Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients

OBJECTIVE: To determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. DESIGN: Prospective population pharmacokinetic study. SETTING: Pediatric intensive care unit. PATIENTS: Twenty-one pediatric intensive care patients aged between 2 days and 17 yrs. INTERVENTIONS: The pharmacokinetics of midazolam and metabolites were determined during and after a continuous infusion of midazolam (0.05-0.4 mg/kg/hr) for 3.8 hrs to 25 days administered for conscious sedation. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken at different times during and after midazolam infusion for determination of midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations via high-performance liquid chromatography-ultraviolet detection. A population analysis was conducted via a two-compartment pharmacokinetic model by the NPEM program. The final population model was used to generate individual Bayesian posterior pharmacokinetic parameter estimates. Total body clearance, apparent volume distribution in terminal phase, and plasma elimination half-life were (mean +/- sd, n = 18): 5.0 +/- 3.9 mL/kg/min, 1.7 +/- 1.1 L/kg, and 5.5 +/- 3.5 hrs, respectively. The mean 1-OH-midazolam/midazolam ratio and (1-OH-midazolam + 1-OH-midazolam-glucuronide)/midazolam ratio were 0.14 +/- 0.21 and 1.4 +/- 1.1, respectively. Data from three patients with renal failure, hepatic failure, and concomitant erythromycin-fentanyl therapy were excluded from the final pharmacokinetic analysis. CONCLUSIONS: We describe population and individual midazolam pharmacokinetic parameter estimates in pediatric intensive care patients by using a population modeling approach. Lower midazolam elimination was observed in comparison to other studies in pediatric intensive care patients, probably as a result of differences in study design and patient differences such as age and disease state. Covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors are important predictors of altered midazolam and metabolite pharmacokinetics in pediatric intensive care patients. The derived population model can be useful for future dose optimization and Bayesian individualization.     

Vancomycin pharmacokinetics and dose recommendations for preterm infants.

The pharmacokinetics of intravenous vancomycin was studied in 20 preterm infants (gestational age, 26.5 weeks +/- 2.6 weeks [standard deviation]; birthweight, 880 +/- 340 g). At the time of the studies their postconceptional age was 36.4 +/- 4.5 weeks. The drug was infused over 30 min in a dose between 9.2 and 18 mg/kg. A highly significant correlation existed between postconceptional age or body weight and vancomycin t1/2 and clearance. Serum creatinine concentrations correlated with vancomycin t1/2 and clearance. Serum creatinine tended to decrease with increasing postconceptional age. Based on the excellent correlation between age (or weight) and vancomycin pharmacokinetics, dose and dose-interval recommendations are presented.     

Pharmacokinetics of imipenem/cilastatin in neutropenic patients with haematological malignancies

The pharmacokinetics of imipenem/cilastatin were studied in febrile neutropenic patients with haematological malignancies. The peak plasma concentrations (36.4 +/- 4.96 mg/l), plasma half-life (60 min), volume of distribution (0.28 +/- 0.02 l/kg) and plasma clearance (3.23 +/- 0.38 ml/min/kg) were comparable with those in normal healthy volunteers suggesting that the drug handling is not appreciably altered in this group of patients. The administration of 12.5 mg/kg (max 1 g), 6-hourly achieved levels that were up to 3.5 times MICs of most relevant bacteria. The drug therefore has a potential use as empirical monotherapy in febrile neutropenic patients.     

Flumazenil reduces midazolam-induced cognitive impairment without altering pharmacokinetics

