[논문]프라바스타틴에서 <tex>$SLCO1B1^*15$</tex>의 약동학적 영향: 체계적 고찰 및 메타분석

김종윤; 나오토 나카가와; 윤현옥; 천부순; 유기연

**프라바스타틴에서 $SLCO1B1^15$의 약동학적 영향: 체계적 고찰 및 메타분석
Effect of $SLCO1B1^15$ on Pravastatin Pharmacokinetics: A Systematic Review and Meta-analysis** 원문보기

한국임상약학회지 = Korean journal of clinical pharmacy, v.24 no.4, 2014년, pp.231 - 239

김종윤 (서울대학교병원 약제부) , 나오토 나카가와 (도호쿠대학병원 약제과) , 윤현옥 (경상대학교 약학대학) , 천부순 (인제대학교 약학대학) , 유기연 (동덕여자대학교 약학대학)

Abstract ▼ AI-Helper

Background and objective: Pravastatin has been shown to have favorable risk-benefit profile when it is administered to hypercholesterolemic subjects to prevent cardiovascular events. However, subjects with impaired OATP1B1 activity may be more susceptible to pravastatin-induced muscle toxicity than subjects with normal OATP1B1 activity. A systematic review was conducted to evaluate the effect of SLCO1B1 genetic polymorphism on pharmacokinetics of pravastatin. Method: Medline$^{(R)}$ and Embase$^{(R)}$ were searched for relevant studies until July 2013. The search terms used were pravastatin AND (SLCO1B1 OR OATP1B1 OR LST1 OR SLC21A6) AND (gene OR $genetic^*$ OR $genomic^*$ OR $pharmacogenet^*$ OR $pharmacogenom^*$ OR $polymorph^*$). Results: A meta-analysis of the area under the concentration-time curve (AUC) of pravastatin in $SLCO1B1^*15$ and $SLCO1B1^*1a/^*1a$ was conducted. Five studies met all the inclusion criteria and methodological requirements. There was no statistically significant difference in the AUC value between $SLCO1B1^*15$ and $SLCO1B1^*1a/^*1a$ (p=0.728). However, $SLCO1B1^*15$ participants exhibited significantly higher AUC values than $SLCO1B1^*1b/^*1b$ carriers (p<0.001). In case of $SLCO1B1^*15^*15$ carriers, they had significantly higher AUC value than $SLCO1B1^*1a/^*1a$ subjects (p=0.002). Lastly, compared with to the subjects of $SLCO1B1^*1a/^*1a$, the carriers of heterozygous $SLCO1B1^*15$ increased the AUC value of pravastatin statistically significantly in Asian population (p=0.014). Conclusion: The present meta-analysis suggests that subjects with $SLCO1B1^*15$ are associated with increased AUC of pravastatin.

주제어

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제안 방법

A sensitivity analysis presented there is no considerable differences. The publication bias was conducted for available meta-analyses. The shape of the funnel plots were symmetry.
¹⁵⁾ However, as only 1% of the AA participants were genotyped as SLCO1B1 521TC (SLCO1B1*5, SLCO1B1*15), it cannot be certain that ethnicity is the factor of exclusion of genotype. To determine whether the AUC values of pravastatin is affected by ethnicity, this study also examined the AUC values in SLCO1B1*15 carriers and non-carriers according to the races. As a result, there was no statistically significant difference in the AUC values between Asian-only population and all ethnicity population in two studies (95% CI, -0.
Two investigators (JYK and PC) independently reviewed the full-text of the research articles and extracted the data on genotypes of SLCO1B1*15, number of total subjects, mean and standard deviation of AUC of pravastatin, pravastatin dosage, ethnicity of subjects, and nation of correspondence. Disagreements regarding inclusion of studies were compromised by sufficient discussion and consensus with a third investigator (KYR).

대상 데이터

. After removal of duplicates, titles and abstracts of 139 candidate articles were screened for eligibility criteria prior to full text review. Among these articles, 66 were excluded due to inappropriate form, which included 42 reviews, 17 conference abstracts, 3 conference papers, 1 article in press, 1 editorial, 1 letter, and 1 note.

데이터처리

If published studies were more than three, publication bias was analyzed with funnel plot by using Begg’s rank correlation method and Egger’s regression method.

이론/모형

05 was considered statistically significant publication bias. All statistical analyses were performed with two-sided test by using Comprehensive Meta-analysis Software, Version 2 (Biostat, Englewood, USA).

성능/효과

To determine whether the AUC values of pravastatin is affected by ethnicity, this study also examined the AUC values in SLCO1B1*15 carriers and non-carriers according to the races. As a result, there was no statistically significant difference in the AUC values between Asian-only population and all ethnicity population in two studies (95% CI, -0.524, 1.337, p=0.434;95% CI, -0.285,2.181, p=0.132). However, the thing that most of them were Asian (64% of the subjects included in this SLCO1B1*15 heterozygous carriers) cannot be ignored.
observed significantly lower AUC value in the group of SLCO1B1*1b/*15 than in the group of SLCO1B1*1a/*1a. Based on the pharmacokinetics of SNP-related pravastatin observed in the three studies, effect size (standard differences in means) of pravastatin AUC increase was 0.090 (95% CI. -0.417, 0.597), which was not statistically significant (p=0.728) (Fig. 2(A)).
^20,21) The findings from our systematic review are consistent with the previous suggestion. The results of our meta-analysis conclude that heterozygous SLCO1B1*15 seems to be an important determinant of pravastatin pharmacokinetics.

후속연구

The finding supports a rationale in terms of clinical SLCO1B1 transporter gene test, especially for patients with high doses of pravastatin to predict potential toxicities. Further studies are required to assess efficacy and toxicity of pravastatin for SLCO1B1 polymorphisms including SLCO1B1*15 genotypes.
The findings from this study may be clinically applied for the subjects on high-dose pravastatin therapy. Further studies of large trials with unbiased selection methods and with more detailed individual data are required to confirm these findings.

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