Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

Abstract

Nitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT exposure, there is still limited understanding of the interplay between NFT exposure, its disposition, and the risk of developing liver toxicity. In this study, we aim to develop a physiologically based pharmacokinetic (PBPK) model for NFT in three different species (rabbits, rats, and humans) that can be used as a standard tool for predicting drug-induced liver injury (DILI). We created several versions of the PBPK model using previously published kinetics data from rabbits, and integrated enterohepatic recirculation (EHR) using rat data. Our model showed that active tubular secretion and reabsorption in the kidney are critical in explaining the non-linear renal clearance and urine kinetics of NFT. We subsequently extrapolated the PBPK model to humans. Adapting the physiology to humans led to predictions consistent with human kinetics data, considering a low amount of NFT to be excreted into bile. Model simulations predicted that the liver of individuals with a moderate-to-severe glomerular filtration rate (GFR) is exposed to two-to-three-fold higher concentrations of NFT than individuals with a normal GFR, which coincided with a substantial reduction in the NFT urinary concentration. In conclusion, people with renal insufficiency may be at a higher risk of developing DILI due to NFT exposure, while at the same time having a suboptimal therapeutic effect with a high risk of drug resistance. Our PBPK model can in the future be used to predict NFT kinetics in individual patients on the basis of characteristics like age and GFR.

SWOT and Root Cause Analyses of Antimicrobial Resistance to Oral Antimicrobial Treatment of Cystitis

“…The self-medication of OAT also does not burden doctors or nurses as is the case with the parenteral administration of antimicrobials. The primary weaknesses of OAT are inter-individual variability in the clinical outcomes and AMR owing to inter-individual variability in pharmacokinetics [25,29,30,[96][97][98] and hepatobiliary vs. renal clearance [20] delaying the achievement of the minimum inhibitory concentration (MIC) in urine [23,87]. The oral bioavailability of OAT differs with race [32,99], food intake [97], inter-individual variability in the gastric emptying time [100], posture (supine or ambulatory) [101,102], and the general health status of the patient [103].…”

“…Weaknesses-inter-individual variability in oral absorption [25,96,97] and hepatobiliary vs. renal clearance [20,26,35,105] is compounded into a larger inter-individual variability in clinical outcomes and AMR.…”

“…The root cause analysis of AMR described here is limited to the factors within the intravesical space [25,113] that contribute to the determinations of antibiotic efficacy whereby OAT failures can provoke cystitis progression to pyelonephritis, urosepsis [10], and recurrent infections. The general factors that contribute to success of uropathogens, marked by AMR development rest with numbers and time, i.e., higher bacterial loads existing for longer time are likely to evolve AMR for dissemination [5][6][7].…”

“…The variability in the initial drug concentration due to variable absorption from the gut [25,32,[96][97][98][99][100][101][102][103], hepatobiliary vs. renal clearance delaying the achievement of the MIC in urine [20,23,28,30,87,101,105,109], and variability in urine in-flow rate of 0.3-15 mL/min (~50× difference) [26,56] could reduce the delay in achieving the urinary MIC; B.…”

“…From a clinical perspective, AMR refers to a microbial phenotype capable of surviving the exposure to a drug treatment course at a concentration anticipated to prevent its survival [20]. While the efficacy of antimicrobials for treating systemic infections (bacteriemia) can be reliably indexed by the plasma levels of antimicrobials above the minimum inhibitory concentration (MIC), the killing of the uropathogens causing cystitis is determined by urine levels above the MIC [23][24][25][26]. As illustrated by over 40-year-old studies on oral [27] and intravenous Fosfomycin [28], the delay in oral absorption and urinary excretion leads to a significant delay in urinary MIC in the treatment of uncomplicated cystitis [29,30] and could foster AMR development, which has not received adequate attention.…”