Midazolam

Additional information

Women on average display higher expression and activity of CYP3A4. Sex-related differences in exposure could be of relevance for several substrates of the CYP3A family [1].

Pharmacokinetics and dosing

Midazolam is a model substrate of the CYP3A family of drug metabolizing enzymes, which makes it a widely used probe substance for drug interaction studies.

Based on three meta-analyses, the mean weight-adjusted clearance of midazolam appears to be approximately 10-30 % higher in women than in men [2-4]. The clinical significance of this difference is likely to be small in most circumstances, especially since midazolam is typically titrated to effect based on clinical response during repeated dosing or continuous infusion.

Sex differences in volumes of distribution of midazolam appear less investigated. Women have larger volumes of distribution for midazolam according to FDA approved drug label information, not specifying the magnitude of sex differences [5]. In a pharmacokinetic study of 21 women and 19 men, mean weight-adjusted (L/kg) central volumes of distribution were approximately 40-70 % higher in the women depending on age category [5]. Mean weight-adjusted total volumes of distribution were approximately 30-50 % higher in the women [6]. Interestingly, no information regarding sex differences in the pharmacokinetics of midazolam is provided in the Swedish summary of product characteristics [7].

Slightly higher weight-adjusted loading (mg/kg) and maintenance doses (mg/kg/h) would be expected in women in order to reach similar systemic exposures, based on the assumption of higher weight-adjusted volumes of distribution and clearance. However, in the absence of established therapeutic intervals for midazolam there is no obvious rationale for sex differentiated dosing recommendations. Dose titration based on individual clinical response, without regarding patient’s sex, seems prudent until further knowledge emerges.

Effects

No information regarding sex differences in the therapeutic effects of midazolam is provided by the pharmaceutical company [5, 7]. A number of clinical trials have addressed the influence of patient’s sex on the anxiolytic, sedative and cardiorespiratory effects of midazolam, mainly in the context of anesthetic premedication or procedural sedation. These studies are described below.

The clinical trial with the most relevant sex analysis, which also included plasma concentration measurements, involved 398 patients (195 women, 203 men) randomly assigned to receive one of four weight-adjusted doses of midazolam (0.05-0.15 mg/kg) intramuscularly 45 minutes before general or local anesthesia for elective surgical or orthopedic procedures [8]. The male subjects achieved higher sedation scores on average in all four dose groups (approximately 0.3-0.5 points higher on a 4-point scale, P<0.05 for the three highest dose groups) and significantly more men in the highest dose group required airway support (11/53=21% vs. 1/51=2% of female subjects, P<0.01). Twenty patients (10 female, 10 male) in the highest dose group were randomly selected for plasma concentration measurement of midazolam immediately after sedation and respiratory assessments, and showed approximately 25 % higher mean concentrations in the male subjects (171±30 ng/mL vs. 137±31 ng/mL in the females). The clinical endpoints of sedation and airway patency were arguably more prone to confounding than the plasma concentration measurements, which support the previously suggested pharmacokinetic differences between men and women.

Two additional studies have been identified which support the notion that weight-adjusted doses of midazolam might result in slightly higher mean sedation levels in men [9]. Instead, similar (fixed) doses of midazolam might render more similar pharmacological effects between men and women [10] respectively. One study has been identified which found no significant sex difference in sedation or cardiorespiratory parameters 15 minutes after weight-adjusted intramuscular doses of midazolam [11]. Plasma concentration measurements of midazolam were not performed in any of these three studies.

Potential pharmacodynamic sex differences of midazolam are likely to be dependent on the specific indication and effect of interest. Further research is required in order to properly elucidate concentration-effect relationships, but factors other than patient’s sex (e.g. age and comorbidities) are probably more important to consider. When careful individual titration to effects is exercised, the use of weight-adjusted or fixed dosing is arguably of minor relevance. 

Adverse effects

No studies with a clinically relevant sex analysis regarding the adverse effects of midazolam have been found. However, please refer to the above section regarding adverse effects in relation to systemic exposure.

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).