume of Rotterdam: 4 hour AUC 104 profiles in 45 children C 0 C 10 C 30 C 80 C 120 C 240 Amsterdam: 2 hour AUC 16 profiles in 9 children C 0 C 120 clearance Univariate analysis P < 0.001 • recombinant growth hormone P < 0.005 • CYP3A5*1 allele • gamma glutamyl transpeptidase • 1-alfacalcidol • ferrous fumarate P < 0.05 • male gender • hematocrit • serum creatinine Baseline characteristics Number (% of total) Median (IQR) gender (boys) 28 (52) age (years) 11.1 (6.2) time since commencement TAC (months) 8.1 (7.2) time since transplantation (months) 16.2 (24.9) CYP3A5 genotype (n=49) *1/*1 *1/*3 *3/*3 1 (2) 12 (25) 36 (73) ABCB1 C->T genotype (n=49) T/C C/C T/T 32 (65) 9 (19) 8 (16) CYP3A5 *3/*3 *1/3 or *1/*1 ,5 ,4 ,3 ,2 ,1 ,0 0.15 mg/kg/day 0.12 mg/kg/day P = 0.04 Final model Final model Structural model • weight (not age) Co-variate analysis • CYP3A5*1 allele • Gamma glutamyl transpeptidase • hematocrit

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Background

Conclusions•low weight, CYP3A5*1 allele, low gamma glutamyl transpeptidase and low hematocrit are associated with a higher tacrolimus clearance in children > 1 year following kidney transplantation• no association between tacrolimus pharmacokinetics and age• no association between tacrolimus pharmacokinetics and concomitant medications in our model

• to develop a population model for tacrolimus exposure in pediatric renal transplant recipients at least 1 year after transplantation

• to identify co-variates contributing to the variability in tacrolimus pharmacokinetics

• to develop individualized dosage recommendations

POPULATION PHARMACOKINETICS OF TACROLIMUS IN STABLE PAEDIATRIC RENAL TRANSPLANT RECIPIENTS TRANSLATED INTO CLINICAL PRACTICE Agnieszka Prytuła (1) Karlien Cransberg (2) Antonia Bouts (3) Saskia de Wildt (2) Ron van Schaik (4) Ron Mathôt (5)

(1) Ghent University Hospital (2) Erasmus MC - Sophia Children’s Hospital, Rotterdam (3) Emma Children’s Hospital, Amsterdam (4) Erasmus MC, Rotterdam (5) Academic Medical Center, Amsterdam

Tacrolimus clearance in de novo pediatric kidney recipients is related to:• body weight• hematocrit• CYP3A5 polymorphismZhao et al. Clinical Pharm & Ther 2009

What changes > 1 year after transplantation ?- corticosteroids- antiviral prophylaxis+ antihypertensive medications

Objectives

Patients and Methods

Results

Study design:• retrospective cohort study; 54 patients included• renal transplantation April 1993- June 2011• genetic analysis: CYP3A5*3 and ABCB1 C3435T polymorphism

Inclusion criteria• AUC at least 1 year after renal transplantation• functioning allograft with eGFR> 30 ml/min/1.73m² at baseline• on twice-daily tacrolimus formulation Prograft®

Pharmacokinetic analysis• non-linear mixed-effects modelling (NONMEM)• structural model (oral clearance, inter-compartment clearance, volume of distribution, the delay between ingestion and start of absorption, absorption rate constant)• co-variate analysis

Rotterdam: 4 hour AUC 104 profiles in 45 children

C0 C10 C30 C80 C120 C240

Amsterdam: 2 hour AUC16 profiles in 9 children

C0 C120

NONMEM analysis- tacrolimus clearanceUnivariate analysisP < 0.001

• recombinant growth hormoneP < 0.005

• CYP3A5*1 allele • gamma glutamyl transpeptidase • 1-alfacalcidol • ferrous fumarate

P < 0.05 • male gender• hematocrit• serum creatinine

Baseline characteristics Number (% of total)

Median (IQR)

gender (boys) 28 (52) age (years) 11.1 (6.2) time since commencement TAC (months) 8.1 (7.2)

time since transplantation (months) 16.2 (24.9)