Pengaruh Variasi Genetik SLC22A1 rs628031 terhadap Farmakokinetik/Farmakodinamik Metformin Berbasis Populasi: Kajian Indirect Response Model pada Pasien Diabetes Melitus (DM) Tipe 2 Suku Jawa
Dimas Adhi Pradana, Prof. Dr. Dra. Erna Kristin, Apt., M.Si.
2023 | Disertasi | S3 Kedokteran Umum
Latar belakang: Sebanyak 40% pasien tidak memperoleh efek terapi yang optimal pada awal penggunaan metformin sebagai monoterapi DM tipe 2. Hal tersebut dapat disebabkan oleh variasi gen SLC22A1 rs628031 pada transporter OCT1.
Tujuan: Studi ini bertujuan untuk mengetahui pengaruh variasi genetik SLC22A1 rs628031 Met408Val pada OCT1 terhadap farmakokinetik/farmakodinamik metformin.
Metode penelitian: Penelitian ini bersifat observasional dengan rancangan cohort prospektif pada 123 pasien DM tipe 2 yang menggunakan monoterapi metformin 2x500 mg. Variasi genetik SLC22A1 rs628031 Met408Val dianalisis dengan metode PCR-RFLP. Pengembangan dan validasi metode penetapan kadar metformin dalam plasma dilakukan dengan metode HPLC-UV. Parameter FK/FD berbasis data populasi yang ditetapkan meliputi ka, Vd, k, Cssmaks, Cssmin, AUC, Tmak, Cl, t1/2, Cc0, R0, IC50, kin, kout menggunakan software monolix versi 2023R1 dengan pendekatan metode indirect response model. Analisis pengaruh variasi genetik terhadap kadar HbA1c, glukosa darah puasa (GDP), glukosa darah 2 jam postprandial (G2PP) dilakukan dengan membandingkan perubahan nilai baseline dengan minggu ke-12. Analisis pengaruh kovariat seperti body mass index (BMI), usia, jenis kelamin, kliren kreatinin, GFR, kepatuhan pengobatan dianalisis dengan strategi COSSAC covariate model monolix versi 2023R1 dan uji regresi linier. Uji statistika dinyatakan bermakna pada (p kurang dari 0,05).
Hasil: Hasil identifikasi variasi genetik SLC22A1 rs628031 Met408Val dari 123 responden menunjukkan frekuensi kelompok allele AA sebesar 14 persen allele AG-GG sebesar 86 persen. Pemodelan FK/FD metformin berbasis populasi menunjukkan fitting kurva yang baik dengan pendekatan indirect response model. Kelompok allele AG-GG mengalami penurunan nilai ka, Vd, t1/2, kin, kout dan mengalami peningkatan parameter Cssmaks dan k (p kurang dari 0,05). Kelompok allele AG-GG juga mengalami penurunan parameter HbA1c, GDP dan G2PP yang lebih rendah jika dibandingkan dengan kelompok allele AA (p kurang dari 0,05).
Kesimpulan : Variasi genetik SLC22A1 rs628031 Met408Val menurunkan nilai ka, Vd, t1/2, kin, kout , meningkatkan nilai Cssmaks dan k, serta menurunkan respon terapi metformin berdasarkan parameter HbA1c, GDP dan G2PP.
Background: Up to forty percent of individuals do not attain maximum therapeutic outcomes when using metformin as a standalone treatment for diabetes. Genetic variations in the OCT1 transporter gene SLC22A1 rs628031 can lead to this condition.
Objective: The objective of this study is to investigate the impact of the genetic polymorphism SLC22A1 rs628031 Met408Val in OCT1 on the pharmacokinetics/pharmacodynamics of metformin.
Method: This study was conducted on 123 individuals with type 2 diabetes mellitus who were receiving metformin monotherapy at a dosage of 2x500 mg. The genetic variant of SLC22A1 rs628031 Met408Val was examined using PCR-RFLP. The HPLC-UV method was employed to validate and optimize the procedure for quantifying metformin levels in plasma. Population PK/PD parameters include ka, Vd, k, Cssmax, Cssmin, AUC, Tmak, Cl, t1/2, Cc0, R0, IC50, kin, and kout, calculated using Monolix software version 2023R1 using indirect response model method structure. The impact of genetic variations on HbA1c levels, fasting blood glucose (FBG), and fasting blood glucose after 2-hour postprandial (FBG2PP) was analyzed by comparing baseline to 12-week changes in values. The influence of covariates, including body mass index (BMI), age, gender, creatinine clearance, GFR, and treatment adherence, was analyzed using the COSSAC covariate model monolix version 2023R1 and linear regression testing. At (p lower than 0.05), the statistical test was deemed significant.
Result: Identifying the genetic variation SLC22A1 rs628031 Met408Val in 123 respondents revealed a frequency of 14 percent in the allele AA group and 86 percent in the allele AG-GG group. Using the indirect response model approach, population-based PK/PD modeling of metformin reveals decent curve fitting. The parameters ka, Vd, t1/2, kin, and kout decreased in the allele AG-GG group, while Cssmax and k increased (p lower than 0.05). HbA1c, FBG, and FBG2PP parameters decreased less in the allele AG-GG group compared to the allele AA group (p lower than 0.05).
Conclusion: The genetic variation SLC22A1 rs628031 Met408Val reduces ka, Vd, t1/2, kin, and kout values, increases Cssmax and k, and decreases the response to metformin therapy, based on HbA1c, FBG, and FBG2PP parameters.
Kata Kunci : Metformin, DM tipe 2, SLC22A1 rs628031, farmakokinetik/farmakodinamik populasi, indirect response model.