Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics

Itraconazole is a triazole antifungal agent with a broad spectrum of activity. It is well tolerated and highly efficacious, particularly because its main metabolite, hydroxy-itraconazole, also has considerable antifungal activity. Two new formulations of itraconazole, an oral solution and an intravenous formulation, have recently been developed, which combine lipophilic itraconazole with cyclodextrin. These formulations have improved the solubility of itraconazole, leading to enhanced absorption and bioavailability compared with the original capsule formulation, without having an impact on the tolerability profile of itraconazole. The oral solution and intravenous formulations of itraconazole produce consistent plasma concentrations and are ideal for the treatment of systemic fungal infections in a wide range of patient populations. The additional flexibility offered by the different routes of administration means that itraconazole treatment can be specifically tailored for use in all patients, including children and those requiring intensive care.     

Different effects of light food on pharmacokinetics and pharmacodynamics of three benzodiazepines, quazepam, nitrazepam and diazepam

OBJECTIVE: Quazepam, nitrazepam and diazepam are administered under fed or fasted conditions for insomnia or anxiety disorder. Light bedtime food may have clinically relevant effects on the plasma levels of those drugs and hence on psychomotor performance. This study assessed the effect of light food on the pharmacokinetics and pharmacodynamics of these drugs. METHOD: Twenty-one eligible subjects were randomized to one of three groups of seven subjects: quazepam 20 mg, diazepam 5 mg or nitrazepam 5 mg. Each healthy subject took a single oral dose of the assigned drug after overnight fasting and after light food, on a separate occasion. Blood samples were collected until 72 h after dosing. The plasma samples were assayed using high-pressure liquid chromatography with spectrophotometric detection. Reaction time, critical flicker fusion test and visual analogue scales were conducted. RESULTS: The peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) of quazepam with light food were 1.2-fold [90% confidence interval (CI): 1.1-1.5; P < 0.05] and 1.5-fold (90% CI: 1.3-1.9; P < 0.05) higher than that without light food, respectively. For nitrazepam and diazepam, the time to peak was delayed about 1 h in fed condition (P > 0.05). However it had no effect on their C(max) and AUC. Reaction time of quazepam with light food was prolonged at 4 and 6 h after dosing and its area under the effect-time curve from 0 to 10 h was increased (P < 0.05). CONCLUSION: Light food increased the bioavailability of quazepam and affected psychomotor performance. Light food delayed T(max) of nitrazepam and diazepam but had no effect on C(max) and AUC.     

Population pharmacokinetics and pharmacodynamics of biapenem in paediatric patients

Objective: To develop a population pharmacokinetic model for biapenem in paediatric patients and to use the parameter estimates to assess pharmacodynamic exposure of common bacterial populations. Methods: Biapenem plasma concentrations (n = 125) from 25 paediatric patients were analysed using nonmem . The parameter estimates were used in a Monte Carlo simulation to predict the exposure time during which the drug concentration remains above the minimum inhibitory concentration. Results: A two‐compartment model fitted the data, and creatinine clearance (CL_cr) and total body weight (TBW) were the most significant covariates. The final model was CL (L/h) = 0·0458 × CL_cr, V_c (L) = 0·162 × TBW, Q (L/h) = 2·05, V_p (L) = 1·73, where CL is the clearance, V_c is the volume of distribution of the central compartment, Q is the intercompartmental clearance and V_p is the volume of distribution of the peripheral compartment. Biapenem regimens of 5 mg/kg q8h and 10 mg/kg q8h provided sufficient pharmacodynamic exposures to Pseudomonas aeruginosa and Streptococcus pneumoniae in most typical patient populations. Conclusion: These results better define the pharmacokinetics of biapenem and help in the choice of the appropriate dosage regimens for paediatric.     

