Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms.
OBJECTIVE
To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age.


METHODS
A total of 104 pediatric patients (aged 0.36-16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation.


RESULTS
In the whole population, the mean+/-SD cyclosporine oral bioavailability was 0.38+/-0.09, volume of distribution was 2.3+/-0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88+/-0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51+/-0.13, and the hepatic extraction ratio was 0.24+/-0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64+/-0.09 in those with the ABCB1 c.2677GG genotype, 0.52+/-0.11 in those with the c.2677GT genotype, and 0.41+/-0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28+/-0.07, 0.36+/-0.07, and 0.44+/-0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations.


CONCLUSIONS
Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.
Fanta
Samuel
S
Department of Clinical Pharmacology, University of Helsinki, and Pediatric Nephrology and Transplantation, Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland. samuel.fanta@helsinki.fi
Niemi
Mikko
M
Jönsson
Siv
S
Karlsson
Mats O
MO
Holmberg
Christer
C
Neuvonen
Pertti J
PJ
Hoppu
Kalle
K
Backman
Janne T
JT
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000367:Age Factors; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000494:pharmacology*; D017931:DNA Primers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D000089762:Multidrug Resistance-Associated Protein 2; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D000089762:Multidrug Resistance-Associated Protein 2; D016572:Cyclosporine