Midazolam In Healthy Volunteers Research Articles

Physiologically-based pharmacokinetic modeling for investigating the effect of simeprevir on concomitant drugs and an endogenous biomarker of OATP1B.

The orally available anti-hepatitis C virus (HCV) drug simeprevir exhibits nonlinear pharmacokinetics at the clinical doses due to saturation of cytochrome P450 (CYP) 3A4 metabolism and organic anion transporting peptide (OATP) 1B mediated hepatic uptake. Additionally, simeprevir increases exposures of concomitant drugs by CYP3A4 and OATP1B inhibition. The objective of this study was to develop physiologically-based pharmacokinetic (PBPK) models that could describe drug-drug interactions (DDIs) of simeprevir with concomitant drugs via CYP3A4 and OATP1B inhibition, and also to capture the effects on coproporphyrin-I (CP-I), an endogenous biomarker of OATP1B. PBPK modeling estimated unbound simeprevir inhibitory constant (Ki ) of 2.89 μM against CYP3A4 in the DDI results between simeprevir and midazolam in healthy volunteers. Then, we analyzed the DDIs between simeprevir and atorvastatin, a dual substrate of CYP3A4 and OATP1B, in healthy volunteers, and unbound Ki against OATP1B was estimated to be 0.00347 μM. Finally, we analyzed the increase in the blood level of CP-I by simeprevir to verify the Ki,OATP1B . Because CP-I was measured in subjects with HCV with various hepatic fibrosis state, Monte Carlo simulation was performed to involve the decreases in expression levels of hepatic CYP3A4 and OATP1B and their interindividual variabilities. The PBPK modeling coupled with Monte Carlo simulation using the Ki,OATP1B value obtained from atorvastatin study reasonably recovered the observed relationship between CP-I and simeprevir blood levels. In conclusion, the simeprevir PBPK model developed in this study can quantitatively describe the increase in exposures of concomitant drugs and an endogenous biomarker via inhibition of CYP3A4 and OATP1B.

Drug-drug Interaction Studies with Coadministration of Cannabidiol (CBD) and Clobazam, Valproate, Stiripentol or Midazolam in Healthy Volunteers and Adults with Epilepsy

Drug-drug Interaction Studies with Coadministration of Cannabidiol (CBD) and Clobazam, Valproate, Stiripentol or Midazolam in Healthy Volunteers and Adults with Epilepsy

The Prediction of the Area under the Curve and Clearance of Midazolam from Single-Point Plasma Concentration and Urinary Excretion in Healthy Volunteers.

There are large inter- and intra-individual variations in CYP3A4 activity. Midazolam, which is predominantly metabolized to 1'-hydroxymidazolam and 4-hydroxymidazolam by CYP3A4, is considered an effective probe for CYP3A4. To determine the area under the curve (AUC) of midazolam or midazolam clearance for CYP3A4 activity, multiple plasma samples of midazolam are required. This study aimed to evaluate whether measurement of a single plasma concentration or urinary excretion of midazolam could be used to predict the AUC of midazolam in healthy volunteers. We conducted a retrospective analysis of two pharmacokinetic studies. Nineteen volunteers received intravenous (5, 15, and 30 µg/kg) and oral (15, 50, and 100 µg/kg) administration of midazolam on sequential days. The midazolam concentration in plasma and urine was determined by LC-MS/MS. Plasma midazolam concentrations showed a good correlation with the AUC at all blood sampling points after the administrations. The coefficient of determination was highest at 1-2 and 2-4 h after intravenous (>0.96) and oral administration (>0.94), respectively, among all the sampling times. The errors for bias and accuracy of prediction were the lowest at 1.5 and 4 h after intravenous and oral administration, respectively. In case of urinary excretion, a significant positive correlation between midazolam and the AUC was observed only after oral administration. Thus, the AUC of midazolam can be evaluated by blood sampling at 1.5 h after intravenous administration and at 4 h after oral administration.

Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers.

Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes.