Population pharmacokinetics of intravenous itraconazole in patients with persistent neutropenic fever

Purpose:  Empirical use of intravenous (IV) itraconazole (ITZ) for febrile neutropenic patients has recently been introduced in Korea. This study was designed to investigate the population pharmacokinetics (PK) of IV-ITZ.
Methods:  Sparse PK data were collected from febrile neutropenic patients undergoing empirical ITZ therapy at 200 mg/day after loading doses. NONMEM (Version. 5·1·1) was used to estimate population PK parameters.
Results:  Forty-two patients were enrolled in the study. Mean population CL and V of IV-ITZ were 10 L/h and 1050 L, respectively. Body weight was the only contributing covariate of CL. The median simulated trough concentration of ITZ after 10 days was predicted to be about 700 ng/mL.
Conclusions:  In this study, we explored the population PK profile of ITZ given in IV formulation. We found that the current dosage regimen of IV-ITZ (200 mg/day) was appropriate to obtain therapeutic trough concentrations for neutropenic patients in Korea.     

头孢曲松-舒巴坦复方制剂体外药动学/药效学研究

目的 通过体外药动学/药效学(PK/PD)研究,确定头孢曲松-舒巴坦(4:1)对产超广谱β内酰胺酶(ESBL)肠杆菌科细菌作用特点,评价其组方的合理性.方法 建立体外PK/PD模型,模拟人体单剂静脉注射头孢曲松、头孢曲松-舒巴坦(4:1)(同步与非同步消除)、头孢哌酮、头孢哌酮-舒巴坦(1:1)药动学过程,比较药物对肺...     

The individual variation in pharmacokinetics and pharmacodynamics of furosemide in young normal male subjects

Abstract. Following a 24 h control period in the ward 80 mg furosemide was injected intravenously to ten young healthy, male volunteers. The serum clearance of furosemide (Cl_s) was between 140 and 201 ml min^-1 and on the average the renal clearance was 66% of Cl_s. During the initial 30 min period a maximum additional excretion rate of sodium of 3·3 mmol min^-1 was reached at an excretion rate of 0·8 mg furosemide min^-1. A marked initial drop in creatinine clearance (Cl_cr) was noted and Cl_{cr(24 h)} showed an average decrease of 12% after the drug administration. The serum concentration of potassium was decreased at 1 and 2 h after the injection and of sodium from 2 h and on. The concentration of albumin in serum increased by 3% ( P < 0·05) already after 5 min. After 2 h a maximum increase of 14% was reached. After 8 min diastolic blood pressure was increased by 13% ( P < 0·05), whereas systolic blood pressure reached a significant decrease gradually (7% after 3 h).     

Paracetamol revisited: A review of the pharmacokinetics and pharmacodynamics

Paracetamol is an important drug in the armoury of the acute pain clinician, yet many of us know little of its pharmacodynamics and pharmacokinetics. In this review we discuss the mechanism of action of paracetamol, including the role of central prostaglandin synthesis, serotonergic pathways and spinally mediated mechanisms of action. We review the importance of the formulation and route of administration on the plasma level achieved and have included a section on the intravenous use of the prodrug, which has many advantages over the rectal route.We discuss the way in which paracetamol may be metabolised and excreted. Current guidelines recommend a dose not exceeding 90 mg kg⁻¹ day⁻¹.Many workers have sought to compare the efficacy of paracetamol with that of paracetamol/mild opiate combinations and non-steroidal anti-inflammatory drugs (NSAIDs). We have conducted an exhaustive review of the literature and found that for many types of pain, the addition of codeine to paracetamol conveys some advantage. For dental pain in particular, NSAIDs are superior to either paracetamol alone or in combination with weak opiates. We have discovered that little work has been done to establish the E_max for analgesia with paracetamol and that in view of this, studies comparing paracetamol with combination preparations or NSAIDs are, to some degree, invalid.     