OBJECTIVES: Intravenous midazolam is used as an in vivo biomarker of hepatic cytochrome P450 (CYP) 3A activity. Midazolam is a central nervous system depressant and can produce cognitive impairment. The purpose of this study was 2-fold: (1) to determine whether administration of intravenous flumazenil given before intravenous midazolam minimizes cognitive impairment and (2) to determine whether flumazenil pretreatment has an effect on midazolam pharmacokinetics during hepatic CYP3A phenotyping. METHODS: Eleven healthy subjects (8 men) received intravenous flumazenil (0.005 mg/kg) or placebo followed 7 minutes later by intravenous midazolam (0.025 mg/kg) in a randomized, double-blind crossover study. Plasma midazolam concentrations were obtained before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing and were assayed by liquid chromatography-tandem mass spectrometry. Midazolam pharmacokinetics were determined by noncompartmental methods. The two 1-sided tests procedure was used to compare area under the curve (AUC) between study phases. Data were log-transformed before analysis, and bioequivalence criteria were applied. Digit symbol substitution tests, performed before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing, were used to measure cognition. General linear modeling was used to compare scores between study phases. RESULTS: Midazolam AUC extrapolated to infinity [AUC(0-infinity)] between phases was bioequivalent. The AUC ratio (flumazenil plus midazolam/midazolam) was 0.99, with a 90% confidence interval of 0.98 to 1.00. Statistically significant differences(P 相似文献   

Prediction of cyclosporine clearance in liver transplant recipients by the use of midazolam as a cytochrome P450 3A probe

BACKGROUND: Interindividual differences in the kinetics of cyclosporine (INN, ciclosporin) result in part from variations in the activity of cytochrome P450 3A (CYP3A). The biotransformation of midazolam to 1'-hydroxymidazolam is also catalyzed by CYP3A. The objective of this study was to examine the usefulness of midazolam as a CYP3A probe to predict cyclosporine clearance. METHODS: Twenty-six stable liver transplant recipients receiving immunosuppressive therapy with oral cyclosporine (Neoral) were studied. Midazolam (0.015 mg/kg) was administered intravenously and a blood sample was obtained 1 hour later. The plasma concentration of midazolam and 1'-hydroxymidazolam was measured by gas chromatography-mass spectrometry. Blood concentration of cyclosporine was measured by a fluorescence polarization assay. Cyclosporine clearance was calculated as daily dose divided by trough level. RESULTS: There were large interindividual variations in cyclosporine clearance and in midazolam metabolism. Cyclosporine blood levels correlated poorly with dose (r = -0.016). However, there was a significant correlation between cyclosporine clearance and the plasma concentration of 1'-hydroxymidazolam (r = 0.559; P < .001) or the midazolam/1'-hydroxymidazolam plasma concentration ratio (r = 0.668; P < .001). CONCLUSION: Heterogeneity in CYP3A activity contributes to interpatient differences in cyclosporine dosage requirements after liver transplantation. Midazolam metabolism correlated with cyclosporine clearance, but it accounted for only about 40% of the variability in the apparent oral clearance of cyclosporine and this relationship is not tight enough to be useful in the prediction of cyclosporine dosage requirements in the clinical setting.     

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

OBJECTIVE: Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. RESULTS: Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. CONCLUSION: When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.     

Pharmacokinetics of indomethacin in the premature infant

Indomethacin (I) pharmacokinetics was evaluated in 6 premature infants who received the drug for treatment of patent ductus arteriosus. Administered by oral or rectal route, I (0.2 mg/kg/24 h X 3) was promptly absorbed with peak plasma concentrations attained within 1 and 3 h. The elimination of I appeared to follow two compartment open model kinetics, with terminal plasma half-lives ranging from 30 to 90 h. Apparent plasma clearance values were between 0.076 and 0.335 ml/min/kg. Ductal closure was observed in 4 of the 6 infants. Data point to a possible relationship between therapeutic effects and I plasma concentrations.     

Changes in cerebral venous prostanoids during midazolam-induced cerebrovascular hypotension in newborn piglets

