Ji-yeong Byeon, Ki Soon Kim, Eben Jung, Seongmee Jeong, Woo-Yong Oh, Yoonsook Lee
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Republic of Korea
Objectives: In 2013, the recommended initial dose of zolpidem changed to 5 mg for female in FDA[1]. The concern is an increased driving impairment caused by Cmax and AUC of zolpidem, which are higher in female than in male. Unlike FDA’s decision, EMA highlighted the risk of re-administration due to lower dose during the same night which affects the increase of the next day’s driving impairment[2]. Therefore, we aimed to develop a population PK-PD model of zolpidem to evaluate the PK/PD difference in male and female Korean subjects and to examine the need for dose adjustment for Koreans.
Methods: 15 male and 15 female healthy subjects were administered a single oral dose of zolpidem 10 mg. Blood samples were collected up to 12 hours post-dose to determine plasma concentration of zolpidem. Digital Symbol Substitution Test (DSST) and Visual Analogue Scale (VAS) of sleepiness were used to evaluate PD of zolpidem (baseline, post-dose 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h). Popualation PK-PD analysis was used a sequential approach which was as follows: plasma concentrations of zolpidem were fitted first to a PK model and subsequently the relationships between DSST, VAS and zolpidem concentration were fitted to PD model. All models were developed using NONMEM (version 7.3). Simulations were performed using the final PK and PD model to evaluate the effect of change in doses, sex difference, need for dose adjustment in Koreans.
Results: The PK of zolpidem was adequately described by a 2-compartment model with erlang-type absorption with lag time followed by zero-order absorption with lag time. Body weight was identified as a covariate showing significant influence on the central volume (V2/F). The obeserved mean Cmax and AUC of zolpidem were not significantly different between male and female. The mean Cmax of zolpidem was 154.0 ng/mL in male and 172.9 ng/mL in female (P= 0.335) and the mean AUC of zolpidem was 506.81 ng*h/mL and 679.32 ng*h/mL, respectively (P=0.058). The simulated PK profiles were similar with the observed PK profiles. The simulated PK profiles of zolpidem 10 mg were not shown significantly different between male and female profiles. About 7% and 6% of simulated 2,500 male and female, respectively, exceeded the criteria (50 ng/mL, at high risk of traffic accidents) set by FDA after 8 hours, which was 0.4 times that of FDA results (15%).
The PK-PD relationship between DSST, VAS and plasma concentration of zolpidem was described by a direct effect model using sigmoid Emax model. The time to reach the maximum effect of DSST and VAS was similar with the time to maximum plasma concentration of zolpidem. After dosing, the maximum effect of DSST and VAS was shown at 32 out of 140 and 6 out of 10, respectively. There was no significant difference between male and female with respect to the simulated PK-PD profiles for DSST and VAS. When simulating the regimen of 5 mg BID in female group, the cognitive decline and sleepiness lasted two to three hours longer than when taking that of 10 mg QD.
Conclusions: The PK and PK-PD modelling of zolpidem were successfully developed and applied to analyze PK and PD data with regard to the effect of sex difference in Koreans. The results of modelling and simulation show that it is not necessary to reduce the dose of zolpidem in female from 10 mg to 5 mg and it may increase the chance of taking an oral dose of zolpidem ( 5 mg) again when reducing the dose of zolpidem in female. Also, since the score of DSST and VAS was not significantly different according to gender, the recommended dose of zolpidem in MFDS is reasonable.
References:
[1] https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-risk-next-morning-impairment-after-use-insomnia-drugs-fda-requires-lower
[2] https://www.ema.europa.eu/en/medicines/human/referrals/zolpidem-containing-medicines
Reference: PAGE 29 (2021) Abstr 9687 [www.page-meeting.org/?abstract=9687]
Poster: Drug/Disease Modelling - Safety