Exploring the Impact of Developmental Clearance Saturation on Propylene Glycol Exposure in Adults and Term Neonates Using Physiologically Based Pharmacokinetic Modeling

TL;DR

This study uses models to explore how propylene glycol metabolism and toxicity differ in adults and newborns, focusing on enzyme saturation.

Contribution

The study introduces PBPK models to assess developmental clearance saturation of propylene glycol in adults and term neonates.

Findings

PBPK models accurately described propylene glycol pharmacokinetics in adults and neonates.

Dosing regimens affecting saturation and toxicity depend on dose amount and frequency.

Daily doses up to 200 mg/kg/day in adults and 50 mg/kg/day in neonates are unlikely to cause toxicity.

Abstract

Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)‐mediated clearance pathway. This study aims to explore the impact of the saturation of ADH‐mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (Vmax) and Michaelis–Menten's constant (Km) of ADH‐mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug‐related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The Vmax and Km of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100‐200 mg/kg/day in adults and 25‐50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation.

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