Influence of Acetaminophen on Pharmacokinetics and Pharmacodynamics of Midazolam in Healthy Volunteers

Background: Midazolam and acetaminophen are often co-administered in anesthesia practice. Both are metabolized by CYP 3A4 enzyme in the liver, and hence compete for the enzyme sites. This might lead to reduced metabolic breakdown and enhanced pharmacodynamic effects of midazolam in the presence of acetaminophen. Methods: The present study was undertaken to test this hypothesis. After IRB approval from Mount Sinai Medical Center, 15 healthy volunteers were used for 2 tests. For the first test, they were randomly assigned to receive oral doses of either midazolam 0.3 mg/kg in cherry syrup (Protocol A), or midazolam 0.3 mg/kg plus cherry flavored acetaminophen 15 mg/kg (Protocol B). At set intervals from 0 to 480 min, the blood levels of midazolam and the subjects pulse rate, mean arterial pressure, respiratory rate, BIS index, and OAA/S scores were determined. After 2 weeks, the same subjects underwent the second test; they received the other medication protocol. Results: Acetaminophen slightly, but not significantly, increased the half life of blood midazolam, and the depressive effects of midazolam on the clinical signs of the subjects. Conclusion: These results lead us to conclude that there is no need to reduce the doses of midazolam when used in combination with acetaminophen.

Determination of Triazolam and Midazolam in Human Plasma Using Gas Chromatography with Microelectron Capture Detection for Clinical Application

A method for the simple and reliable determination of triazolam and midazolam in human plasma using gas chromatography with microelectron capture detection has been developed. Samples (0.5 mL of plasma) were prepared using a simple solvent extraction with 3% isoamyl alcohol/benzene in the presence of NaOH. Two microlitres of the extract were injected onto the capillary column ((5%-phenyl)-methylpolysiloxane). The method was found to be valid in terms of selectivity, linearity, precision, accuracy, and recovery over the concentration range of 0.2 to 20 ng/mL for triazolam, and from 0.5 to 200 ng/mL for midazolam, respectively. Intra- and inter-day precisions determined at three concentrations were from 4.1 to 9.3% for triazolam and from 2.9 to 13.0% for midazolam. The accuracies were within 17.7% for triazolam and within 13.0% for midazolam. This proposed method was successfully applied to a pharmacokinetic study of triazolam or midazolam in healthy volunteers.

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.

Lack of effect of tofacitinib (CP‐690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data

• Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.

Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers

Objectives: The aim of the study is to determine the effect of posaconazole, an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin.Methods: This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 – 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 – 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 – 13).Results: Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the Cmax and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC).Conclusion: These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

An open-label, randomized, single-center, two-period, phase I, crossover study of the effect of zibotentan (ZD4054) on the pharmacokinetics of midazolam in healthy male volunteers

