Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes

Abstract

AimsOur aim was to investigate associations between the single nucleotide polymorphisms (SNPs) in the SLCO1B1 (encoding OATP1B1) and ABCB1 (encoding P-glycoprotein) genes with the pharmacokinetics and efficacy of pravastatin in children with heterozygous familial hypercholesterolaemia (HeFH) and in paediatric cardiac transplant recipients. MethodsTwenty children with HeFH (aged 4.9-15.6 years) and 12 cardiac transplant recipients (aged 4.4-18.7 years and receiving triple immunosuppressive medication) who had participated in previous pharmacokinetic and pharmacodynamic studies with pravastatin were genotyped for the − 11187G > A and 521T > C SNPs in the SLCO1B1 gene and for the 2677G > T/A and 3435C > T SNPs in the ABCB1 gene. ResultsTwo HeFH patients with the − 11187GA genotype had a 81% lower peak plasma pravastatin concentration ( C max ) (difference in means − 13.9 ng ml − 1 , 95% CI − 21.1, − 6.7; P < 0.001) and a 74% smaller area under the plasma concentration-time curve (AUC(0, ∞ )) ( − 25.3 ng ml − 1 h, 95% CI − 35.6, − 15.0; P < 0.0001) and significantly greater increase in high density lipoprotein (HDL) cholesterol after 2 months treatment with pravastatin than patients with the reference genotype. No significant differences were seen in the pharmacokinetics or effects of pravastatin between HeF H patients with the SLCO1B1 521TC and 521TT genotypes. The cardiac transplant recipients with the SLCO1B1 521TC genotype ( n = 3) had a 46% lower C max ( − 67.7 ng ml − 1 , 95% CI − 135.7, 0.3; P = 0.055) and 62% lower AUC(0,24 h) ( − 228.5 ng ml − 1 h, 95% CI − 402.7, − 54.3; P = 0.016) and a shorter half-life ( t 1/2 ) (0.9 ± 0.1 vs. 1.3 ± 0.4 h, P = 0.015) of pravastatin than those with the reference genotype. Decreases in total and low-density lipoprotein cholesterol by pravastatin were significantly smaller, and the increase in HDL-cholesterol was greater in the transplant recipients with the 521TC genotype compared with patients with the 521TT reference genotype. Pharmacokinetics of pravastatinBr J Clin Pharmacol 61 :6 707 ConclusionsIn children with HeFH and in paediatric cardiac transplant recipients receiving immunosuppressive medication, the − 11187G > A and SLCO1B1 521T > C SNPs were associated with decreased plasma concentrations of pravastatin. These differences are opposite to those seen previously in healthy adults. The mechanisms underlying these phenomena are unclear and warrant further study.

Association between <i>SLCO1B1 521 T</i>＞<i>C</i> and <i>388 A</i>＞<i>G </i>Polymorphisms and Statins Effectiveness: A Meta-Analysis

“…Thus, well-designed original studies involving more ethnicities and larger sample sizes are needed to confirm our findings. [30] short-term [25] [30] short-term [20,21,25,28] [30] short-term [25] [30] short-term [24,25] [30] short-term [24,31] [30] short-term [24,31] [30] short-term [24,31] [30] short-term [24,31] [30] short-term [22,24,31] [30] short-term [22,24,31] [30] short-term [22,24,29,31] [30] short-term [22,24,31] [30] short-term [24,31] 1 2 2.43 [ 16.59, 11.73] 3.00 [ 14.26, 8.26] 0.74 0.60 AG: AA long-term [30] short-term [24,31] …”

“…Conversely, some trials did not find a significant effectiveness [22][23][24][25][26][27] . In addition, Hedman et al found that decreases in the total and low-density lipoprotein cholesterol by pravastatin were significantly smaller, and the increase in the high-density lipoprotein cholesterol (HDL-C) was greater in transplant recipients with the 521TC genotype compared with patients with the 521TT reference genotype 28) . For 388 A G, Rodrigues et al and Sortica et al found that the polymorphism caused a significant increase in the response to statins and may be an important marker for predicting the effectiveness of lipid-lower-between the SLCO1B1 521 T C and 388 A G polymorphisms and the effectiveness of statins.…”

“…The follow-up duration ranged from 1 month to 1 year and not all studies reported both SLCO1B1 521 T C or 388 A G polymorphisms. [19,22,23,[25][26][27]30] TC: TT [19-23, 25-28, 30] CC: TC TT [19,22,23,[25][26][27]30] CC TC: TT [19, 22-27, 29, 30] [22,23,25,30] TC: TT [20-23, 25, 28, 30] CC: TC TT [22,23,25,30] CC TC: TT [22-25, 29, 30] [23,25,27,30] TC: TT [20,21,23,25,27,28,30] CC: TC TT [23,25,27,30] CC TC: TT [23-25, 27, 30] [25,30] TC: TT [20,21,25,28,30] CC: TC TT [25,30] CC TC: TT …”

“…There were 8 studies which included subjects with essential hyperlipidemia, and two studies which included subjects with coronary heart disease (CHD); in two studies, this information was unavailable. All of the studies enrolled participants aged ≥ 45 years old except one study 28) which concentrated on children aged 4.4-18.7 years old. The sample sizes ranged from 32 to 2,891.…”

Pharmacogenetics of response to statins

“…Despite being a single-dose study, this study again adds to the growing evidence of SLCO1B1 as a candidate gene in statin pharmacogenetics with publication of subsequent supportive reports [11]. Of interest, a recent study has extended the findings of SLCO1B1-associated differential statin-lipid response to include HDL cholesterol [12].…”