A minimal physiologically-based pharmacokinetic model to investigate CNS distribution of metronidazole in ICU patients

Alexia Chauzy (1, 2) , Salim Bouchène (3) , Nicolas Grégoire (1, 2) , William Couet (1, 2, 4) , Olivier Mimoz (1, 2, 4) , Sandrine Marchand (1, 2, 4) , Claire Dahyot-Fizelier (4, 1, 2)

1 PHAR [Poitiers] - Pharmacologie des anti-infectieux
2 Université de Poitiers - Faculté de Médecine et de Pharmacie
3 Certara
4 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital

Objectives: Metronidazole is used to treat brain infections due to anaerobic bacteria. The aim of this study was to develop a Physiologically-Based Pharmacokinetic (PBPK) model to characterize its pharmacokinetics in brain, from extracellular fluid (ECF) or cerebrospinal fluid (CSF) concentrations in ICU patients. Methods: Height male patients (age = 56±12 yrs, weight = 87±13 kg) were included in the analysis. They received 500 mg of metronidazole every 8 h through a 30-min IV-infusion. Serial metronidazole concentrations were measured in the CSF of 4 patients equipped with an external ventricular drainage (EVD) system into their lateral brain ventricles, and in the dialysates of the other 4 patients equipped with microdialysis probes placed in brain tissue. Serial blood samples were collected simultaneously. Plasma unbound concentrations were determined by ultrafiltration and all samples were assayed by LC-MS/MS. A minimal PBPK model was developed, representing the CNS by a vascular compartment separated from brain ECF and CSF compartments. The rest of the tissues were lumped as a single, perfusion limited and well-stirred tissue compartment. Metronidazole elimination was implemented as a plasma clearance representing both renal excretion and hepatic metabolism. Volumes and blood flows were fixed to their physiological value obtained from literature [1-4]. Diffusion clearances characterizing transport across the blood brain barrier (BBB) and blood–CSF barrier (BCSFB) were estimated using NONMEM 7.4 [5]. Results: The model well described unbound metronidazole pharmacokinetic profiles in plasma, ECF and CSF (Figure 1). No active transport was implemented in the model but the bidirectional passive diffusion across the BBB was estimated to be almost 10 times more rapid (1.56 L/h) than across the BCSFB (0.176 L/h). Conclusion: The developed PBPK model succeeded in capturing the pharmacokinetic profiles of metronidazole in plasma, brain ECF and CSF. It will then be used to make simulations in various dosing regimen or/and physio-pathological situations.

Mots clés: Physiologically-Based Pharmacokinetic model; metronidazole; CNS distribution; ICU patients

Domaines: Sciences du Vivant [q-bio]; Sciences pharmaceutiques

Alexia Chauzy, Salim Bouchène, Nicolas Grégoire, William Couet, Olivier Mimoz, et al.. A minimal physiologically-based pharmacokinetic model to investigate CNS distribution of metronidazole in ICU patients. 39ème Réunion Interdisciplinaire de Chimiothérapie Anti-Infectieuse (RICAI), Dec 2019, Paris, France. ⟨hal-02528416⟩