Midazolam Pharmacokinetics in Morbidly Obese Patients Following Semi-Simultaneous Oral and Intravenous Administration: A Comparison with Healthy Volunteers

Abstract

BackgroundWhile in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers.MethodsTwenty morbidly obese patients [mean body weight 144 kg (range 112–186 kg) and mean body mass index 47 kg/m2 (range 40–68 kg/m2)] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM®.ResultsIn the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min–1, P < 0.001].ConclusionsIn morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-014-0166-x) contains supplementary material, which is available to authorized users.

Drug Disposition in Obesity: Toward Evidence-Based Dosing

“…The significant difference in oral bioavailability reported in this study (87) may result from the larger body weights of the subjects compared to the previous study by Greenblatt et al (81), who reported no difference in bioavailability (mean body weight of 144 kg versus 117 kg). The observed higher bioavailability could be explained by an increased splanchnic blood flow (19), which may lead to reduced contact between midazolam and intracellular CYP3A enzymes in the gut wall.…”

“…This study design allowed for the characterization of both clearance and bioavailability in a single pharmacokinetic study. Results of this study show an increased bioavailability (60 ± 13% versus 28 ± 7%, P < 0.01) and a lower oral absorption rate (0.057 ± 14% min −1 versus 0.13 ± 5 min −1 , P < 0.01), but no influence of obesity on systemic clearance in morbidly obese patients compared to healthy volunteers (87). Dose simulations of the final population pharmacokinetic model showed that after a 7.5-mg oral midazolam, C max is only slightly lower, whereas T max is increased for morbidly obese patients (Figure 2c).…”

“…Also, the increase in bioavailability may be explained by increased paracellular absorption through the gut wall, or a combination of both (51,52,88,89). The higher midazolam bioavailability found in morbidly obese patients, however, does not seem to result in higher C max values (Figure 2c); this may be explained by the higher volume of distribution (87) which was also reported by Greenblatt et al (81). The lower absorption rate (and therefore increased T max ) in morbidly obese patients may be the result of the difference in midazolam formulation, as healthy volunteers received an oral solution and morbidly obese patients a tablet.…”

Adaptation posologique chez le sujet obèse

“…Ulvestad et al ont d'ailleurs décrit une diminution du contenu hépa-tique et intestinal en CYP3A4 avec l'IMC [22]. En revanche, dans une étude récente, Brill et al ont évalué la pharmacocinétique du midazolam administré par voie orale et par voie intraveineuse chez des sujets obèses et des sujets non obèses [23]. Ils ont montré que la biodisponibilité du midazolam était supérieure chez les sujets obèses, tandis que la clairance n'était pas modifiée (après administration orale ou intraveineuse), ces données allant dans le sens d'une diminution de l'effet de premier passage, voire d'une augmentation de la perméabilité intestinale chez les patients obèses.…”

Comment on van Rongen et al., “Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults”

“…The authors attributed a higher midazolam clearance in the obese adolescents group to higher cytochrome P450 3A enzyme activity when compared to the morbidly obese adults group. However, the surgery type in the obese adults appears to have been exclusively laparoscopic procedures, whereas the surgery in the obese adolescents appears to have been predominantly orthopaedic and otolaryngeal procedures [2,3]. Laparoscopy, with the associated pneumoperitoneum, has been shown to decrease portal venous blood flow by approximately half, with a paradoxical increase in hepatic artery blood flow by approximately 20%, and apparent effects on drug clearance [4].…”