Background: Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur. Objectives: The primary objective of this study was to evaluate the effect of zibotentan on the pharmaco-kinetics of a clinically relevant dose of midazolam in healthy volunteers. Secondary objectives were to evaluate exposure to zibotentan, ensure the safety of the healthy volunteers dosed, and investigate the effect of zibotentan on the pharmacokinetics of the midazolam metabolites 1-hydroxy midazolam and 4-hydroxy midazolam. The potency of zibotentan as a CYP3A4 inhibitor was also assessed. Methods: This was an open-label, randomized, singlecenter, 2-period, Phase I, crossover study. Volunteers were randomized in a 1:1 ratio to 1 of 2 cohorts. In cohort 1, volunteers received a single dose of midazolam 7.5 mg on day 1 (treatment A) of a 2-day study period. After a minimum 7-day washout period, volunteers received zibotentan 10 mg once daily on days 1 through 7, plus a single dose of midazolam 7.5 mg on day 6 (treatment B) of a 7-day study period. In cohort 2, volunteers received treatment B followed by treatment A, with a minimum 7-day washout period between treatments. AUC 0−∞ and C max data were expressed as geometric least squares mean ratios and 90% CIs for midazolam + zibotentan:midazolam. A moderate interaction between midazolam and zibotentan was predefined to have occurred if the upper 90% CI of the ratio was >1.5. Adverse events (AEs) were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3. AE data were assessed based on information provided by the volunteer, through open-ended and nonleading verbal questions to the volunteer at each visit, and through observation by the investigational team, other care providers, or relatives. Results: Six volunteers (all white) were included in each cohort (cohort 1, mean [SD] age, 48 [7] years; mean weight, 74 [6] kg; cohort 2, mean age, 51 [11] years; mean weight, 75 [13] kg). Steady-state levels of zibotentan, achieved over 7 days, increased the midazolam AUC 0−∞ by 1.2-fold compared with midazolam alone. The upper limits of the 90% CIs for the AUC 0−∞ and C max ratios were below the predefined level of 1.5 (1.37 and 1.32, respectively). Zibotentan had no apparent effect on the pharmacokinetics of 1-hydroxy midazolam and 4-hydroxy midazolam. Fatigue was reported in 11 volunteers (92%) receiving midazolam monotherapy and 10 (83%) receiving midazolam combined with zibotentan. Headache was reported in all 12 volunteers after zibotentan monotherapy. Conclusions: In this population of healthy male volunteers, once-daily zibotentan 10 mg increased the AUC 0−∞ of midazolam 1.2-fold; however, the treatment ratio was below the predefined limit for clinical significance. Zibotentan was well tolerated when given alone or in combination with midazolam. The results indicate that once-daily zibotentan 10 mg acted as a weak inhibitor of the CYP3A4 pathway. ClinicalTrials. gov identifier: NCT00709553.

In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A

To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE). A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM) and recombinant CYP3A4 (rCYP3A4) by zolpidem. Experiments involving a 10-fold dilution step were employed to determine the kinetic constants of inactivation (K (I) and k (inact)) and to assess the in vitro mechanism-based inactivation (MBI) criteria. Inactivation data were entered into the Simcyp population-based ADME simulator to predict the increase in the area under the plasma concentration-time curve (AUC) for orally administered midazolam. Consistent with MBI, the inhibitory potency of zolpidem toward CYP3A was increased following pre-incubation. In HLMs, the concentration required for half maximal inactivation (K (I)) was 122 microM and the maximal rate of inactivation (k (inact)) was 0.094 min(-1). In comparison, K (I) and k (inact) values with rCYP3A4 were 50 microM and 0.229 min(-1), respectively. Zolpidem fulfilled all other in vitro MBI criteria, including irreversible inhibition. The mean oral AUC for midazolam in healthy volunteers was predicted to increase 1.1- to 1.7-fold due to the inhibition of metabolic clearance by zolpidem. Elderly subjects were more sensitive to the interaction, with mean increases in midazolam AUC of 1.2- and 2.2-fold for HLM IV-IVE and rCYP3A4 IV-IVE, respectively. Zolpidem is a relatively weak mechanism-based inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.

Effects of Statins on the Pharmacokinetics of Midazolam in Healthy Volunteers

Lipid-lowering agents, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), are widely used to prevent coronary artery disease and often coadministered with other drugs, but there is a possibility that they induce pharmacological interactions with concomitant drugs. The authors aimed to investigate whether statins have any influence on cytochrome P450 (CYP) 3A4 enzyme activity. Eleven healthy volunteers were enrolled and evaluated for the effects of statins on the pharmacokinetics of midazolam in an open-label, randomized, 3-way crossover trial with simvastatin 10 mg, atorvastatin 10 mg, and pitavastatin 2 mg. The statins had no effects on the pharmacokinetics of midazolam and its metabolite, 1'-hydroxymidazolam. Furthermore, the area under the concentration-time curve ratios for 1'-hydroxymidazolam/midazolam from 0 to 10 hours showed no significant differences among 3 statins (simvastatin: 0.32 +/- 0.09, atorvastatin: 0.31 +/- 0.09, and pitavastatin: 0.31 +/- 0.12). These data suggest that statins, at least at low doses used in the present study, do not affect CYP3A4 and can be used safely without influencing CAP3A4 enzyme activity.

Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers

To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of midazolam, a probe drug of CYP3A, and its metabolite 1'-hydroxy midazolam in healthy volunteers. Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 7 days. Pharmacokinetic investigations of oral midazolam administration at 15 mg were performed both before and at the end of the SchE treatment period. The plasma midazolam and 1'-hydroxy midazolam concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques. Following administration of SchE, the average increases (%) of individual increases in AUC, AUMC and C(max) of midazolam were 119.4% [95% confidence interval (CI) 83.9, 155.0], 183.4% (95% CI 120.5, 246.2) and 85.6% (95% CI 14.4, 156.9), respectively (P < 0.01 or 0.05). On average, there was a 133.3% (95% CI 8.9, 257.7) increase in midazolam t(max) (P < 0.01). The average decrease (%) in CL/F was 52.1% (95% CI 44.9, 59.4) (P < 0.01). No significant changes were seen in midazolam half-life. After co-administration of SchE, the average increase (%) in t(max) of 1'-hydroxy midazolam was 150.0% (95% CI 22.2, 277.8) (P < 0.05). No significant differences were observed in the other pharmacokinetic parameters of 1'-hydroxy midazolam. SchE can markedly increase the oral bioavailability of midazolam in healthy volunteers. SchE is an inhibitor of CYP3A and has a high susceptibility to alter the disposition of drugs metabolized by CYP3A.

Plasma concentrations and sedation scores after nebulized and intranasal midazolam in healthy volunteers

BackgroundAn efficacious, reliable, and non-invasive route of administration for midazolam, a drug used for sedation and pre-anaesthetic medication, would have obvious advantages. This study compares two potential methods of administering midazolam by the nasal and nebulized routes. MethodsMidazolam (0.2 mg kg−1) was given by both nebulizer and nasally by liquid instillation to 10 healthy volunteers in a randomized, double-blind crossover study. Plasma concentrations of midazolam, Ramsay sedation scores, visual analogue scores, critical flicker fusion frequency, and parameters of cardiovascular and respiratory function were measured over 60 min and summarized using ‘area under the curve’. ResultsNasal instillation caused more sedation than nebulized administration. This was demonstrated by higher Ramsay sedation scores (P=0.005), lower visual analogue scores (P<0.001), and lower critical flicker fusion frequency (P<0.02). Nasal instillation was associated with higher plasma concentrations of midazolam (P<0.001). Unpleasant symptoms were recorded by six volunteers in the intranasal and one in the nebulized group (P=0.06). ConclusionsThere was some evidence that midazolam caused less discomfort when given by nebulizer compared with intranasally. Comparative bioavailability of midazolam, estimated by the ratio (nebulized:nasal) of area under the 60 min plasma concentration curve, was 1:2.9. A higher dose may need to be administered for adequate pre-anaesthetic medication when midazolam is given by nebulizer.

Effects of ursodeoxycholic acid on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam in healthy volunteers

Animal and in vitro studies suggest that ursodeoxycholic acid (UDCA) can induce cytochrome P450 3A (CYP3A) expression and enhance its activities. On the other hand, Becquemont et al. demonstrated that UDCA had no influence on intestinal CYP3A activities. The aim of this study was to investigate the effects of UDCA on the intestinal and hepatic CYP3A activities by administration of midazolam (MDZ), as a specific probe for CYP3A activity, in humans. This was a randomized, open-label, crossover study with two phases in 14 healthy volunteers. The volunteers received UDCA (300 mg/day) or placebo orally for 9 days. The pharmacokinetics and pharmacodynamics of intravenous MDZ (5 microg/kg) and oral MDZ (15 microg/kg) were assessed on days 8 and 9, respectively. The pharmacodynamics of MDZ was estimated by measuring peak saccadic velocity, postural away length, critical fusion flicker frequency, and visual analogue scale. UDCA did not affect the pharmacokinetic and pharmacodynamic parameters of intravenous and oral MDZ administrations. Our study suggests that the clinical dosage of UDCA could not affect both hepatic and intestinal CYP3A activities and that the drug interaction between UDCA and substrates for CYP3A is unlikely in humans.

