A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications.

Sundus Khalid,Abdul Majeed,Hamid Saeed,Faleh Alqahtani,Imran Imran,Muhammad Fawad Rasool,Anees Ur Rehman,Yousef A Bin Jardan,Waseem Ashraf,Tanveer Ahmad

doi:10.3390/pharmaceutics13091480

Abstract

Diazepam is one of the most prescribed anxiolytic and anticonvulsant that is administered through intravenous (IV), oral, intramuscular, intranasal, and rectal routes. To facilitate the clinical use of diazepam, there is a need to develop formulations that are convenient to administer in ambulatory settings. The present study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for diazepam that is capable of predicting its pharmacokinetics (PK) after IV, oral, intranasal, and rectal applications using a whole-body population-based PBPK simulator, Simcyp®. The model evaluation was carried out using visual predictive checks, observed/predicted ratios (Robs/pred), and the average fold error (AFE) of PK parameters. The Diazepam PBPK model successfully predicted diazepam PK in an adult population after doses were administered through IV, oral, intranasal, and rectal routes, as the Robs/pred of all PK parameters were within a two-fold error range. The developed model can be used for the development and optimization of novel diazepam dosage forms, and it can be extended to simulate drug response in situations where no clinical data are available (healthy and disease).

Highlights

This study aims to develop a physiologically based pharmacokinetic (PBPK) model in a healthy population for the prediction and evaluation of diazepam pharmacokinetics after the administration of the drug through different routes, i.e., IV, oral, intranasal, and rectal
The visual predictive checks showed that the developed model successfully predicted diazepam PK after its IV administration within the dose range of 2–10 mg
Our diazepam PBPK model successfully predicted diazepam PK in the adult population after doses administered through IV, oral, intranasal, and rectal routes

Summary

Introduction

The amnesic and anxiolytic properties of benzodiazepines make this pharmacological class clinically useful in several indications, including insomnia, anxiety, muscle relaxation, and epilepsy, but their use is associated with several unwanted side effects [1,2]. Diazepam is the most commonly prescribed medium potency long-acting drug [3,4]. Diazepam is uniquely metabolized in the liver into a pharmacologically active metabolite, N-desmethyldiazepam, by demethylation and hydroxylation [2,5,6]. Diazepam shows wide interindividual variability in its metabolism, which results in marked differences in its systemic concentrations.

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