Senior Research Scientist Clinical Trial & Consulting (CTI), United States
Disclosure(s):
Leyanis Rodriguez Vera: No financial relationships to disclose
Objectives: To evaluate the influence of obesity on the pharmacokinetics (PK) of midazolam oromucosal solution in adults and assess whether dose adjustment is needed in obese individuals.
Methods: A population PK model of midazolam and its equipotent active metabolite was used as the basis for simulations [1-3]. The model incorporated dual absorption pathways—buccal and gastrointestinal (GI)—and was initially developed using Phase I study data from adults ≤70 years with BMI < 34 kg/m². To explore the impact of obesity, the model was extended to include literature-derived effects of BMI and weight on GI absorption and distribution parameters [4]. Simulations were performed in virtual adult populations stratified by obesity class and age, evaluating exposure metrics (Cmax, AUC₀–₂₄) at 10 mg and 15 mg doses. Simulations were performed in NONMEM v7.5 and data handling and graphics were done with R-software version 4.3.1 (www.r-project.org).
Results: Cmax decreased progressively with increasing BMI, consistent with slower GI absorption and increased distribution volume. However, AUC₀–₂₄ remained stable across BMI categories due to the dominant buccal absorption (~74%) and the equipotency of midazolam and its metabolite, whose combined exposures determine pharmacologic activity. A modest increase in AUC was observed in morbid obesity. Simulated exposures for the 10 mg dose were within the reference range in normal-weight adults, supporting the adequacy of this dose across BMI groups. The reduction in Cmax was therefore not clinically significant and did not impact predicted efficacy.
Conclusions: The 10 mg midazolam oromucosal dose provides safe and effective exposure levels across adult BMI categories, without the need for dose adjustment in obesity. The combined effect of buccal absorption and equipotent active moieties ensures robust systemic exposure. These findings support a weight-independent dosing strategy and reinforce the utility of this formulation for rapid, socially acceptable seizure intervention in community settings.
Citations: 1. Bauer, T. M., Ritz, R., Haberthür, C., Ha, H. R., Hunkeler, W., Sleight, A. J., Scollo-Lavizzari, G., & Haefeli, W. E. (1995). Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet (London, England), 346(8968), 145–147. 2. Mandema, J. W., Tuk, B., van Steveninck, A. L., Breimer, D. D., Cohen, A. F., & Danhof, M. (1992). Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clinical pharmacology and therapeutics, 51(6), 715–728. 3. Ziegler, W. H., Schalch, E., Leishman, B., & Eckert, M. (1983). Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites. British journal of clinical pharmacology, 16 Suppl 1(Suppl 1), 63S–69S. 4. Brill, M. J. E., van Rongen, A., Houwink, A. P. I., Burggraaf, J., van Ramshorst, B., Wiezer, R. J., van Dongen, E. P. A., & Knibbe, C. A. J. (2014). Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: A comparison with healthy volunteers. Clinical Pharmacokinetics, 53(10), 931–941.
