Introduction

Zolpidem (ZPD) is a non-benzodiazepine sedative indicated for the treatment of insomnia. ZPD exhibits sex differences in pharmacokinetics, and females have higher systemic exposure than males. The recommended dose is 5 mg for women and 10 mg for men. The reduction in dose for females might be insufficient to produce the desired therapeutic efficacy. Hence, the dose adjustment is required to ensure the safety and efficacy of the therapy, especially in females.

Objective

The pharmacokinetics of ZPD were studied using the physiologically based pharmacokinetic model (PBPK) using covariates such as sex, body weight, and clearance with the objective of dose adjustment in females using virtual bioequivalence (VBE) studies.

Methods

The modeling and simulation were performed using Gastroplus 9.8.3 software. Various models published in the literature were screened. The selected model was modified and validated using intravenous and oral pharmacokinetic data. Three in silico VBE trials were carried out using males as a test and females as reference groups. The reference groups of females consist of three covariates such as weight, weight normalized, and clearance with weight normalized data. The rest of the validated model parameters were kept constant.

Results

The prediction errors of developed models were high (> 20%) for peak plasma drug concentration (C_max) and well within the limit for the area under the plasma drug concentration curve (AUC) in body weight normalized in female subjects with male subjects. Young females have 20% lower body weight when compared to males, and hence higher systemic exposure resulted in females due to body weight. The clearance rate was lesser in females when compared with males. However, higher CYP3A4-mediated metabolism was observed in females than in males. Moreover, there is no significant difference in systemic drug exposure (92.7% vs 104% AUC_0–i) due to the lower clearance rate in females.

ConclusionThe results obtained from virtual bioequivalence data suggest that the dose adjustment for females according to their body weight could be beneficial. Normal-weight females could be recommended with a 30% lower dose and overweight females with a normal dose of 10 mg.

By Rajkumar Malayandi, Arka Karmakar, Pratik Dhake, Adarsh Malgave, Subramanian Natesan & Ravichandiran Velayutham