Zolpidem: Pharmacokinetics, Pharmacodynamics, and Clinical Evidence Overview

Pharmacokinetic-Pharmacodynamic Relationship

Due to safety concerns associated with zolpidem—including impaired driving, somnambulism, and the risk of traffic accidents—the Pharmacovigilance Risk Assessment Committee (PRAC) requested data on the pharmacokinetic-pharmacodynamic (PK-PD) relationship, particularly regarding 5mg and 10mg doses and their effects on special populations.

While several studies have examined zolpidem’s pharmacokinetics (PK) and pharmacodynamics (PD), direct analyses of PK-PD relationships are limited. In total, six key publications were reviewed:

• Only one study (Richens et al., 1993) directly compared PK-PD effects at the 5mg and 10mg levels. The study found only slight differences in pharmacodynamic outcomes such as saccade velocity, Critical Flicker Fusion Threshold (CFFT), reaction time, and mood between these doses.
• Other studies focused on comparisons with different medications or higher zolpidem doses (10mg and 20mg) (Greenblatt et al., 1998; Drover et al., 2000; Allain et al., 1995; De Hass et al., 2010; Greenblatt et al., 2000).

Overall, the evidence indicates a dose-dependent PK-PD relationship for most pharmacodynamic parameters. Specifically, De Hass et al. (2010) highlighted how variables such as eye movement control, alertness levels, body sway, pharmaco-EEG, and adaptive tracking are influenced by rapid increases in zolpidem plasma levels.

Most studies reported that pharmacodynamic effects return to baseline approximately 8 hours post-dose. However, these studies primarily involved small groups of healthy volunteers.

Special Populations

• Gender: Women exhibited approximately 45% higher plasma exposure (Cmax and AUC) compared to men. About half of this difference was attributed to lower average body weight in women, leading to slightly higher mg/kg dosing. The remaining difference (~25%) was not statistically significant.
• Age: Clearance in children was found to be three times higher than in young adults, resulting in similar overall exposure despite higher mg/kg doses. Elderly individuals exhibited reduced clearance and increased exposure, prompting the recommendation of a 5mg/day starting dose.
• Weight: Obese individuals had lower Cmax values due to larger distribution volumes and smaller mg/kg doses. Absorption was slower, and half-life slightly increased, but dose adjustment was not considered necessary.
• Liver Function: In patients with hepatic impairment, Cmax doubled, AUC increased fivefold, and half-life tripled compared to healthy adults. Despite this, the duration and onset of drowsiness remained comparable. A starting dose of 5mg/day is recommended for these patients.
• Renal Function: Patients undergoing haemodialysis eliminated zolpidem more slowly, with a 20% increase in AUC compared to healthy adults. In individuals with chronic renal insufficiency not yet on dialysis, AUC increased by 60%, and the half-life doubled. However, these differences were not substantial enough to warrant dose adjustment.
• Race: No significant differences in zolpidem pharmacokinetics were observed across racial groups.

Randomised Controlled Clinical Trials (RCTs)

Adult Population

In total, 19 clinical studies contributed to zolpidem’s development, including seven pivotal double-blind, randomized controlled trials (RCTs) and 12 supportive studies. Of the pivotal studies, three focused on dose-finding at the 5mg level, while the others primarily assessed 10mg and higher doses.

Key Dose-Finding Studies

• Study MR113 (Roth et al., 1995): A randomized, double-blind, placebo-controlled trial evaluated five zolpidem doses (5mg, 7.5mg, 10mg, 15mg, 20mg) in 462 healthy adults with transient insomnia. Using polysomnography (PSG), the study found that 7.5mg and 10mg doses significantly improved all PSG sleep parameters. The 5mg dose showed only mild, non-significant improvements in sleep latency for both men and women. Post-hoc analysis revealed no gender-based differences in efficacy, and weight adjustments did not influence these results.
• Study MR114: This single-centre, double-blind, randomized trial evaluated zolpidem doses of 5mg, 10mg, 15mg, and 20mg in 34 healthy volunteers aged 18-60 years. The study assessed sleep quality using PSG, questionnaires, psychomotor tests, and daytime sleep latency. Results showed mixed, mostly non-significant effects. Due to the small sample size and low female participation, gender-specific analyses were not feasible.
• Study MR115: A multicentre, double-blind, placebo-controlled study assessed zolpidem’s hypnotic efficacy and safety at doses of 5mg, 10mg, and 20mg in 114 adults (71 women, 43 men) with chronic insomnia. Sleep parameters were measured both in a sleep lab (nights 1, 2, and 8) and at home (nights 3-7) using PSG and questionnaires.

Conclusion

Overall, zolpidem demonstrates a dose-dependent PK-PD relationship, with various patient factors—such as gender, age, weight, and hepatic function—playing important roles in pharmacokinetic variability. However, except for elderly individuals and those with hepatic impairment, standard dose adjustments are generally not necessary. Clinical trials show optimal efficacy at 7.5mg and 10mg doses, while the 5mg dose presents more modest improvements. Gender and weight do not appear to significantly affect treatment efficacy, supporting current dosing recommendations. (https://medicaldeviceevents.com)