Pharmacokinetics of midazolam in patients recovering from cardiac surgery

Summary The pharmacokinetics of midazolam has been studied in patients recovering from cardiac surgery, who required sedation for postoperative mechanical ventilation. Twelve males (mean age 64.5 years) with severe heart disease received an infusion of midazolam 15 mg·h^–1 for 4 h, starting 1 to 3 h post surgery. Multiple blood samples were collected from each patient during the infusion and up to 48–93 h after it. The pharmacokinetic parameters of midazolam were determined using both moment analysis and the program NONMEM.The average terminal half-life was 10.6 h. The prolonged elimination was mainly due to a decrease in its metabolic clearance (0.25 l·min^–1).The maintenance infusion dose of midazolam in such patients should be reduced. The time to recovery after stopping an infusion depends upon the amount of drug in the body at that time and a simulation of the plasma concentrations after various infusion regimens suggests that recovery will be delayed after prolonged (>48 h) administration of midazolam to these patients. However, after shorter infusions (<12 h), redistribution of the drug away from the site of action was still occurring and recovery would be expected to be relatively rapid.     

Pharmacokinetics and pharmacodynamics of midazolam in the enflurane-anesthetized dog

Midazolam (Mid) is widely used as an anesthetic adjunct. To test its anesthetic effect vs. concentration relationships, it is desirable to establish stable and predictable Mid concentrations in plasma (and brain). Therefore, the pharmacokinetics of Mid in the enflurane-anesthetized dog were determined, and the ability of Mid to reduce the enflurane concentration required for anesthesia was measured and correlated with the Mid concentration in plasma [MID]. Mongrel dogs (n=9) were anesthetized with enflurane and the enflurane EC₅₀ (MAC—the end-tidal concentration at which one-half the dogs respond to the noxious stimulation of clamping of the tail, and one-half do not) was determined. Group 1 (n=5) received Mid 2.5mgJkg iv over 60 sec. Plasma for determination of [MID] was collected and the enflurane EC₅₀ was determined repeatedly over the 7–8-hr period following injection. Based on the pharmacokinetic parameters determined for Group 1, dogs in Group 2 (n=4) received Mid as a continuous infusion of 21 kg^–1 min^–1 for 5hr accompanied by an initial loading dose (3 mg/kg infused over 20 min) designed to produce a stable [MID] of 1000 ng/ml in plasma. Enflurane MAC and [MID] were determined regularly during the infusion and for 6hr after discontinuation of the infusion. There were no important differences in the pharmacokinetic parameters determined for Group 1 vs. Group 2: t_1/2,z=98±5 vs. 95±10min (mean ±SEM); V=3.94±0.27 vs. 2.98±25 L/kg; Cl=28.5±3.1 vs. 22.3±1.1 ml kg^–1 min^–1,respectively. When administered as a continuous intravenous infusion (Group 2), [MID] remained stable at 949 ± 53 ng/ml for more than 5hr. The enflurane EC₅₀ was reduced by 55% and the reduction remained stable during the 5 hours of Mid infusion. After a single iv bolus dose or after discontinuation of the continuous infusion, the degree of enflurane EC₅₀ reduction diminished toward the control (i.e., enflurane alone) value as [MID] declined. Midazolam's pharmacokinetics and plasma concentration vs. effect relationships have been determined to be consistent under two different experimental conditions.     

The pharmacokinetics of midazolam in man

Summary Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1–2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25–0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37±0.45 h) did not differe significantly (t=2.04, df=10,p>0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74±0.45 h). The terminal half-life, (t_1/2), of midazolam in plasma was 1.77±0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383±0.094 l·kg^–1·h^–1. The first pass effect, F, determined experimentally (0.36±0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%–0.028%).     

Sleep laboratory study of the effects of midazolam in insomniac patients

Summary The effects of midazolam, a short-acting imidazobenzodiazepine, on the sleep cycle of insomniac patients were assessed by means of polygraphic recordings. Baseline placebo nights were compared with drug (30 mg p.o.) and placebo withdrawal nights. The compound was effective in inducing and maintaining sleep on short- and intermediate-term administration. Tolerance was not observed following two weeks of drug use. Subjective reports corroborated the effectiveness of midazolam as a hypnotic. In regard to its effects on sleep stages, midazolam markedly decreased Stage 3 and abolished Stage 4 sleep, while Stage 2 was augmented. REM sleep percentage was not significantly affected. Withdrawal of midazolam was followed by rebound insomnia, in which sleep latency, total wake time and wake time after sleep onset were increased above baseline. Side-effects related to midazolam administration included headache, muscular weakness and dizziness. They were mild and wore off 1–2 hours after awakening.     

