Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis

Abstract

Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using ~10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease.

Keywords: PBPK; linezolid; tuberculous meningitis.

Figure 1

Schematic outline of the PBPK model, including four CNS compartments, adapted from Verscheijden et al. (2019) [20], with permission. Qsin and Qsout represent CSF shuttle flow between cranial CSF and spinal CSF compartments. Qssink and Qcsink are the flows from CSF compartments to blood. Qbulk represents bulk flow from brain mass to cranial CSF. PSB, PSC, and PSE represent permeability surface area products between brain blood and brain mass, brain blood and cranial CSF, and brain mass and cranial CSF, respectively. CLbout represents overall clearance of efflux transporters P-gp and BCRP expressing at BBB. Subscripts lu, br, ad, bo, he, ki, mu, sk, li, re, gu, sp, and ha denote lung, brain, adipose tissue, bone, heart, kidney, muscle, skin, liver, rest tissue, gut, spleen, and hepatic artery, respectively. CL is the total clearance from the model. IV is an intravenous dose, and oral is an oral dose route of administration.

Figure 2

Simulations of linezolid concentration–time profiles in plasma (A–E) and cranial CSF (F–J) in critically ill adult and paediatric patients. Figures relate to intravenous administration of 600 mg linezolid twice daily for >two days in adults, as well as 10 mg/kg intravenous administration twice daily for two days in children (0.25–21 years). The x-axis indicates time after the last dose. The solid black lines indicate mean simulated profiles, the grey areas represent the area between the 16th and 84th percentile (equal to the standard deviation) of the mean, and the dotted lines indicate the 5th and 95th percentiles of the mean. Closed dots indicate measured individual data derived from the literature [6], and open circles indicate the mean with reported standard deviation derived from the literature [5,7,8,33]. The names in the headings of the figures relate to the first authors of the papers from which clinical data points were derived.

Figure 3

Simulations of linezolid concentration–time profiles in plasma and cranial CSF in adults (A,B) and paediatric (C,D) TB patients. The results relate to oral administration of 600 mg (adults) or 9.24 mg/kg (children; 0.6–9.4 years) linezolid twice daily. The x-axis indicates time after the last dose. The solid black lines indicate simulation of the mean profile, the grey areas represent the area between the 25th and 75th percentile (A,B) or 16th and 84th percentile (equal to the standard deviation) of the mean (C,D), and the dotted lines indicate the 5th and 95th percentiles of the mean. Open black circles and open light grey squares indicate median with interquartile range from the literature [30,31]. Closed dots indicate measured individual data derived from literature [29]. Dashed horizontal line indicate the MIC value of 1 mg/L linezolid for Mycobacterium tuberculosis [30,31]. In the clinical studies, linezolid was provided in addition to standard care.

Figure 4

Simulations of linezolid concentration–time profiles in plasma and cranial CSF after 300 mg BID (A,B) and 1200 mg QD (C,D) in adult TB patients. The x-axis indicates time after the last dose. The solid black lines indicate simulation of the mean profile, and the dotted lines indicate the 5th and 95th percentiles of the mean. Simulations were performed based on plasma PK parameters values in adult TB patients as described by Diacon et al. (2020) [32]. Dashed horizontal lines indicate the MIC value of 1 mg/L linezolid for Mycobacterium tuberculosis [30,31]. In the clinical study provided, linezolid was provided as a monotherapy.