A population pharmacodynamic Markov mixed-effects model for determining remimazolam-induced sedation when co-administered with fentanyl in procedural sedation.

The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the Modified Observer's Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (Emax ) model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with body mass index greater than 25 kg/m2 had ~30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 µg. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 µg is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.

Multifaceted Bioanalytical Methods for the Comprehensive Pharmacokinetic and Catabolic Assessment of MEDI3726, an Anti-Prostate-Specific Membrane Antigen Pyrrolobenzodiazepine Antibody-Drug Conjugate.

Complex biotherapeutic modalities, such as antibody-drug conjugates (ADC), present significant challenges for the comprehensive bioanalytical characterization of their pharmacokinetics (PK) and catabolism in both preclinical and clinical settings. Thus, the bioanalytical strategy for ADCs must be designed to address the specific structural elements of the protein scaffold, linker, and warhead. A typical bioanalytical strategy for ADCs involves quantification of the Total ADC, Total IgG, and Free Warhead concentrations. Herein, we present bioanalytical characterization of the PK and catabolism of a novel ADC. MEDI3726 targets prostate-specific membrane antigen (PMSA) and is comprised of a humanized IgG1 antibody site-specifically conjugated to tesirine (SG3249). The MEDI3726 protein scaffold lacks interchain disulfide bonds and has an average drug to antibody ratio (DAR) of 2. Based on the structural characteristics of MEDI3726, an array of 4 bioanalytical assays detecting 6 different surrogate analyte classes representing at least 14 unique species was developed, validated, and employed in support of a first-in-human clinical trial (NCT02991911). MEDI3726 requires the combination of heavy-light chain structure and conjugated warhead to selectively deliver the warhead to the target cells. Therefore, both heavy-light chain dissociation and the deconjugation of the warhead will affect the activity of MEDI3726. The concentration-time profiles of subjects dosed with MEDI3726 revealed catabolism of the protein scaffold manifested by the more rapid clearance of the Active ADC, while exhibiting minimal deconjugation of the pyrrolobenzodiazepine (PBD) warhead (SG3199).

Generic Olanzapine Substitution in Patients With Schizophrenia: Assessment of Serum Concentrations and Therapeutic Response After Switching.

BACKGROUND: Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switching to generic olanzapine in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response. METHODS: Preswitching and postswitching serum olanzapine concentrations were compared in schizophrenic outpatients who were switched from a chronic treatment with branded olanzapine to the same dose of its generic alternative. The Positive and Negative Syndrome Scale was concurrently administered to assess modifications in schizophrenia symptom control. RESULTS: A total of 25 patients (13 women and 12 men, mean age 41.2 ± 12.8 years) concluded the study. Mean olanzapine dose was 12.2 ± 5.4 mg/d. The mean olanzapine serum concentrations decreased from 27.7 ± 14.4 ng/mL during treatment with the branded formulation to 22.6 ± 12.3 ng/mL after switching to the generic formulation (P < 0.01). The log-transformed ratio of generic/brand-name olanzapine serum concentration at steady state was 0.81 (90% confidence interval: 0.72-0.91). The total Positive and Negative Syndrome Scale scores did not significantly change after switching from branded to generic formulation (49.6 ± 8.3 versus 48.6 ± 9.5, P = 0.777). No patient exhibited disease relapse or required dose adjustment after switching. CONCLUSIONS: Significantly lower serum olanzapine concentrations were found after switching from branded to generic olanzapine. Although these modifications did not significantly impair schizophrenia symptoms control, it cannot be excluded that a longer exposure to lower olanzapine serum concentrations may result in relapse of schizophrenic symptoms. Generic substitution should be considered as an indication for therapeutic drug monitoring in psychiatry.

Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches.

Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition. Physiologically based pharmacokinetic (PBPK) modeling was used to predict steady-state conditions and terminal half-life based on known physicochemical and dispositional properties. The PopPK model described the anacetrapib data well, showing a likely third compartment with estimated apparent volume of 40,700 L. Anacetrapib's estimated half-life for this compartment was 550 days. Simulations for evacetrapib using a hypothetical 3-compartment model, the third compartment being consistent with that of the anacetrapib model, produced predictions inconsistent with reported results, indicating that evacetrapib did not substantially accumulate into a large compartment. The PBPK simulations were consistent with PopPK results, predicting accumulation for anacetrapib (but not evacetrapib) followed by very slow elimination. Based on available data and known physicochemical properties, evacetrapib is not expected to accumulate substantially during long-term treatment.

Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach.