Dose dependent pharmacokinetics of midazolam

Summary The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the C_max and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t_1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.     

Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsions

AIM

To investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions.

METHODS

Thirty-three children with severe malaria and convulsions lasting ≥5 min were given a single dose of MDZ (0.3 mg kg⁻¹) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1′-hydroxymidazolam concentrations. Plasma concentration–time data were fitted using pharmacokinetic models.

RESULTS

Median (range) MDZ C_max of 481 (258–616), 253 (96–696) and 186 (64–394) ng ml⁻¹ were attained within a median (range) t_max of 10 (5–15), 15 (5–60) and 10 (5–40) min, following IV, IM and buccal administration, respectively. Mean (95% confidence interval) of the pharmacokinetic parameters were: AUC(0,∞) 596 (327, 865), 608 (353, 864) and 518 (294, 741) ng ml⁻¹ h; V_d 0.85 l kg⁻¹; clearance 14.4 ml min⁻¹ kg⁻¹, elimination half-life 1.22 (0.65, 1.8) h, respectively. A single dose of MDZ terminated convulsions in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration. Four children (one in the IV, one in the IM and two in the buccal groups) had respiratory depression.

CONCLUSIONS

Administration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics.

WHAT THIS STUDY ADDS

• Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg⁻¹) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64–616 ng ml⁻¹, with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer.

     

咪达唑仑片在中国朝鲜族和汉族健康人体内的药代动力学

目的研究咪达唑仑片(镇静催眠药)在中国朝鲜族和汉族健康人体内的药代动力学。方法9名朝鲜族和10名汉族健康受试者,单剂量口服咪达唑仑片15mg,用高效液相色谱法测定血浆中咪达唑仑的浓度,用DASVer2.0.1软件计算药代动力学参数。结果咪达唑仑片在朝鲜族和汉族健康受试者的主要药代动力学参数:tmax分别为(0.63±0.72),(1.52±0.74)h,Cmax分别为(189.03±82.05),(103.11±26.37)μg.L-1,t1/2(3.82±2.33),(2.96±0.77)h,AUC0-12(369.75±85.47),(368.95±103.63)μg.h.L-1,AUC0-∞(403.29±124.28),(397.29±124.06)μg.h.L-1。结论朝鲜族和汉族健康受试者单剂量口服咪达唑仑片后的药代动力学参数存在较大的个体差异,平均血药浓度-时间曲线存在双峰现象,2组间tmax、Cmax的差异有统计学意义(P<0.05)。     

Pharmacokinetics and pharmacodynamics of nasally delivered midazolam

AIMS

To investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5–30 mg ml⁻¹) complexed with cyclodextrin.

METHODS

An open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test.

RESULTS

Mean bioavailability of midazolam after nasal administration ranged from 76 ± 12% to 92 ± 15%. With formulations delivering 1 mg midazolam, mean C_max values between 28.1 ± 9.1 and 30.1 ± 6.6 ng ml⁻¹ were reached after 9.4 ± 3.2–11.3 ± 4.4 min. With formulations delivering 3 mg midazolam, mean C_max values were between 68.9 ± 19.8 and 80.6 ± 15.2 ng ml⁻¹ after 7.2 ± 0.7–13.0 ± 4.3 min. Chitosan significantly increased C_max and reduced t_max of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1′-hydroxymidazolam were between 0.97 ± 0.15 and 1.06 ± 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 ± 78 ms and 19 ± 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa.

CONCLUSIONS

Effective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMβCD combined with the absorption enhancer chitosan.     

奥丹西酮片在8例老年肺癌患者中的药物动力学

目的：观察奥丹西酮在老年人体内的药物动力学特性。方法：８名接受顺铂化疗的老年原发性肺癌患者单次和多次口服奥丹西酮后，用高效液相色谱法测定血浆药物浓度，用ＰＫＢＰ－Ｎ１药动学程序拟合计算。结果：奥丹西酮口服后在老年人体内表现为二房室模型。单剂量和多剂量给药时主要药动学参数为：Ｔ１／２β为４．５±０．５ｈ和５．９±０．７ｈ，Ｃｍａｘ为２０．３±１．８μｇ·Ｌ－１和２４．７±２．２μｇＬ－１，Ｔｍａｘ为１．９±０．２ｈ和１．８±０．１ｈ，ＡＵＣ０～２４为３１６±４０μｇ·ｈ·Ｌ－１和４０７±４５μｇ·ｈ·Ｌ－１，积蓄因子为１．３。结论：老年患者多次口服奥丹西酮后与单次口服相比，体内消除能力明显下降     

