Physiologically Based Pharmacokinetic (PBPK) Simulation of Supratherapeutic Meropenem Exposure and Potential Pharmacokinetics/Pharmacodynamics (PK/PD) Discordance in a Critically Ill Pediatric Patient: A Case Report
DOI:
https://doi.org/10.56951/je8s9k71Kata Kunci:
PBPK, meropenem, farmakokinetikaAbstrak
Latar belakang: Meropenem digunakan secara luas pada pasien anak dengan kondisi kritis; namun, sepsis dan gangguan fungsi ginjal dapat mengubah profil farmakokinetika secara bermakna, sehingga meningkatkan risiko akumulasi obat. Lebih lanjut, pemantauan kadar obat terapeutik belum tersedia secara memadai di banyak fasilitas kesehatan. Presentasi kasus: Seorang anak berusia 6 tahun (berat badan 18,6 kg, tinggi badan 102 cm) datang dengan pneumonia berat dan sepsis yang disertai gangguan ginjal akut. Pemeriksaan laboratorium menunjukkan peningkatan kreatinin serum (1,9 mg/dl), penurunan estimasi laju filtrasi glomerulus (eLFG) (22,17 ml/menit/1,73 m²), hipoalbuminemia ringan (3,2 g/dl), serta peningkatan kadar transaminase (AST 67 U/l, ALT 89 U/l). Pasien mendapatkan meropenem intravena, dan model farmakokinetika berbasis fisiologi (physiologically based pharmacokinetic/PBPK) digunakan untuk menilai dan memprediksi paparan obat. Metode: Simulasi PBPK dilakukan menggunakan PK-Sim®, dengan mempertimbangkan fisiologi anak, gangguan klirens ginjal, ikatan protein yang rendah, serta sifat fisikokimia spesifik obat. Hasil: Model memprediksi adanya akumulasi meropenem yang bermakna setelah pemberian dosis berulang. Konsentrasi plasma yang diprediksi pada 0,5 jam setelah pemberian dosis (C0,5) adalah 69,82 mcg/ml. Setelah dosis keempat, prediksi konsentrasi puncak (Cmaks) mencapai 183,42 mcg/ml, sementara konsentrasi trough (Ctrough) tetap tinggi pada 139,94 mcg/ml. Konsentrasi obat bebas tetap berada di atas kadar hambat minimum (minimum inhibitor concentration/MIC) sepanjang interval dosis, menghasilkan fT>MIC sebesar 100%. Konsentrasi supraterapeutik akibat perubahan PK/PD dapat menyebabkan neurotoksisitas pada pasien anak dengan kondisi kritis; bahkan pada dosis terapeutik meropenem dapat menyebabkan perubahan pada mikrobiom. Kesimpulan: Kasus ini menunjukkan bahwa pemberian dosis standar meropenem pada pasien anak dengan kondisi kritis disertai gangguan fungsi ginjal dapat menyebabkan paparan supraterapeutik, meskipun target farmakodinamika telah tercapai sepenuhnya. Pemodelan PBPK dapat membantu mengantisipasi paparan yang berlebih dan mendukung penyesuaian dosis secara individual ketika fungsi ginjal tidak stabil dan pemantauan kadar obat terapeutik tidak tersedia.
Unduhan
Referensi
1. Morales Castro D, Dresser L, Granton J, Fan E. Pharmacokinetic alterations associated with critical illness. Clin Pharmacokinet. 2023;62(2):209. doi:10.1007/S40262-023-01213-X.
2. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patientconcepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014;77:3–11. doi:10.1016/J.ADDR.2014.07.006.
3. Goncalves-Pereira J, Silva NE, Mateus A, Pinho C, Povoa P. Assessment of pharmacokinetic changes of meropenem during therapy in septic critically ill patients. BMC Pharmacol Toxicol. 2014;15:21. doi:10.1186/2050-6511-15-21.
4. Osman Abubaker R. Pharmacokinetic changes of meropenem in sepsis patients: a comparative review [dissertation on the Internet]. Uppsala: Uppsala University; 2022. Available from: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-478448
5. Jimenez A, Abbo L, Gebrezgi MT. Importance of carbapenemase production detection in carbapenemresistant enterobacteriaceae: looking beyond epidemiological purposes. Clin Infect Dis. 2017;65(8):1424–5. doi:10.1093/cid/cix537.
6. Cies JJ, Moore WS, Enache A, Chopra A. Population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill young children. J Pediatr Pharmacol Ther. 2017;22(4):276–85. doi:10.5863/1551-6776-22.4.276.
7. Perry C, Davis G, Conner TM, Zhang T. Utilization of physiologically based pharmacokinetic modeling in clinical pharmacology and therapeutics: an overview. Curr Pharmacol Rep. 2020;6(3):71–84. doi:10.1007/S40495-020-00212-X.
