Pharmacokinetics Of Oral Midazolam Research Articles

A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

The Impact of Suboptimal 25-Hydroxyvitamin D Levels and Cholecalciferol Replacement on the Pharmacokinetics of Oral Midazolam in Control Subjects and Patients With Chronic Kidney Disease.

The aim of this study was to investigate the impact of suboptimal 25-hydroxyvitamin D (25-VitD) and cholecalciferol (VitD3 ) supplementation on the pharmacokinetics of oral midazolam (MDZ) in control subjects and subjects with chronic kidney disease (CKD). Subjects with CKD (n=14) and controls (n=5) with suboptimal 25-VitD levels (<30ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD3 (5000IU) and MDZ (2mg). In phase 2 (replete) subjects who achieved 25-VitD repletion after receiving up to 16 weeks of daily cholecalciferol were given the identical single oral doses of VitD3 and MDZ as in phase 1. Concentrations of MDZ and metabolites, 1'-hydroxymidazolam (1'-OHMDZ), and 1'-OHMDZ glucuronide (1'-OHMDZ-G) were measured by liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Under suboptimal 25-VitD, reductions in MDZ clearance and renal clearance of 47% and 87%, respectively, and a 72% reduction in renal clearance of 1'-OHMDZ-G were observed in CKD vs controls. In phase 1 versus phase 2, MDZ clearance increased in all control subjects, with a median (interquartile range) increase of 10.5 (0.62-16.7)L/h. No changes in MDZ pharmacokinetics were observed in subjects with CKD between phases 1 and 2. The effects of 25-VitD repletion on MDZ disposition was largely observed in subjects without kidney disease. Impaired MDZ metabolism and/or excretion alterations due to CKD in a suboptimal 25-VitD state may not be reversed by cholecalciferol therapy. Suboptimal 25-VitD may augment the reductions in MDZ and 1'-OHMDZ-G clearance values observed in patients with CKD.

Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses.

Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem. We enrolled 12 healthy volunteers in a trial investigating the dose-exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05-500mg) and assessed the effect of 0.1and 500mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003mg). Chlorzoxazone area under the concentration-time curve was dose-linear in the dose range between 0.05and 5mg. A nonlinear increase occurred with doses ≥50mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration-time curve increased 2-fold when coadministered with 500mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses. The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.

Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6β-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.

The oral plasma clearance of midazolam and the ratio of 6β-hydroxycortisol (6β-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6β-OHF/F in healthy Chinese. Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6β-OHF concentrations were measured using UPLC. There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6β-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6β-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6β-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6β-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.

Effect of moxidectin on CYP3A4 activity as evaluated by oral midazolam pharmacokinetics in healthy subjects.

In order to evaluate the potential for CYP3A4 induction by moxidectin, midazolam pharmacokinetic (PK) parameters were compared before and after moxidectin administration. Healthy subjects received a single 8 mg dose of moxidectin and 3 single 7.5 mg doses of midazolam 3 days before, and 7 and 89 days after the moxidectin. Blood samples were taken for 24 hours to measure midazolam and metabolites in plasma, and for 89 days to measure moxidectin in plasma after dose administration. Noncompartmental PK analyses were performed for each analyte. Analysis of variance was performed on log-transformed midazolam parameters with treatment day as a fixed effect. Adverse events were recorded and laboratory tests, physical examinations, pulse oximetry monitoring, vital sign measurement, and electrocardiograms performed. Thirty-nine subjects were enrolled in the study; PK data were available for 37 subjects. Moxidectin PK parameters were similar to previous studies. There were no significant changes in PK for midazolam or its metabolites 7 or 89 days after moxidectin administration. Adverse events were generally mild and there were no relevant changes in safety assessments. Thus, 8 mg moxidectin does not induce CYP3A4 activity and other CYP3A4 substrates are unlikely to be affected by moxidectin co-administration.

The Effect of Ticagrelor on the Metabolism of Midazolam in Healthy Volunteers

BackgroundIn vitro studies have demonstrated that ticagrelor, an oral antiplatelet agent, is a substrate, activator, and inhibitor of cytochrome P450 (CYP) 3A. Thus, potential CYP3A-mediated drug–drug interactions may occur. ObjectivesThe goal of this article was to report study results on the effect of ticagrelor on the pharmacokinetics of oral midazolam (oral midazolam study) and oral versus intravenous (IV) midazolam (oral/IV midazolam study). Secondary objectives included assessing the effect of midazolam on ticagrelor pharmacokinetic parameters, and the safety and tolerability of ticagrelor/midazolam coadministration. MethodsTwo randomized crossover studies were conducted in healthy volunteers (n = 28 in each) with ticagrelor and midazolam. In the first study, volunteers received oral ticagrelor (400 mg daily) or placebo for 6 days, then oral midazolam (7.5 mg). The second study regimen was a single dose of ticagrelor 270 mg, then ticagrelor 180 mg BID for 6 days with a single oral (7.5 mg) or IV (2.5 mg) dose of midazolam. ResultsAfter oral midazolam administration, ticagrelor significantly reduced the AUC0–∞ of midazolam (30%–32%) and 4-hydroxymidazolam (42%–47%) but not 1-hydroxymidazolam. After administration of IV midazolam, ticagrelor reduced the AUC0–∞ of midazolam (12%) and 4-hydroxymidazolam (23%) but not 1-hydroxymidazolam. ConclusionsThese results indicate that ticagrelor can weakly activate the metabolism of midazolam to its major 1′-hydroxy metabolite, and at the same time, seems to weakly inhibit midazolam 4′-hydroxylation. Furthermore, ticagrelor affects both hepatic and intestinal CYP3A activity.

Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate

Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders. Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference). The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56-0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39-0.53) compared to volunteers. The mean area under the concentration-time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively. The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.

In vivo effect of Schisandrin B on cytochrome P450 enzyme activity

To investigate the possible drug interaction, this study is designed to evaluate the ability of Schisandrin B (Sch B) to modulate cytochrome P450 3A activity (CYP3A) in vivo and to alter the pharmacokinetic profiles of CYP3A substrate (midazolam) in treated rats. Rats were repeated administered with physiological saline (negative control group), ketoconazole (75mg/kg, positive control group) or varied doses of Sch B (experimental groups) for three consecutive days. Subsequently, changes in hepatic microsomal CYP3A activity and the pharmacokinetic profiles of midazolam and 1′-hydroxy midazolam in plasma were studied to evaluate CYP3A activity. The results indicated that Sch B significantly dose-dependently inhibited rat hepatic microsomal CYP3A activity with Ki value of 16.64mg/kg and showed the characteristic of a noncompetitive inhibitor. Oral administration of Sch B for 3 days in rats produced significant effect on the pharmacokinetics of oral midazolam. Sch B resulted in a significant, dose-dependent increase in midazolam AUC0−∞ except at the dose of 2mg/kg, while AUC0−∞ increased by 26.1% (8mg/kg) and 60.6% (16mg/kg), respectively. In the pharmacokinetic profiles of 1′-hydroxy midazolam, the significant, dose-dependent decrease in AUC0−∞ was observed except at the dose of 2mg/kg, while AUC0−∞ reduced by 44.5% (8mg/kg) and 49.2% (16mg/kg), respectively. These results suggested that 3-day treatment of Sch B could increase concentration and oral bioavailability of drug metabolized by CYP3A. When the drug, consisting of Sch B, is used in the clinic for more than 3 days, the possible drug–drug interactions should be taken into consideration.

A Semi‐Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics

Physiological changes in pregnancy, including changes in body composition and metabolic enzyme activity, can alter drug pharmacokinetics. A semi-mechanistic metabolism model was developed to describe the pharmacokinetics of two cytochrome P450 3A (CYP3A) substrates, midazolam and nifedipine, in obstetrics patients. The model parameters were optimized to fit the data of oral midazolam pharmacokinetics in pregnant women, by increasing CYP3A-induced hepatic metabolism 1.6-fold in the model with no change in gut wall metabolism. Fetal metabolism had a negligible effect on maternal plasma drug concentrations. Validation of the model was performed by applying changes in volume of distribution and metabolism, consistent with those observed for midazolam, to the pharmacokinetics parameters of immediate-release nifedipine in healthy volunteers. The predicted steady-state areas under the concentration–time curve (AUCs) for nifedipine were within 15% of the data observed in pregnant women undergoing treatment for preterm labor. This model predicts the pharmacokinetics of two CYP3A substrates in pregnancy, and may be applicable to other CYP3A substrates as well.

Rifampin's Acute Inhibitory and Chronic Inductive Drug Interactions: Experimental and Model-Based Approaches to Drug–Drug Interaction Trial Design

We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.

Effect of Saquinavir‐Ritonavir on Cytochrome P450 3A4 Activity in Healthy Volunteers Using Midazolam as a Probe

To investigate the inhibitory potential of multiple doses of ritonavir-boosted saquinavir on the pharmacokinetics of oral midazolam, a cytochrome P450 (CYP) 3A4 model substrate. Prospective, open-label, one-sequence, two-period crossover study. Clinical pharmacology unit in the United Kingdom. Eighteen healthy adult male and female volunteers (median age 37.5 yrs). Intervention. A single oral dose of midazolam 7.5 mg was administered on day 1. A second dose was administered on day 16, after 14 days of oral saquinavir 1000 mg-ritonavir 100 mg twice/day. Serial blood samples were taken for measurement of plasma concentrations of midazolam and its metabolite, 1'-hydroxymidazolam. Pharmacokinetic parameters of midazolam and 1'-hydroxymidazolam were determined when midazolam was given alone (day 1) and after coadministration with saquinavir-ritonavir for 14 days (day 16). Two weeks of treatment with saquinavir-ritonavir resulted in a 4.3-fold increase in maximum plasma concentration (C(max)) and a 12.4-fold increase in the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for midazolam. Midazolam's half-life increased from 4.7 to 14.9 hours. Concomitant reductions for 1'-hydroxymidazolam were approximately 7-fold for C(max) and 2-fold for AUC(0-infinity). The 1'-hydroxymidazolam AUC(0-infinity):midazolam AUC(0-infinity) ratio was only 1% during coadministration of midazolam with saquinavir-ritonavir compared with 33% for midazolam alone. Adverse-event reports indicated that the combination of saquinavir, ritonavir, and midazolam was well tolerated but resulted in prolonged sedation. Administration of ritonavir-boosted saquinavir markedly increased the exposure of midazolam by inhibiting its metabolism, confirming that the combination of saquinavir and ritonavir at steady state strongly inhibits CYP3A4 activity.

Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe

Phenotyping intestinal and hepatic cytochrome P450 (CYP) 3A activity with oral midazolam can be limited by midazolam-induced central nervous system (CNS) side effects. Determining methods to minimize CNS side effects optimizes use of midazolam as a CYP3A probe. The objective of this study was to determine the effect of intravenous (i.v.) flumazenil on midazolam apparent oral clearance (a surrogate marker of CYP3A activity). Midazolam pharmacodynamics were also evaluated. This was a randomized, double-blind, placebo-controlled, single-dose, two-way crossover study. 16 healthy volunteers (8 women) were concomitantly administered i.v. flumazenil 0.005 mg/kg or i.v. placebo and oral midazolam 0.075 mg/kg. Blood samples were obtained to determine midazolam and flumazenil plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMR) and 90% confidence intervals (90% CI). Baseline and post dose digit symbol substitution tests (DSST), Groton maze learning tests (GMLT), and Stanford sleepiness scales (SSS) were conducted. Apparent oral clearance was 2,030 +/- 651 and 1,939 +/- 658 ml/min for the midazolam plus flumazenil and midazolam plus placebo groups. Equivalence in midazolam apparent oral clearance was observed (%GMR flumazenil/placebo, 90% CI 104.8, 94 - 116.6%). Flumazenil partially attenuated oral midazolam pharmacodynamics. Exploratory post hoc analyses revealed that midazolam exposure was 1.9-fold higher in men compared to women. i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.

The Effect of Anxiety and Personality on the Pharmacokinetics of Oral Midazolam

The Effect of Anxiety and Personality on the Pharmacokinetics of Oral Midazolam

The effect of anxiety and personality on the pharmacokinetics of oral midazolam.

We investigated the relationship between the pharmacokinetic variables of oral midazolam and patients' state/trait anxiety and personality. Twenty-six patients received the standard 15-mg oral dose for anxiolysis on the evening before otorhinolaryngological surgery. Blood samples were taken over a 9-h period after the administration, and the samples were analyzed for concentrations of midazolam and its two main metabolites by using a gas chromatography-mass spectrometry procedure. The pharmacokinetic variables maximum concentration, time to reach the maximum concentration, the elimination half-life, and the area under the curve were calculated from these data. When the patients were divided into groups with respect to their anxiety and personality scores, no significant differences in the pharmacokinetic variables of midazolam could be found. Only small, insignificant changes in the maximum concentrations were found with respect to nervousness and emotionality. We conclude that personality traits and anxiety levels had no effect on the pharmacokinetic variables of midazolam. We conclude that personality traits and anxiety levels had no effect on the pharmacokinetic variables of midazolam. Therefore, it is not necessary to obtain anxiety or personality scores to find the proper midazolam dose for the individual patient.

The Effect of Anxiety and Personality on the Pharmacokinetics of Oral Midazolam

The Effect of Anxiety and Personality on the Pharmacokinetics of Oral Midazolam

Simvastatin Does Not Affect CYP3A Activity, Quantified by the Erythromycin Breath Test and Oral Midazolam Pharmacokinetics, in Healthy Male Subjects

Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.

Inhibition of hepatic and intestinal CYP3A4 by mibefradil measured by the erythromycin breath test (EBT) and oral midazolam pharmacokinetics (PK)

Inhibition of hepatic and intestinal CYP3A4 by mibefradil measured by the erythromycin breath test (EBT) and oral midazolam pharmacokinetics (PK)

Comparative pharmacokinetics of midazolam and loprazolam in healthy subjects after oral administration

The pharmacokinetics of oral midazolam (Dormicum, 15 mg) and loprazolam (Dormonoct, 1 mg) were studied in eight healthy young volunteers in a cross-over design. Plasma concentrations of midazolam were measured with a gas chromatographic method and loprazolam concentrations were determined by a radio-receptor technique. Absorption of midazolam proceeded very rapidly (median tmax = 0.4 h) and a rapid onset of sedative action was observed. Loprazolam absorption was relatively slow (median tmax = 3 h) and its absorption profile was often irregular. Most subjects fell asleep before peak concentrations were reached. Median peak concentrations were 94 ng ml-1 and 3.1 ng ml-1 for midazolam and loprozolam, respectively. The median elimination half-life of midazolam was 1.8 h and that of loprazolam 15 h. It is possible that the elimination half-life of loprazolam as determined by radioreceptor assay is determined by active metabolites rather than by loprazolam itself. Midazolam elimination half-life was the same when determined by radioreceptor assay or by GLC. There was no significant correlation between the half-lives of the two drugs.