Integrated pharmacokinetics and pharmacodynamics of Ro 48–6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects

Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48–6791, compared with midazolam, in healthy subjects during first administration to man studies. Methods The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48–6791 was administered as a slow i.v. infusion in doses of 0.1–0.3–1 mg in the first group, and 1–2–3 mg in the second. Midazolam was infused at 0.1 mg kg⁻¹. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min⁻¹ ) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (&bgr;-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. Results Ro 48–6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V_ss ) and plasma clearance of Ro 48–6791 were on average markedly larger than those of midazolam (171±65 vs 41±10 l and 2.2±0.9 vs 0.42±0.11 l min⁻¹, respectively). The doses of Ro 48–6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48–6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in &bgr;-power than Ro 48–6791 at the highest administered dose. Ro 48–6792, a metabolite of Ro 48–6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48–6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. Conclusions This first study with Ro 48–6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.     

Pharmacokinetics and pharmacodynamics of low doses of midazolam administered intravenously and orally to healthy volunteers

1. Midazolam, a short‐acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers. 2. The present study was an open‐label, single‐sequence trial in three phases distinguished by differing doses of midazolam. Plasma concentrations of midazolam and its metabolites, as well as pharmacodynamic parameters, were measured simultaneously after administration of 5, 15 and 30 μg/kg, i.v., midazolam and 15, 50 and 100 μg/kg, p.o., midazolam. 3. The area under the concentration–time curve (AUC) of midazolam was significantly correlated with dose after both i.v. and oral administration (both P < 0.001). The AUC_0–6 of midazolam after oral administration was also well correlated with the area under the effect curve for peak saccadic velocity (PSV; P < 0.018), postural sway area (PSA; P < 0.069) and mental sedation as measured on a visual analogue scale (VAS; P < 0.054), but not for critical flicker fusion. 4. The present study has shown that the pharmacokinetics of midazolam at relatively low doses are linear for both intravenous and oral dosing regimens. In addition, PSV, PSA and VAS may be useful for the simultaneous evaluation of the pharmacokinetics and pharmacodynamics of midazolam at subtherapeutic doses.     

Pharmacokinetics of betaxolol in middle aged patients

Summary The pharmacokinetics of betaxolol was studied in 8 middle-aged (40–60 years) subjects after oral (20 mg) and intravenous (10 mg) administration. The principal parameters were almost identical to those observed in young healthy volunteers. The recommended therapeutic regimen, a single daily dose of 20 mg, appears well suited for middle aged, hypertensive patients.     

Remimazolam: Pharmacologic Considerations and Clinical Role in Anesthesiology

Midazolam, fentanyl, and propofol are commonly used for sedation in modern anesthesia practice. These agents possess characteristics that have afforded various anesthetics to be delivered and produce relatively safe and effective outcomes. However, each agent has certain drawbacks in clinical practice. Remimazolam, a novel benzodiazepine created out of so‐called soft drug development, is an ultrashort‐acting intravenous sedative‐hypnotic currently being investigated in clinical trials. In this review, we evaluate the recent literature on the use of remimazolam in clinical practice as compared with current sedative agents, and we describe its potential roles for use in sedation. A literature search of the Medline database (2012–May 2016) was performed. Additional references were identified from a review of literature citations, manufacturer reports, and professional meeting abstracts. All premarket studies involving remimazolam as the primary study drug were evaluated. Literature describing the pharmacokinetics and pharmacodynamics of remimazolam, propofol, and midazolam was also included. Phase I and II studies in the United States have shown remimazolam to be a safe and effective option for procedural sedation. Unlike midazolam and propofol, remimazolam undergoes organ‐independent metabolism to an inactive metabolite. Because remimazolam follows first‐order pharmacokinetics, prolonged infusions or higher doses are unlikely to result in accumulation and extended effect, making it favorable for use as an intravenous anesthetic and for sedation in the intensive care unit. It is expected that phase III trials will further describe the niche that remimazolam may be able to occupy in clinical practice. Postmarket cost‐benefit analyses will need to be performed.     