OBJECTIVES: We hypothesized that the effects of midazolam are associated with altered prostanoid synthesis in the newborn piglet during continuous infusion. To test this hypothesis, we examined the effect of midazolam on prostanoid production in the carotid artery and sagittal sinus vein before and during midazolam infusion. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: Research laboratory at Long Beach Memorial Medical Center. SUBJECTS: Fourteen newborn piglets (1-3 days old, 1-1.5 kg) randomly assigned to receive either midazolam or vehicle (5% dextrose) infusion for 6 hrs. INTERVENTIONS: Two groups of animals received either a) a loading dose of 300 microg/kg of midazolam over 15 mins, followed by a continuous intravenous infusion of 100 microg/kg/hr (n = 6), or b) equivalent volume bolus and intravenous infusions of 5% dextrose (control, n = 8). MEASUREMENTS AND MAIN RESULTS: Changes in systemic and cerebral venous hemodynamics, blood gases, and prostanoid (prostaglandin E2, 6-ketoprostaglandin F1 alpha, thromboxane B2) production were measured at baseline, postbolus, and at 0.5, 2, 4, and 6 hrs. Systemic and cerebral venous midazolam concentrations were measured at 0.5, 1, 2, 3, 4, 5, and 6 hrs. Midazolam infusion did not affect systemic hemodynamics or blood gases. In contrast, midazolam infusion significantly reduced sagittal sinus vein blood pressure, PO2, oxygen saturation, and oxygen content. Cerebral fractional oxygen extraction increased and was positively correlated with cerebral fractional midazolam extraction. Concurrently, systemic and sagittal sinus vein plasma prostaglandin E2 concentrations decreased, whereas 6-ketoprostaglandin F1 alpha concentrations increased with midazolam infusion. Thromboxane B2 concentrations increased transiently in the systemic plasma. CONCLUSIONS: Midazolam infusion preceded by a high bolus dose in newborn piglets alters systemic and sagittal sinus vein prostanoid production. It is also associated with changes in sagittal sinus vein blood pressure and cerebral fractional oxygen extraction. These changes may reflect decreased brain perfusion and metabolism during midazolam infusion.     

Excretion of moxidectin into breast milk and pharmacokinetics in healthy lactating women

Moxidectin, registered worldwide as a veterinary antiparasitic agent, is currently under development for humans for the treatment of onchocerciasis in collaboration with the World Health Organization. The objective of this study was to assess the pharmacokinetics of moxidectin in healthy lactating women, including the excretion into breast milk. Twelve women, ages 23 to 38 years, weighing 54 to 79 kg, all more than 5 months postpartum, were enrolled, following their plan to wean their infants and provision of informed consent. A single 8-mg, open-label dose was administered orally after consumption of a standard breakfast. Complete milk collection was done for approximately 28 days, and plasma samples were collected for 90 days. Moxidectin concentrations were measured by high-performance liquid chromatography (HPLC) with fluorescence detection, with a validated range of 0.08 to 120 ng/ml. Noncompartmental pharmacokinetic methods were used to find the following results: peak concentration in plasma (C(max)), 87 ± 25 ng/ml; time to C(max) (t(max)), 4.18 ± 1.59 h; terminal-phase elimination half-life (t(1/2)), 832 ± 321 h; total area under the concentration-time curve (AUC), 4,046 ± 1,796 ng · h/ml; apparent oral dose clearance (CL/F), 2.35 ± 1.07 l/h; ratio of CL/F to the terminal-phase disposition rate constant, λ(z) (Vλ(z)/F), 2,526 ± 772 liters; percentage of maternal dose excreted in milk, 0.701 ± 0.299%; absolute amount excreted in milk, 0.056 ± 0.024 mg; relative infant dose, 8.73 ± 3.17% of maternal dose assuming complete absorption; clearance in milk (CL(milk)), 0.016 ± 0.009 liter/h. Nine of 12 subjects reported adverse events, all of which were considered treatment emergent but not drug related and were mostly reported during the long outpatient period 8 to 90 days after dose administration. The most frequently reported adverse events were headache and nausea (n = 4), oropharyngeal pain (n = 2), rhinitis, viral pharyngitis, and viral upper respiratory tract infection (n = 2).     

Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is one of the major side effects of corticosteroid therapy. Because corticosteroids are metabolized by hepatic cytochrome P450 (CYP) 3A, a low endogenous activity of this enzyme may contribute to the pathogenesis of ONFH. The purpose of this study was to examine the possible association of hepatic CYP3A activity and the susceptibility to ONFH in patients treated with corticosteroids. METHODS: In this prospective controlled study we measured the clearance of intravenous midazolam (0.25 mg/kg) to estimate hepatic CYP3A activity in patients with steroid-induced ONFH (n = 26), patients with alcohol-related ONFH (n = 29), and non-ONFH control patients (n = 75) undergoing orthopedic surgery. Midazolam clearance was compared between the groups, and the relationship between the level of hepatic CYP3A activity and the prevalence of ONFH was evaluated by multivariate analysis. RESULTS: Midazolam clearance in patients with steroid-induced ONFH was significantly lower than that in control patients and patients with alcohol-related ONFH (7.7 +/- 1.8 mL x kg(-1) x min(-1) versus 11.4 +/- 3.5 mL x kg(-1) x min(-1) and 10.5 +/- 2.8 mL x kg(-1) x min(-1), respectively; P < .001). Patients with low midazolam clearance (<9.5 mL x kg(-1) x min(-1)) had a 9-fold greater risk for steroid-induced ONFH (adjusted odds ratio, 9.08 [95% confidence interval, 2.79-29.6]; P < .001). Midazolam clearance did not show a significant correlation with the prevalence of alcohol-related ONFH. CONCLUSIONS: Low hepatic CYP3A activity may significantly contribute to the risk for steroid-induced ONFH.     

Once-daily versus twice-daily administration of ceftazidime in the preterm infant.

Ceftazidime pharmacokinetics in 28 preterm infants (gestational ages, 25.6 to 31.9 weeks) were studied on day 3 of life. Patients with suspected septicemia were randomized on day 1 of life in two groups. One group (n = 13) was administered 25 mg of ceftazidime per kg of body weight once daily, and the other (n = 15) was given 25 mg of ceftazidime per kg twice daily. Both groups also received 25 mg of amoxicillin per kg twice daily. Blood samples were collected on day 3 of life with an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an intravenous bolus injection. An additional blood sample was taken at 24 h from the group dosed once a day. High-performance liquid chromatography was used to determine serum ceftazidime concentrations. The pharmacokinetics of ceftazidime were best described by using a one-compartment model. The half-life for the elimination of the drug from serum, apparent volume of distribution, total body clearance of ceftazidime, and inulin clearance were not significantly different for both groups. The ceftazidime/inulin clearance ratio was 0.72 for both groups. However, trough concentrations in serum for the twice-daily group were significantly (P < 0.001) higher (42.0 +/- 13.4 mg/liter) than those for the once-daily group (13.1 +/- 4.7 mg/liter). The latter concentrations were all still substantially higher than the MIC of ceftazidime for major neonatal pathogens. We conclude that the currently recommended dosage of 25 mg of ceftazidime per kg twice daily for preterm infants with gestational ages below 32 weeks may be adjusted during the first days of life to one daily dose at 25 mg/kg, provided that for the empirical treatment of septicemia, amoxicillin at 25 mg/kg is also given twice daily.     

Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks.

The multiple-dose pharmacokinetics of amoxicillin (AM [administered twice daily in a 25-mg/kg of body weight intravenous dose]) in 17 preterm infants (11 males; gestational age, 29 +/- 1.9 weeks; birth weight, 1,175 +/- 278 g) were evaluated on day 3 of life. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after the intravenous dose. A high-performance liquid chromatography method was used to determine AM concentrations in serum. AM pharmacokinetics followed a one-compartment open model. The glomerular filtration rates of all patients were simultaneously studied by means of the 24-h continuous inulin infusion technique. The elimination half-life, apparent volume of distribution, and total body clearance of AM (mean +/- standard deviation) were 6.7 +/- 1.7 h, 584 +/- 173 ml, and 62.4 +/- 23.3 ml/h, respectively. The mean (+/- standard deviation) AM peak and trough levels were 53.6 +/- 9.1 and 16.0 +/- 4.9 mg/liter, respectively. All infants had a serum trough level above 5 mg/liter. The total body clearance and apparent volume of distribution of AM and the clearance of inulin increased significantly with increasing gestational age. The total body clearance of AM (1.0 +/- 0.4 ml/min) and the clearance of inulin (1.0 +/- 0.3 ml/min) were similar. The total body clearance of AM increased significantly with increasing clearance of inulin. We conclude that an AM dose of 25 mg/kg every 12 h given to preterm infants in the first week of life with gestational ages of less than 32 weeks results in serum levels well above the MIC for major microorganisms involved in neonatal infections.     