The Effect of Multiple‐Dose, Oral Rifaximin on the Pharmacokinetics of Intravenous and Oral Midazolam in Healthy Volunteers

To evaluate the potential of rifaximin, an oral nonabsorbed (< 0.4%) structural analog of rifampin, to induce human hepatic and/or intestinal cytochrome P450 (CYP) 3A enzymes, with use of a known CYP3A probe, midazolam. Prospective, randomized, open-label, two-period, crossover study. Clinical research center. Twenty-seven healthy adult volunteers. During the first treatment period, subjects received a single dose of either intravenous midazolam 2 mg over 30 minutes or oral midazolam 6 mg on day 0. From days 3-10, they received rifaximin 200 mg every 8 hours. On days 6 (after the 9th dose of rifaximin) and 10 (after the 21st dose of rifaximin), subjects received a concomitant single dose of intravenous or oral midazolam. After a 15-day washout period, subjects were crossed over to the other formulation of midazolam, and the treatment schedule was repeated, with the second treatment period starting on day 26 and single-dose administration of midazolam on days 26, 32, and 36. Serial plasma samples were collected for pharmacokinetic analyses. The pharmacokinetic parameters of single-dose intravenous or oral midazolam were determined alone and after coadministration of rifaximin for 3 and 7 days. Rifaximin coadministration did not alter the measured pharmacokinetic parameters for midazolam or its major metabolite, 1'-hydroxymidazolam. The 90% confidence intervals for the maximum concentration and area under the concentration-time curve from time zero extrapolated to infinity (bioavailability) were all within 80-125% for intravenous and oral midazolam. Therefore, no drug interaction was observed between rifaximin and midazolam. Coadministration of midazolam and rifaximin was well tolerated. Overall, 3-7 days of rifaximin 200 mg 3 times/day did not alter single-dose midazolam pharmacokinetics. Rifaximin also does not appear to induce intestinal or hepatic CYP3A activity.

3LB ZD4054, a potent, specific endothelin A receptor antagonist, improves overall survival in pain-free or mildly symptomatic patients with hormone-resistant prostate cancer (HRPC) and bone metastases

Background: Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur.Objectives: The primary objective of this study was to evaluate the effect of zibotentan on the pharmaco-kinetics of a clinically relevant dose of midazolam in healthy volunteers. Secondary objectives were to evaluate exposure to zibotentan, ensure the safety of the healthy volunteers dosed, and investigate the effect of zibotentan on the pharmacokinetics of the midazolam metabolites 1-hydroxy midazolam and 4-hydroxy midazolam. The potency of zibotentan as a CYP3A4 inhibitor was also assessed.Methods: This was an open-label, randomized, singlecenter, 2-period, Phase I, crossover study. Volunteers were randomized in a 1:1 ratio to 1 of 2 cohorts. In cohort 1, volunteers received a single dose of midazolam 7.5 mg on day 1 (treatment A) of a 2-day study period. After a minimum 7-day washout period, volunteers received zibotentan 10 mg once daily on days 1 through 7, plus a single dose of midazolam 7.5 mg on day 6 (treatment B) of a 7-day study period. In cohort 2, volunteers received treatment B followed by treatment A, with a minimum 7-day washout period between treatments. AUC0−∞ and Cmax data were expressed as geometric least squares mean ratios and 90% CIs for midazolam + zibotentan:midazolam. A moderate interaction between midazolam and zibotentan was predefined to have occurred if the upper 90% CI of the ratio was >1.5. Adverse events (AEs) were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3. AE data were assessed based on information provided by the volunteer, through open-ended and nonleading verbal questions to the volunteer at each visit, and through observation by the investigational team, other care providers, or relatives.Results: Six volunteers (all white) were included in each cohort (cohort 1, mean [SD] age, 48 [7] years; mean weight, 74 [6] kg; cohort 2, mean age, 51 [11] years; mean weight, 75 [13] kg). Steady-state levels of zibotentan, achieved over 7 days, increased the midazolam AUC0−∞ by 1.2-fold compared with midazolam alone. The upper limits of the 90% CIs for the AUC0−∞ and Cmax ratios were below the predefined level of 1.5 (1.37 and 1.32, respectively). Zibotentan had no apparent effect on the pharmacokinetics of 1-hydroxy midazolam and 4-hydroxy midazolam. Fatigue was reported in 11 volunteers (92%) receiving midazolam monotherapy and 10 (83%) receiving midazolam combined with zibotentan. Headache was reported in all 12 volunteers after zibotentan monotherapy.Conclusions: In this population of healthy male volunteers, once-daily zibotentan 10 mg increased the AUC0−∞ of midazolam 1.2-fold; however, the treatment ratio was below the predefined limit for clinical significance. Zibotentan was well tolerated when given alone or in combination with midazolam. The results indicate that once-daily zibotentan 10 mg acted as a weak inhibitor of the CYP3A4 pathway. ClinicalTrials. gov identifier: NCT00709553.