咪哒唑仑在两个年龄组的药物动力学

对健康男性较高年龄及青年志愿者各７例，分别单次快速静滴０．０８ｍｇ／ｋｇ及０．１２ｍｇ／ｋｇ咪哒唑仑后，进行了药物动力学研究。结果两组药物动力学均成二室模型。较高年龄组比青年组的室间转运速率常数Ｋ１２、末相半衰期Ｔ１／２β和平均滞留时间ＭＲＴ０－∞均明显增大，两组Ｋ１２分别为７±６ｈ和２．８±１．４ｈ（Ｐ＜０．０５），Ｔ１／２β为４．０±１．７ｈ和２．１±０．６ｈ（Ｐ＜０．０１），ＭＲＴ０－∞为５．２±１．８ｈ和２．５±０．７ｈ（Ｐ＜０．０１）；而总清除率ＣＬｓ较高年龄组比青年组明显减小，分别为０．１７±０．０３Ｌ／（ｋｇ·ｈ）和０．２８±０．０８Ｌ／（ｋｇ·ｈ）（Ｐ＜０．０１）。且中国人ＣＬｓ较欧洲人为低。提示年龄增大对咪哒唑仑的清除能力下降，中国男性老年人给药剂量和给药间隔应适当调整。     

Pharmacokinetics of midazolam during continuous infusion in critically ill neonates

Summary Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus (0.2 mg·kg^–1) immediately followed by continuous infusion of 0.06 mg·kg^–1·h^–1 was administered to 15 critically ill neonates at a gestational age of 32.8 weeks, who required sedation for mechanical ventilation. Heart rate and blood pressure were closely monitored.Hypotension occurred in 4 patients after the bolus dose or during the continuous infusion. Three of them had also been given fentanyl. Individual pharmacokinetic parameters were calculated: plasma clearance was 3.9 ml·min^–1, elimination half-life was 12.0 h. Because of its short half-life compared to diazepam, midazolam may be used during the neonatal period to achieve rapid, brief sedation. However, it should be administered cautiously to neonates, particularly in premature infants, or if fentanyl is also given.     

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.     

Pharmacokinetics of linezolid in critically ill patients

Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion.

Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population.

Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.     

Pharmacokinetics and metabolism of oral midazolam in preterm infants

AIMS: To characterize the pharmacokinetics and metabolism of oral midazolam in 15 preterm infants. METHODS: After an oral dose (0.1 mg kg(-1)), blood was drawn up to 24 h after administration. Midazolam and 1-OH-midazolam concentrations were determined with GC-MS. In 8 out of these 15 patients the pharmacokinetics of intravenous midazolam was also studied. RESULTS: Apparent oral clearance, apparent volume of distribution, plasma half-life and 1-OH-Midazolam/Midazolam AUC ratio were [median (range)]: 2.7 [0.67-15.5] ml kg(-1) min(-1), 1.4 [0.3-12.1] l kg(-1), 7.6 [1.2-15.1], h and 0.03 [0.01-0.96], respectively. Absolute bioavailability was 0.49 [0.12-1.0]. CONCLUSIONS: Midazolam oral clearance is markedly decreased in preterm infants as compared with older children, probably because of immature CYP3A4 activity.     

Pharmacokinetics and metabolism of midazolam in chimeric mice with humanised livers

1. The pharmacokinetics and biotransformation of midazolam were investigated following single oral doses of 0.1, 1 and 10 mg/kg to chimeric mice with humanised livers (PXB mice) and to severe combined immunodeficient (SCID) mice used as controls.

2. Pharmacokinetic analysis, on whole blood, revealed rapid absorption of the administered midazolam with a higher C_max in PXB compared to SCID. The exposure to 1′-hydroxymidazolam was approximately 14-fold greater than to midazolam in the SCID mice and close to equivalent in the PXB mice. The metabolism of midazolam in SCID mice was faster than in the PXB mice such that pharmacokinetic data for midazolam in SCID mice could not be generated from the lowest dose in these animals.

3. Both oxidative and conjugative metabolic pathways were identified in the PXB mice. All the major circulating metabolites observed in humans; 1′-hydroxymidazolam, 4′-hydroxymidazolam, 1′,4′-dihydroxymidazolam and 1′-hydroxymidazolam glucuronide, were detected in the blood of PXB mice. However, 4′-hydroxymidazolam and the 1′-hydroxymidazolam glucuronide were not detected in blood samples obtained from SCID mice.

4. The midazolam metabolite profile in the PXB mouse was similar to that previously reported for human suggesting that the PXB mouse model can provide a model system for predicting circulating human metabolites.