Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets

Abstract

Ingesting food can impact the pharmacokinetics of sedative-hypnotic drugs. A buffered zolpidem sublingual tablet (ZST) recently became available for the treatment of middle-of-the-night awakening. In this randomized, open-label, single-site study, the pharmacokinetic profile of ZST was evaluated when administered while fasting and following a standard high-fat meal (fed state). Healthy adults aged 18-64 years received a single morning dose of 3.5 mg ZST in the fed or fasting state. From 20 min to 3 h post-dose, zolpidem plasma levels were lower in the fed state compared to the fasting state. After 4 h post-dose (corresponding to "morning wake time"), higher zolpidem plasma levels were evident in the fed state. Area under the concentration-time curve (AUC) values for the 0-8 h interval were 160 ng/mL h in the fed state and 203 ng/mL h in the fasting state (P < .001). In the fed versus fasting states, Cmax was 32.0 ng/mL versus 57.3 ng/mL (P < .001), respectively, and Tmax was 3.0 h versus 0.92 h (P < .001), respectively. Together these data suggest that administration of ZST in the fed state is not optimal for maximizing the likelihood of therapeutic benefit and minimizing the probability of residual sedation.

Comparative bioavailability of two zolpidem hemitartrate formulations in healthy human Brazilian volunteers using high‐performance liquid chromatography coupled to tandem mass spectrometry

“…As demonstrated by Greenblatt et al (), the AUC averaged 40–50% higher in females than in males receiving the same dose. In our study (Table and Figure ), C max , AUC, half‐life, elimination constant, volume of distribution and clearance showed statistically significant differences when comparing women (604.34 ng h/ml, 127.36 ng/ml, 4.4 h, 0.18 1/h, 50.56 L and 8.55 L/h, respectively) and men (276.1 ng h/ml, 70.9 ng/ml, 3.3 h, 0.26 1/h, 91.42 L and 24.34 L/h, respectively), receiving the same dose (5 mg).…”

“…As demonstrated by Greenblatt et al (2013), the AUC averaged 40-50% higher in females than in males receiving the same dose. In our study (Table 4 and Figure 4), C max , AUC, half-life, elimination constant, volume of distribution and clearance showed statistically signifi- Based on intra-subject CV for C max (14.30%) and for AUC last (13.51%), it is proposed that 14-16 volunteers should be used for future bioequivalence studies of zolpidem.…”

“…The sublingual tablet (1.75 mg women; 3.5 mg for men) is indicated for middle-of-the-night wakefulness, oral spray (5 mg) for difficulty with sleep initiation and nasal spray (1.75 mg, 3.5 mg, 5.0 mg) for sleep initiation difficulty and middle-ofthe-night awakening (Greenblatt & Roth, 2012;Hoehns & Perry, 1993;Holm & Goa, 2000;Langtry & Benfield, 1990;Li et al, 2016;Neubauer, 2010;Pergolizzi, Taylor, Raffa, Nalamachu, & Chopra, 2014;Salva & Costa, 1995;Swainston Harrison & Keating, 2005). The pharmacokinetics of zolpidem by sublingual administration is influenced by food intake and gender (Greenblatt et al, 2013;Greenblatt et al, 2014;Li et al, 2016;Pergolizzi et al, 2014).…”

In-vitro–in-silicoinvestigation of the negative food effect of zolpidem when administered as immediate-release tablets

“…The clinical study was conducted exclusively in male patients, which is worth noting because women tend to exhibit higher zolpidem exposure than men. Interestingly, a gender effect on the pharmacokinetics of zolpidem has been reported not only for immediate‐release tablets but also for other types of zolpidem formulation, such as sublingual and modified‐release tablets (Ambien CR ® ) …”

“…Interestingly, a gender effect on the pharmacokinetics of zolpidem has been reported not only for immediate-release tablets but also for other types of zolpidem formulation, such as sublingual and modified-release tablets (Ambien CR â ). [15,16,33,34] Dissolution experiments used to build the PBPK model for zolpidem in the fasted state…”