Effects of Ginkgo Biloba Extract on Pharmacokinetics and Pharmacodynamics of Tolbutamide and Midazolam in Healthy Volunteers

This study was undertaken to clarify the influence of repeated oral administration of Ginkgo biloba extract (GBE) on CYP2C9 and CYP3A4. CYP2C9 probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10 male healthy volunteers before and after GBE intake (360 mg/d) for 28 days, and they received 75 g glucose after the dosing of tolbutamide. Plasma drug concentrations and blood glucose levels were measured. The area under concentration versus time curve (AUC0-infinity) for tolbutamide after GBE intake was slightly but significantly (16%) lower than that before GBE intake. Concomitantly, GBE tended to attenuate AUC0-2 of blood glucose-lowering effect of tolbutamide. AUC0-infinity for midazolam was significantly (25%) increased by GBE intake and oral clearance was significantly (26%) decreased. Thus, it is suggested that the combination of GBE and drugs should be cautious in terms of the potential interactions, especially in elderly patients or patients treated with drugs exerting relatively narrow therapeutic windows.

The effect of rifaximin on the pharmacokinetics (PK) of single doses of intravenous (IV) and oral (PO) midazolam in healthy volunteers

Introduction Rifaximin (RFX) is a broad-spectrum, poorly absorbed, rifamycin S derived antibiotic being developed to treat traveler's diarrhea. Objective: To evaluate the effect of RFX on the PK of IV and PO midazolam (MDZ), a CYP 3A probe. Methods: An open label, randomized, crossover study to determine the effect of RFX 200 mg PO administered Q8 hr for 3 days and Q8 hrs for 7 days on the PK of single doses of MDZ 2 mg IV or MDZ 6 mg PO. Subjects were randomly assigned as to the order of PO and IV MDZ. Plasma samples were harvested at specified intervals to characterize the plasma concentration-time profiles of RFX, and of MDZ and 1'-hydroxymidazolam (OHM) with the 9th or 21st dose of RFX. Results: No significant differences were observed in metrics of systemic exposure of IV or PO midazolam (see table) or its major metabolite, with MDZ alone or for MDZ with RFX. All drugs were well tolerated. Conclusion: RFX does not significantly affect intestinal or hepatic CYP 3A activity. Clinical Pharmacology & Therapeutics (2004) 75, P66–P66; doi: 10.1016/j.clpt.2003.11.246 PK (Mean + SD) MDZ alone MDZ +9th dose RFX MDZ +21st dose RFX IV MDZ Cmax (ng/mL) 45.68 ± 11.49 44.62 ± 10.96 48.84 ± 9.06 AUC0-last (ng.h/mL) 81.68 ± 23.08 76.99 ± 19.21 78.76 ± 16.45 Clearance (L/h) 24.86 ± 6.06 25.62 ± 6.91 24.71 ± 4.93 PO MDZ Cmax (ng/mL) 32.40 ± 15.54 29.12 ± 8.79 31.87 ± 12.00 AUC0-last (ng.h/mL) 72.91 ± 32.20 66.47 ± 25.59 68.70 ± 24.43 Bioavailability 0.29 ± 0.07 0.28 ± 0.07 0.27 ± 0.05 Clearance (L/h) 24.78 ± 5.95 24.87 ± 6.00 25.24 ± 4.50