Perioperative pharmacology: pharmacotherapeutics, pharmacokinetics, and pharmacodynamics

Results of current research into perioperative medication errors have revealed that more than half of medication errors occur during the administration phase of the medication-use process. The administration phase is the point at which the medication and the patient intersect and the medication imposes its pharmacological effect. During this phase, the only safety net between the patient and the medication is the health care provider's attention and care when administering the medication. To help mitigate these errors, perioperative nurses must understand pharmacotherapeutics: the use of medications to prevent, treat, cure, or alleviate symptoms of disease. Pharmacotherapeutics incorporates pharmacokinetics (ie, what the body does to a medication after it enters the system) and pharmacodynamics (ie, how a medication acts on the body to achieve a desired therapeutic effect).     

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers

Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography–tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post‐dose. Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC_0–∞ and C_max in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 μg·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 μg/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half‐life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (ΔC_glu11) in group C was significantly higher than that of group A (?1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.     

Combination of long-acting furosemide and instant-acting amiloride: pharmacokinetics and pharmacodynamics in human subjects

Summary— The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 times 2.5 mg) and long-acting furosemide (2 times 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 ± 1.6 years and weighing 68.8 ± 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption ( t _max = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half-life was 2.77 ± 1.04 h after the combination treatment and 2.76 ± 0.98 h alone, amiloride plasma half-life was respectively 15.7 ± 4.6 h and 14.6 ± 3.7 h. The urinary elimination of furosemide was significantly higher in the 2–4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased ( P < 0.01) and the potassium excretion was significantly decreased ( P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.     

Reduced oral itraconazole bioavailability by antacid suspension

AIMS: To investigate the effects of antacid suspension on oral absorption of itraconazole. METHODS: A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: Time to reach maximal concentration (Tmax), maximal concentration (Cmax) and area under the curve (AUC0-infinity) were markedly decreased in antacid-treated group. Tmax for treatment A was 3.0 +/- 0.4 and 5.1 +/- 2.7 h for treatment B. Cmax and AUC0-infinity of treatments A and B were 146.3 +/- 70.5 vs. 43.6 +/- 16.9 (ng/mL) and 1928.5 +/- 1114.6 vs. 654.8 +/- 452.2 (ng x h/mL) respectively. 90% Confidence interval (90% CI) of Cmax and AUC0--infinity were 24.1-42.1 and 16.2-65.9 respectively. CONCLUSIONS: Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided.     

Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease

Objective:  The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment.
Methods:  Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n  = 12) or moderate renal impairment ( n  = 10) and matched healthy subjects with normal renal function ( n  = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD ( n  = 16) and matched healthy subjects with normal renal function ( n  = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 μ m adenosine diphosphate as agonist.
Results:  Across all studies, prasugrel's C _max and AUC_{0– t} were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC_{0– t} did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects.
Conclusion:  There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.     

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people

BACKGROUND: To investigate whether the pharmacodynamics and pharmacokinetics of omeprazole (OPZ) are dependent of the CYP2C19 genotype status in Chinese people. METHODS: Eighteen healthy subjects were voluntary to participate in the study, whose CYP2C19 genotype status were determined by polymerase chain reaction-restriction fragment length polymorphism method. There were six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers (PMs). All subjects were Helicobacter pylori-negative, determined by serology method and (13)C-urea breath test. After d1 and d8 orally received OPZ 20 mg once daily in the morning, intragastric pH values were monitored for 24 h by Digitrapper pH. Meanwhile, blood samples were collected at various time-points until 24 h after administration. The serum concentrations of OPZ were measured by liquid chromatography. RESULTS: After single or repeated doses, the PMs showed a significantly higher mean area under the serum concentration-time curves (AUC) values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers, with a relative ratio of 1.0 : 1.1 : 4.2 and 1.0 : 1.3 : 3.3 (homozygous extensive metabolizers:heterozygous extensive metabolizers:poor metabolizers), respectively. After a single dose of OPZ, significant differences in intragastric pH median, pH > 3 holding time and pH > 4 holding time were observed among the three groups. After repeated doses, the PMs showed a significantly higher intragastric pH values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers. CONCLUSION: The pharmacodynamic effects of OPZ and its pharmacokinetics depend on the CYP2C19 genotype status in Chinese people.     