8. Jamei M, Bajot F, Neuhoff S, Barter Z, Yang J, Rostami-Hodjegan A, et al. A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine. Clin Pharmacokinet. 2014;53(1):73–87. doi:10.1007/S40262-013-0097-Y.
9. Roberts JA. Using PK/PD to optimize antibiotic dosing for critically ill patients. Curr Pharm Biotechnol. 2011;12(12):2070–9. doi:10.2174/138920111798808329.
10. Bertino JS. Therapeutic drug monitoring of antibiotics. Lancet Infect Dis. 2014;14(12):1180–1. doi:10.1016/S1473-3099(14)70988-0.
11. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 441130, Meropenem; [cited 2025 Dec 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Meropenem.
12. Rubino CM, Bhavnani SM, Loutit JS, Lohse B, Dudley MN, Griffith DC. Single-dose pharmacokinetics and safety of meropenem-vaborbactam in subjects with chronic renal impairment. Antimicrob Agents Chemother. 2018;62(3):e02103–17. doi:10.1128/AAC.02103-17.
13. Zhou W, Johnson TN, Xu H, Cheung S, Bui KH, Li J, et al. Predictive performance of physiologically based pharmacokinetic and population pharmacokinetic modeling of renally cleared drugs in children. CPT Pharmacometrics Syst Pharmacol. 2016;5(9):475–83. doi:10.1002/PSP4.12101.
14. Ganguly S, Edginton AN, Gerhart JG, Cohen-Wolkowiez M, Greenberg RG, Gonzalez D. Physiologically based pharmacokinetic modeling of meropenem in preterm and term infants. Clin Pharmacokinet. 2021;60(12):1591–604. doi:10.1007/S40262-021-01046-6.
15. McConaughey B, Daniels Z, Miller D, LaRochelle J, Corte T, Mirfiq A. Meropenem-induced neurotoxicity in setting of impaired renal function and sepsis case report. [Preprint]. SSRN; Posted: 24 Mar 2023. [cited 2025 Dec 21]. Available from: https://doi.org/10.2139/ssrn.4386056.
16. An G, Creech CB, Wu N, Nation RL, Gu K, Nalbant D, et al. Evaluation of empirical dosing regimens for meropenem in intensive care unit patients using population pharmacokinetic modeling and target attainment analysis. Antimicrob Agents Chemother. 2023;67(1):e0131222. doi:10.1128/AAC.01312-22.
17. Germovsek E, Barker CIS, Sharland M, Standing JF. Scaling clearance in paediatric pharmacokinetics: all models are wrong, which are useful? Br J Clin Pharmacol. 2017;83(4):777–90. doi:10.1111/BCP.13160.
18. Gijsen M, Elkayal O, Annaert P, Van Daele R, Meersseman P, Debaveye Y, et al. Meropenem target attainment and population pharmacokinetics in critically ill septic patients with preserved or increased renal function. Infect Drug Resist. 2022;15:53–62. doi:10.2147/IDR.S343264.
19. Theuretzbacher U. Pharmacokinetic and pharmacodynamic issues for antimicrobial therapy in patients with cancer. Clin Infect Dis. 2012;54(12):1785–92. doi:10.1093/CID/CIS210.
20. Charlton M, Thompson JP. Pharmacokinetics in sepsis. BJA Educ. 2018;19(1):7–13. doi:10.1016/J. BJAE.2018.09.006.
21. Phe K, Heil EL, Tam VH. Optimizing pharmacokinetics-pharmacodynamics of antimicrobial management in patients with sepsis: a review. J Infect Dis. 2020;222(Suppl 2):S132–41. doi:10.1093/infdis/jiaa118.
22. Bahnasawy SM, Parrott NJ, Gijsen M, Spriet I, Friberg LE, Nielsen EI. Physiologically-based pharmacokinetic modelling in sepsis: a tool to elucidate how pathophysiology affects meropenem pharmacokinetics. Int J Antimicrob Agents. 2024;64(6):107352. doi:10.1016/j.ijantimicag.2024.107352.
23. Wang H, Li J, Li X, Li H, He Y, Tan R, et al. Clinical characteristics and early identification of augmented renal clearance in PICU patients with severe sepsis associated with MRSA infection. Front Pediatr. 2024;12:1433417. doi:10.3389/fped.2024.1433417.
24. Pata RK, Bastola C, Nway N, Patel MJ, Adhikari S. Augmented renal clearance in a case of sepsis leading to vancomycin failure despite increasing dose as per the estimated glomerular filtration rate. Cureus. 2021;13(3):e14183. doi:10.7759/ cureus.14183.