Cisapride: a potential model substrate to assess cytochrome P4503A4 activity in vivo

OBJECTIVES: Cisapride was compared with midazolam in vivo to determine its potential applicability as a cytochrome P450 (CYP) 3A4 "probe." As well, we evaluated whether cisapride was transported by P-glycoprotein. METHODS: Bidirectional transport assays were conducted in LLC-PK1 cells and the derivative cell line L-MDR1 to determine whether cisapride was a substrate for P-glycoprotein. A pharmacokinetic study was also conducted in 17 healthy adults (n = 8 women) who received intravenous midazolam (0.025 mg/kg), oral midazolam (0.15 mg/kg), and oral cisapride (0.07 mg/kg) in a randomized crossover design. Plasma concentrations were quantitated from repeated after-dosing blood samples by HPLC with ultraviolet detection for midazolam and HPLC with tandem mass spectrometry detection for cisapride and norcisapride. Pharmacokinetic parameters were determined by noncompartmental methods. Both linear and nonlinear regression analyses were used to examine the association between the apparent plasma clearance of midazolam and cisapride and the cisapride/norcisapride plasma concentration ratios. RESULTS: Although not a substrate for P-glycoprotein, cisapride inhibited P-glycoprotein with an apparent inhibition constant (K(i)) of 16.1 micromol/L. Linear correlations between cisapride clearance and both intravenous and oral midazolam clearance (P =.01, r(2) = 0.43 and P =.001, r(2) = 0.46, respectively) were found. Cisapride/norcisapride plasma concentration ratios at 8 hours (P =.001, r(2) = 0.90) and 12 hours (P =.001, r(2) = 0.96), as well as cisapride plasma concentrations at these time points, were shown to accurately predict the area under the plasma concentration versus time curve for cisapride. CONCLUSIONS: CYP3A4 activity reflected by the total body clearance after oral administration of cisapride should be independent of transport by P-glycoprotein. Concordance between the pharmacokinetics for cisapride and midazolam support the applicability of oral cisapride as a pharmacologic substrate to assess total CYP3A4 activity in vivo. Cisapride plasma concentration ratios at 8 or 12 hours after a single oral cisapride dose may prove useful as a single-point determination to reflect the area under the plasma concentration versus time curve and the plasma clearance of cisapride and, as well, total CYP3A4 activity in vivo.     

Pharmacokinetic-pharmacodynamic relationships of morphine in neonates.

Morphine pharmacokinetics and pharmacodynamics (analgesia and sedation) were evaluated after continuous intravenous infusion of morphine in 19 neonates, both preterm and term, whose lungs were ventilated to relieve respiratory distress. Elimination half-life, total plasma clearance, and volume of distribution (mean +/- SD) were 9.6 +/- 3.0 hours, 2.55 +/- 1.65 ml/min/kg (area analysis) or 2.09 +/- 1.19 ml/min/kg (steady-state data), and 2.05 +/- 1.05 L/kg, respectively, and were not significantly different in preterm and term neonates. In neonates with adverse effects of morphine, the plasma clearance was decreased twofold. Mean morphine concentration required to produce adequate sedation in 50% of patients was found to be 125 ng/ml, but concentrations above 300 ng/ml may be associated with adverse effects of morphine. Morphine-6-glucuronide was not detected in the plasma of any neonate, which may explain why neonates require high plasma concentrations of unchanged morphine for sedation.     

Pharmacokinetics of theophylline in premature infants on the first day of life

The disposition of theophylline in premature infants on the first day of life was studied in nine preterm infants after intravenous administration of the drug. Theophylline concentrations in the blood were measured by means of high-pressure liquid chromatography. Theophylline's apparent volume of distribution (mean +/- SD) was 1.02 +/- 0.13 L/kg, a value similar to those previously reported, but the half-life (16.9 +/- 6.2 hr) was considerably shorter. The elimination rate constant (0.046 +/- 0.020/hr) and the clearance rate (46 +/- 14 ml/kg/hr) were faster than in older infants. Follow-up studies in three infants on the third day of life showed lower clearance rates than were obtained on the first day. The newborn preterm infants in this study eliminated theophylline at an unexpectedly rapid rate. Dosage calculations for therapy at this age should be based on these kinetic data.     

Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping

OBJECTIVES: Determination of hepatic and intestinal cytochrome P450 (CYP) 3A activity is important, because CYP3A substrates show substantial variability in plasma concentrations as a result of variations in both hepatic and intestinal metabolism. The goals of this study were (1) to determine whether the hepatic and intestinal extraction ratios (ER(H) and ER(G), respectively) of the CYP3A probe drug midazolam are different when determined after semisimultaneous administration, as compared with administration on separate occasions (traditional method), and (2) to evaluate the hepatic and intestinal metabolism of midazolam in the presence and absence of ketoconazole by the semisimultaneous method. METHODS: Midazolam pharmacokinetics was assessed in 12 healthy volunteers after administration of midazolam, 5 mg orally, followed at 6 hours by 2 mg given by intravenous infusion. Concentration-time data were fitted to a combined oral-intravenous infusion model by nonlinear regression (semisimultaneous method). Data from the semisimultaneous method were compared with those obtained after individual midazolam doses, 1 week apart (traditional approach). The effect of ketoconazole on midazolam pharmacokinetics after semisimultaneous administration was also determined in 4 healthy volunteers. RESULTS: There were no significant differences in bioavailability (0.343 +/- 0.100 versus 0.343 +/- 0.094), ER(H) (0.269 +/- 0.064 versus 0.267 +/- 0.077), and ER(G) (0.534 +/- 0.135 versus 0.531 +/- 0.124) between the traditional and semisimultaneous methods. As expected, ketoconazole markedly increased the mean bioavailability to 0.838 (2.4-fold), the mean ER(H) was decreased 3.7-fold, and the mean ER(G) was decreased 5.7-fold. CONCLUSIONS: Midazolam pharmacokinetic parameters that are specific to liver and intestinal metabolism were not different between the traditional and semisimultaneous methods. The semisimultaneous method also yielded expected marked changes in the parameters as a result of ketoconazole inhibition. Thus the semisimultaneous midazolam method appears to be a suitable approach to determine hepatic and intestinal CYP3A activity at baseline and with enzyme inhibition.     

Pharmacokinetics, safety, and tolerability of ascending single intravenous doses of oritavancin administered to healthy human subjects

Oritavancin (LY333328 diphosphate) is a novel glycopeptide antimicrobial agent with potent microbiological activity in vitro against Gram-positive bacteria. A single-dose, open-label, noncontrolled, dose-escalation study in 11 healthy human subjects was carried out to evaluate the safety and pharmacokinetics of oritavancin. One subject at each dose level received a single intravenous dose of 0.02, 0.03, 0.05, 0.08, 0.125, 0.20, and 0.325 mg/kg infused over 1 hour and four subjects each received a single-dose of 0.5 mg/kg. Safety and tolerability were evaluated by monitoring adverse events and laboratory parameters. Oritavancin pharmacokinetics were assessed by blood, urine, and fecal sampling. The plasma concentrations of oritavancin after the end of infusion followed a multiexponential decline over a 2-week period. Median (range) C(max) for the 0.5 mg/kg dose group was 6.5 (4.7-7.6) microg/mL. In every subject, plasma concentrations declined to < or =10% of the C(max) within 24 hours. Following a short, constant-rate infusion, the pharmacokinetics of oritavancin were linear across a total dose range from 3.66-44.6 mg. Renal clearance was approximately 0.457 mL/min. The mean (range) plasma terminal half-life of oritavancin was 195.4 (135.8-273.8) hours across all dose levels from 0.05-0.5 mg/kg. Less than 5% and 1% of administered drug were recovered in the urine and feces, respectively, after 7 days. This first time in man evaluation of oritavancin revealed that single doses of oritavancin of up to and including 0.5 mg/kg were safe and well tolerated. Although no clinically relevant changes in renal, hepatic and hematologic indices from baseline were observed, five subjects did manifest asymptomatic and transient elevations of hepatic transaminase concentrations. Because this study was not placebo-controlled and enrolled a small number of subjects, the safety and pharmacokinetic profiles of oritavancin need to be confirmed in additional studies.     

Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study.

OBJECTIVE: To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to elucidate the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4. METHODS: In an in vivo, double-blind randomized study, 24 patients received 0.2 mg/kg midazolam and either 2 mg/kg propofol (propofol group) or placebo (placebo group) for induction of anesthesia. In the propofol group, continuous infusion of propofol at 9 mg/kg/h was started immediately after the bolus infusion of propofol and was maintained for an hour. In the placebo group the same dose of soybean emulsion as a placebo was given and infused intravenously for an hour instead of propofol. In an in vitro study the effect of propofol on the metabolism of midazolam was studied with human liver microsomes and recombinant CYP3A4. RESULTS: In the propofol group the mean clearance of midazolam was decreased by 37% (P = .005) and the mean elimination half-life was prolonged by 61% (P = .04) compared with the placebo group. The mean plasma concentrations of 1'-hydroxymidazolam were lower in the propofol group than in the placebo group at 5, 10, 15, 20, and 30 minutes after midazolam was administered (P < .05). The mean (+/-SD) Michaelis-Menten constant for midazolam 1'-hydroxylation by human liver microsomes was 5.6 +/- 3.3 micromol/L. The formation of 1'-hydroxymidazolam was competitively inhibited by propofol, and the mean inhibition constant was 56.7 +/- 16.6 micromol/L. The mean Michaelis-Menten constant and mean inhibition constant values for midazolam 1'-hydroxylation by recombinant CYP3A4 were 4.0 micromol/L and 61.0 micromol/L, respectively, consistent with the mean values obtained from human liver microsomes. CONCLUSION: Propofol decreases the clearance of midazolam, and the possible mechanism is the competitive inhibition of hepatic CYP3A4.     

PHARMACOKINETICS OF INTRAVENOUS MIDAZOLAM DURING EPIDURAL ANAESTHESIA

Midazolam concentration curves versus time were analysed in 10 otherwise healthy patients (ASA I-II) with inferior limb pathologies. The benzodiazepine was used as an adjuvant agent to epidural anaesthesia in view of its lower residual effect compared with other intravenous benzodiazepines. Midazolam pharmacokinetics in these patients fitted an open two-compartment model. The plasma levels versus time corresponded to a biexponential process with a very rapid distribution phase (t1/2a = 5.7 +/- 2.4 min) and an elimination phase (t1/2 beta = 66 +/- 37 min). Mean values for distribution volumes in the central compartment and extrapolated values were Vc = 0.12 +/- 0.04 l/kg and V beta = 1.28 +/- 0.92 l/kg. This kinetic behaviour explains the rapid but short duration of midazolam action. The induction time, estimated from the start of hypnosis (eye closure), was from 60 to 120 s with i.v. injection. The duration of action for the dose administered was from 15 to 60 min, with plasma levels below 90 ng/ml upon eye opening.     

Midazolam kinetics in women of two age groups

Midazolam kinetics were determined in 11 younger (22 to 30 yr) and 11 older (50 to 60 yr) women to determine age-related differences in the kinetics of this water-soluble benzodiazepine. Midazolam, 0.2 mg/kg, was injected intravenously over 30 sec for induction of anesthesia that was maintained with 67% nitrous oxide in oxygen and intravenous fentanyl doses. There were no differences between the groups with respect to awakening times or plasma concentrations. Midazolam kinetics were described by a three-compartment open mamillary model. The only differences were small increases in the slow and total volumes of distribution in the older women. The kinetics we determined, including the steady-state volume of distribution of 1.23 l/kg and the elimination clearance of 419 ml/min, are in excellent agreement with those reported by others. Our data suggest that midazolam has advantages over other benzodiazepines, not only because of its water solubility and shorter elimination t1/2, but also because of little change in its kinetics with age.