Population pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients

The aims of this study were to develop a population pharmacokinetic model for meropenem in Japanese pediatric patients, and to use this model to assess the pharmacodynamics of meropenem regimens against common bacterial populations. Pharmacokinetic data were pooled from nine separate studies (229 plasma samples and 61 urine samples from 40 infected children), modeled using the NONMEM program, and used for a pharmacodynamic simulation to estimate the probabilities of attaining the bactericidal target (40% of the time above the MIC for the bacterium). In the final population pharmacokinetic model, body weight (BW, kg) was the most significant covariate: Cl_r (l/h) = 0.254 × BW, Cl_nr (l/h) = 3.45, V _c (l) = 0.272 × BW, Q (l/h) = 1.65, and V _p (l) = 0.228 × BW, where Cl_r and Cl_nr are the renal and non-renal clearances, V _p and V _c are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central–peripheral) clearance. In most typical patients (BW = 10, 20, and 30 kg), the approved regimens of 10–40 mg/kg, three times a day (0.5-h infusions), achieved a target attainment probability of >80% against Escherichia coli, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa isolates. The results of this study provide a better understanding of the pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.     

Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in healthy Korean subjects

What is known and Objective: Dexmedetomidine is a selective alpha2‐adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects. Methods: A randomized, double‐blind, placebo‐controlled study with three parallel dosage groups was conducted. Twenty‐four subjects were randomly assigned to placebo or one of three dexmedetomidine dosing regimens, 3 μg/kg/h for 10 min followed by 0·17 μg/kg/h for 50 min (low dose), 6 μg/kg/h for 10 min followed by 0·34 μg/kg/h for 50 min (middle dose) and 3·7 μg/kg/h for 35 min followed by 0·7 μg/kg/h for 25 min (high dose). Serial blood samples for PK analysis were taken up to 12 h. PK parameters were determined using non‐compartmental methods (WinNonlin^®), and a population PK model was developed using nonmem ^®. The sedative effect of dexmedetomidine was assessed by Ramsay sedation score and visual analogue scales/sedation. Adverse events, clinical laboratory tests, electrocardiograms, physical examinations and vital signs were monitored for tolerability assessment. Results: Six subjects were assigned to each of the three active treatment group or placebo group. The AUC_last of the low‐, middle‐ and high‐dose group were 1096·8 ± 119·9 (mean ± SD) ng*h/L, 2643·0 ± 353·2 ng*h/L and 5600·6 ± 411·0 ng*h/L, respectively. PK of dexmedetomidine was best described using a two‐compartment model. The typical value of the population model can be calculated using the following equations: central volume of distribution (L) = 19·9 (age/27)^0·954, peripheral volume of distribution (L) = 59·4, clearance (L/h) = 33·7 (albumin level/4·3)^1·42 and inter‐compartment clearance (L/h) = 67·7. Sedative effects were significantly increased by dexmedetomidine compared to placebo. The blood pressure and heart rate were decreased, but oxygen saturation was maintained stable. What is new and Conclusion: Dexmedetomidine shows linear PK characteristics and dose‐dependent sedative effects. A two‐compartment population PK model was developed for healthy Korean subjects. The PK parameter estimates are similar in Koreans and Caucasians.     

Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin

Introduction  The pharmacokinetic/pharmacodynamic effects of warfarin were assessed in the presence and absence of taranabant, an orally active, highly selective, potent, cannabinoid-1 receptor inverse agonist, which was being developed for the treatment of obesity. Methods  Twelve subjects were assigned to two open-label treatments in fixed sequence separated by a 14-day washout. Treatment A was single-dose warfarin 30 mg on day 1. Treatment B was multiple-dose taranabant 6 mg each day for 21 days (days −14 to day 7) with coadministration of singledose warfarin 30 mg on day 1. Blood samples were collected predose and up to 168 hours postdose for assay of R(+)-and S(−)-warfarin and prothrombin time/international normalized ratio (PT/INR). Results  The geometric mean ratios (GMR; warfarin+taranabant/warfarin 90% confidence interval [CI] primary endpoints) for area under the curve (AUC)_0-∞ for R(+)-and S(−)-warfarin were 1.10 (90% CI: 1.03, 1.18) and 1.06 (90% CI: 1.00, 1.13), respectively. The GMRs (warfarin+taranabant/warfarin) for the maximum plasma concentration (C_max) of S(−)-and R(+)-warfarin were 1.16 (90% CI: 1.05, 1.28) and 1.17 (90% CI: 1.07, 1.29), respectively. For R(+)-and S(−)-warfarin, the 90% CIs for AUC_0-∞ GMRs fell within the prespecified bounds. Taranabant did not produce a clinically meaningful effect on PT/INR. Conclusion  No clinically significant alterations of the pharmacokinetics of R(+)-and S(−)-warfarin were seen following coadministration of multipledose taranabant 6 mg and single-dose warfarin 30 mg.     

Intrapulmonary pharmacokinetics and pharmacodynamics of itraconazole and 14-hydroxyitraconazole at steady state

We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (C(max)) (mean +/- standard deviation) in plasma, ELF, and AC were 2.1 +/- 0.8 and 3.3 +/- 1.0, 0.5 +/- 0.7 and 1.0 +/- 0.9, and 5.5 +/- 2.9 and 6.6 +/- 3.1 microg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 microg. hr/ml. The ratio of the C(max) and the MIC at which 90% of the isolates were inhibited (MIC(90)), the AUC/MIC(90) ratio, and the percent dosing interval above MIC(90) for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.     

The effects of diazepam on anxiety-related cognition

It has generally been assumed that the therapeutic action of benzodiazepines results from the effect of these drugs on mood. We suggest, however, that in reducing anxiety, benzodiazepines may have a direct effect on anxiety-related cognitions. The investigation was designed to examine the question of whether anxiety-related cognitive bias is reduced by diazepam in subjects selected according to DSM-III(R) criteria for generalized anxiety disorder (American Psychiatric Association, 1987). A modification of the Stroop color-naming task was used to measure bias toward the processing of threatening material. The results demonstrate that the reduction in anxiety shown by anxious patients after diazepam is not accompanied by a reduction in cognitive bias toward the processing of threatening material. This suggests that diazepam fails to reduce anxiety-related cognitive bias in clinically anxious subjects. It would seem, therefore, that diazepam alleviates anxious mood rather than cognitive manifestations of anxiety.We would like to thank Malcolm Lader and Andrew Mathews for their help in developing this research. We would also like to thank the Medical Research Council for supporting the investigation.     

The effect of age on the pharmacokinetics and pharmacodynamics of midazolam.

OBJECTIVE: We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect. METHODS: Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model. RESULTS: The total doses needed to reach the defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age. CONCLUSIONS: These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.     

The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam

To determine the effect of fluoxetine on diazepam's pharmacokinetic and psychomotor responses, single oral doses of 10 mg diazepam were administered to six normal subjects on three occasions, either alone or in combination with 60 mg fluoxetine. Diazepam was given alone, after a single dose of fluoxetine, and after eight daily doses of fluoxetine. Psychometric data showed that fluoxetine had no significant effect on the psychomotor responses to diazepam. However, the pharmacokinetic data indicated a change in diazepam disposition after fluoxetine administration. Diazepam AUC was larger, the half-life was longer, and the plasma clearance was lower after fluoxetine administration, suggesting that fluoxetine inhibited the metabolism of diazepam. The reduced formation of an active metabolite, N-desmethyldiazepam, also suggested that fluoxetine inhibited diazepam's metabolism. The clinical implications of this pharmacokinetic drug-drug interaction are minor because psychomotor responses were unaffected and offsetting changes in the kinetics of diazepam and its metabolite occurred. Dosage modification of either fluoxetine or diazepam is unlikely to be necessary.