Disertasi

Peran Kadar Plasma, Rasio Cmax/MIC Bedaquilin dan Lecofloksasin terhadap Luaran Terapi TB Multidrug Resistant = Role ofPlasma Concentrations, Cmax/MIC Ratio of Bedaquiline and Levofloxacin on The Outcome of MDR-TB Treatment.

Tuberkulosis (TB) adalah penyebab utama kematian akibat penyakit infeksi. Saat ini, jumlah kasus TB-Resistan Rifampisin (RR) dan Multidrug Resistant (MDR) di Indonesia berada pada peringkat ketiga dengan jumlah pasien terbanyak di dunia. Pada tahun 2024, angka keberhasilan pengobatan TB-RR/MDR 58% dari target global 75%, dan angka loss to follow up 24–26%, mayoritas TB-RR adalah TB MDR. Hal itu menjadi masalah dalam tata laksana TB-MDR sehingga perlu dipertimbangkan pendekatan farmakokinetik/farmakodinamik dalam memantau pengobatan TB. Variasi farmakokinetik obat utama (bedaquilin dan levofloksasin) pada individu, serta variasi MIC terhadap M.tb mungkin penyebab perbedaan efek terapi dan efek samping akibat kadar plasma subterapi atau supraterapi. Oleh karena itu, perlu dilakukan penelitian untuk mengevaluasi peran kadar plasma, rasio Cmax/MIC bedaquilin dan levofloksasin berdasarkan luaran terapi TB MDR. Penelitian kohort dilakukan di RSPI Sulianti Saroso, Jakarta Utara; RSUD Pasar Rebo, Jakarta Timur; dan RS Paru Dr. Cisarua mulai Desember 2023 sampai November 2024. Terdapat 74 subjek TB-MDR berusia 18–65 tahun yang mendapat regimen obat oral 18–20 bulan, 16 subjek drop out pada masa pengamatan, dan 58 subjek berhasil diamati sampai empat bulan fase awal pengobatan. Pemeriksaan kadar plasma obat dilakukan di laboratoium Farmametrik, Jakarta Pusat. Pemeriksaan MIC dilakukan di laboratorium BB Binomika, Jakarta Pusat. Kadar plasma maksimum (Cmax)/MIC bedaquilin dan levofloksasin ditentukan untuk menilai efektivitas pengobatan (konversi sputum), sedangkan kadar plasma minimum (Cmin) ditentukan untuk menilai efek pemanjangan QTcF dalam 4 bulan pertama pengobatan. Hasil penelitian menunjukkan rerata Cmax bedaquilin 1,44 mg/L (SB 0,84 mg/L) dan rerata Cmin bedaquilin 0,99 mg/L (SB 0,54 mg/L). Rerata Cmax levofloksasin 11,31 mg/L (SB 5,75 mg/L) dan Cmin levofloksasin 6,98 mg/L (SB 4,66 mg/L). MIC bedaquilin dan levofloksasin berada pada rentang kadar 0,06–1 mg/L. Terdapat 41,2% MIC bedaquilin dengan nilai 0,25 mg/L; 35,5% MIC bedaquilin dengan nilai ≤ 0,12 mg/L, dan 23,3% MIC bedaquilin dengan nilai ≥ 0,50 mg/L. Sebanyak 35 (68,6%)MIC levofloksasin dengan nilai 0,25 mg/L. Nilai Cmax atau Cmax/MIC bedaquilin lebih tinggi secara bermakna pada kelompok pasien dengan konversi sputum dalam empat bulan pertama pengobatan, yang menunjukkan adanya potensi hubungan antara Cmax atau Cmax/MIC bedaquilin dengan konversi sputum pada pasien TB-MDR. Hal tersebut tidak ditunjukkan oleh levofloksasin. Selain itu, terdapat perbedaan bermakna Cmin levofloksasin pada kelompok perpanjangan QTcF dan kelompok tanpa pemanjangan QTcF, hal tersebut tidak ditunjukkan oleh bedaquilin. Rasio Cmax/MIC bedaquilin dapat memprediksi konversi sputum, dan Cmin levofloksasin dapat memprediksi perpanjangan QTcF pada empat bulan pengobatan TB-MDR di Indonesia.
Kata Kunci: bedaquilin, farmakokinetik/farmakodinamik, konversi sputum, levofloksasin, pemanjangan QTcF, tuberkulosis MDR


Tuberculosis remains the leading cause of death caused by infectious disease. Currently, MDR/RR-TB cases are on the rise. Indonesia was ranked third in the world with the highest number ofMDR/RR-TB cases. The success rate ofMDR-TB treatment in Indonesia remains at 58% in 2024, compared to the global target of 75%. A pharmacokinetic/pharmacodynamic approach may be necessary in cases of MDR-TB. Treatment failure of MDR-TB cases due to suboptimal drug treatment or side effects, especially those related to the plasma concentration of the drug, needs to be investigated. Individual variations in the pharmacokinetics of the core drugs (bedaquiline and levofloxacin), as well as variations in the MIC against M.tb in different regions, might cause differences in therapeutic effects and adverse drug reactions due to subtherapeutic or supratherapeutic plasma drug concentration. This study aimed to determine the role of plasma concentrations and the Cmax/MIC ratio of bedaquiline and levofloxacin to clinical outcomes in MDR-TB treatment in Indonesia. This was a cohort study from December 2023 to November 2024, in which 74 MDRTB subjects aged 18–65 years who received an 18–20 month regimen of all oral drugs. During the follow-up period, 16 subjects dropped out, and 58 patients completed the analysis up to four months of treatment. The study was conducted at 3 hospitals. Approval by the Ethics Committee of FKUI was received. The drug plasma concentration was examined at Farmametrik. MIC examination was conducted at the BB Binomika. The Cmax and MIC of bedaquiline and levofloxacin were determined to assess sputum conversion, while the Cmin was determined to assess the QTcF prolongation in the initial phase of MDR-TB treatment. In this study, the mean Cmax of bedaquilin was 1.44 mg/L (SD 0.84 mg/L), while the mean Cmin of bedaquilin was 0.99 mg/L (SD 0.54 mg/L). The mean Cmax of levofloxacin was 11.31 mg/L (SD 5.75 mg/L), and the mean Cmin of levofloxacin was 6.98 mg/L (SD 4.66 mg/L). The bedaquiline MICs of 0.25 mg/L were 21 (41.2%) isolates, the MICs of ≤ 0.12 mg/L were 18 (35.5%) isolates, and the MICs of ≥ 0.50 mg/L were 12 (23.3%) isolates. The MICs of levofloxacin against Mtb of 0.25 mg/L were 35 (68.6%) isolates. This study showed a significantly higher bedaquiline Cmax or Cmax/MIC in patients with sputum conversion in the first 4 months of treatment, which suggests a potential relationship between the bedaquiline Cmax or Cmax/MIC ratio and sputum conversion in patients with MDR-TB, which was not shown in the case of levofloxacin. There was a statistically significant difference in the Cmin of levofloxacin between the QTcF prolongation and non-QTcF prolongation groups, whereas this was not shown with bedaquiline. Cmax/MIC ratio of bedaquiline can predict sputum conversion, and Cmin of levofloxacin can predict QTcF prolongation in the early phase of MDR-TB treatment in Indonesia.
Keywords: Bedaquiline, Levofloxacin, MDR Tuberculosis, Pharmacokinetics/ Pharmacodynamics, sputum conversion, QTcF prolongation