25. Heffernan AJ, Sime FB, Lipman J, Dhanani J, Andrews K, Ellwood D, et al. Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by gram-negative bacilli: a systematic review. Int J Antimicrob Agents. 2019;53(3):234–45. doi:10.1016/j.ijantimicag.2018.11.011.
26. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Challenges and potential solutions–individualised antibiotic dosing at the bedside for critically ill patients: a structured review. Lancet Infect Dis. 2014;14(6):498–509. doi:10.1016/S1473-3099(14)70036-2.
27. Chytra I, Stepan M, Benes J, Pelnar P, Zidkova A, Bergerova T, et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized openlabel controlled trial. Crit Care. 2012;16(3):R113. doi:10.1186/cc11405.
28. Tournayre S, Mathieu O, Villiet M, Besnard N, Brunot V, Daubin D, et al. Factors associated with meropenem pharmacokinetic/pharmacodynamic target attainment in septic critically ill patients treated with extended intermittent infusion or continuous infusion. Int J Antimicrob Agents. 2023;62(2):106868. doi:10.1016/j.ijantimicag.2023.106868.
29. Anderson BJ, Hannam JA. Considerations when using pharmacokinetic/pharmacodynamic modeling to determine the effectiveness of simple analgesics in children. Expert Opin Drug Metab Toxicol. 2015;11(9):1393–408. doi:10.1517/17425255.2015.1061505.
30. Wenzler E, Scoble PJ. An appraisal of the pharmacokinetic and pharmacodynamic properties of meropenem-vaborbactam. Infect Dis Ther. 2020;9(4):769–84. doi:10.1007/S40121-020-00344-Z.
31. Steffens NA, Zimmermann ES, Nichelle SM, Brucker N. Meropenem use and therapeutic drug monitoring in clinical practice: a literature review. J Clin Pharm Ther. 2021;46(3):610–21. doi:10.1111/jcpt.13369.
32. Roger C, Louart B. Beta-lactams toxicity in the intensive care unit: an underestimated collateral damage? Microorganisms. 2021;9(7):1505. doi:10.3390/microorganisms9071505.
33. Al Yami MS. Comparison of the incidence of acute kidney injury during treatment with vancomycin in combination with piperacillin–tazobactam or with meropenem. J Infect Public Health. 2017;10(6):770–3. doi:10.1016/j.jiph.2016.11.007.
34. McDonald C, Cotta MO, Little PJ, McWhinney B, Ungerer JP, Lipman J, et al. Is high-dose β-lactam therapy associated with excessive drug toxicity in critically ill patients? Minerva Anestesiol 2016;(82):957–65.
35. Beumier M, Casu GS, Hites M, Seyler L, Cotton F, Vincent JL, et al. β-lactam antibiotic concentrations during continuous renal replacement therapy. Crit Care. 2014;18(3):R105. doi:10.1186/cc13886.
36. Yap GC, Hong PY, Lee BW. Microflora of the intestine: the natural microflora of humans. In: Batt CA, Tortorello ML, editors. Encyclopedia of Food Microbiology. 2nd ed. Academic Press; 2014. p.634–8. doi:10.1016/B978-0-12-384730-0.00207-X.
37. Ribeiro FM, Ribeiro CFA, de Souza Cândido E, Buccini DF, Cardoso MH, Greice de Oliveira Silva Silveira G, et al. Absence of gut microbiota restoration following meropenem treatment in a systemic infection model. NPJ Antimicrob Resist. 2025;3(1):60. doi:10.1038/s44259-025-00129-9.
38. Miller WD, Keskey R, Alverdy JC. Sepsis and the microbiome: a vicious cycle. J Infect Dis. 2021;223(12 Suppl 2):S264–9. doi:10.1093/infdis/jiaa682.
39. Peto L, Fawcett N, Kamfose MM, Scarborough C, Peniket A, Danby R, et al. The impact of different antimicrobial exposures on the gut microbiome in the ARMORD observational study. Elife. 2025;13: RP97751. doi:10.7554/eLife.97751.
40. Becattini S, Taur Y, Pamer EG. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med. 2016;22(6):458–78. doi:10.1016/J.MOLMED.2016.04.003.
41. Wilson DN. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol. 2014;12(1):35–48. doi:10.1038/NRMICRO3155.
42. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA. 2011;108(S1):4554–61. doi:10.1073/pnas.1000087107.
43. Palleja A, Mikkelsen KH, Forslund SK, Kashani A, Allin KH, Nielsen T, et al. Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol. 2018;3(11):1255–65. doi:10.1038/S41564-018-0257-9.
Unduhan
Terbitan
Bagian
Diterbitkan
Unduhan
Lisensi
Hak Cipta (c) 2026 Andika Yusuf Ramadhan
Artikel ini berlisensi Creative Commons Attribution-NonCommercial 4.0 International License.
Cara Mengutip