OBJECTIVES: Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and pharmacodynamic modeling tools to relate CAT with D2RO in rats and to compare that with the relationship between D2RO and EPS in humans. METHODS: Severity of CAT was assessed in rats at hourly intervals over a period of 8 h after antipsychotic drug treatment. An indirect response model with and without Markov elements was used to explain the relationship of D2RO and CAT. RESULTS: Both models explained the CAT data well for olanzapine, paliperidone and risperidone. However, only the model with the Markov elements predicted the CAT severity well for clozapine and haloperidol. The relationship between CAT scores in rat and EPS scores in humans was implemented in a quantitative manner. Risk of EPS not exceeding 10% over placebo correlates with less than 86% D2RO and less than 30% probability of CAT events in rats. CONCLUSION: A quantitative relationship between rat CAT and human EPS was elucidated and may be used in drug discovery to predict the risk of EPS in humans from D2RO and CAT scores measured in rats.

Quantitative drug benefit-risk assessment: utility of modeling and simulation to optimize drug safety in older adults.

BACKGROUND: More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging. OBJECTIVE: The aim of this study is to evaluate the use of modeling, simulation, and risk-benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk. METHODS: The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ≥50 years old, who had been on oral olanzapine for ≥2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint. RESULTS: The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit-risk balance was 17.8 mg/d. CONCLUSIONS: Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed.

A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation.

BACKGROUND: A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. METHODS: A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. RESULTS: A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 µg/mL; γ: 1.6, 8.6; k(e0): 0.14, 0.053 min(-1); I(MAX): 39, 19, and MOAA/S-IC(50): 0.4, 0.08 µg/mL; γ: 1.4, 3.4; k(e0): 0.25, 0.050 min(-1) for remimazolam and midazolam, respectively. Simulations to obtain >70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%-74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at >2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%-91%) of the treated population after this loading/maintenance dose regimen. CONCLUSIONS: Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65-90 kg).

Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: expected variations in clearance.

BACKGROUND AND OBJECTIVES: The maintenance dose of a drug is dependent on drug clearance, and thus any biochemical and physiological changes in obesity that affect parameters such as cardiac output, renal function, expression of drug-metabolizing enzymes and protein binding may result in altered clearance compared with that observed in normal-weight subjects (corrected or uncorrected for body weight). Because of the increasing worldwide incidence of obesity, there is a need for more information regarding the optimal dosing of drug therapy to be made available to prescribers. This is usually provided via clinical studies in obese people; however, such studies are not available for all drugs that might be used in obese subjects. Incorporation of the relevant physiological and biochemical changes into predictive bottom-up pharmacokinetic models in order to optimize dosage regimens may offer a logical way forward for the cases where no clinical data exist. The aims of the current report are to apply such a 'systems approach' to identify the likelihood of observing variations in the clearance of drugs in obesity and morbid obesity for a set of compounds for which clinical data, as well as the necessary in vitro information, are available, and to provide a framework for assessing other drugs in the future. METHODS: The population-specific changes in demographic, physiological and biochemical parameters that are known to be relevant to obese and morbidly obese subjects were collated and incorporated into two separate population libraries. These libraries, together with mechanistic in vitro-in vivo extrapolations (IVIVE) within the Simcyp Population-based Simulator™, were used to predict the clearance of oral alprazolam, oral caffeine, oral chlorzoxazone, oral ciclosporin, intravenous and oral midazolam, intravenous phenytoin, oral theophylline and oral triazolam. The design of the simulated studies was matched as closely as possible with that of the clinical studies. Outcome was measured by the predicted ratio of the clearance of the drug in obese and lean subjects ± its 90% confidence interval, compared with observed values. The overall statistical measures of the performance of the model to detect differences in compound clearance between obese and lean populations were investigated by measuring sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A power calculation was carried out to investigate the impact of the sample size on the overall outcome of clinical studies. RESULTS: The model was successful in predicting clearance in obese subjects, with the degree to which simulations could mimic the outcome of in vivo studies being greater than 60% for six of the eight drugs. A clear difference in the clearance of chlorzoxazone was correctly picked up via simulation. The overall statistical measures of the performance of the Simcyp Simulator were 100% sensitivity, 66% specificity, 60% PPV and 100% NPV. Studies designed on the basis of the ratio of the absolute values required substantial numbers of participants in order to detect a significant difference, except for phenytoin and chlorzoxazone, where the ratios of the weight-normalized clearances generally showed statistically significant differences with a smaller number of subjects. CONCLUSION: Extension of a mechanistic predictive pharmacokinetic model to accommodate physiological and biochemical changes associated with obesity and morbid obesity allowed prediction of changes in drug clearance on the basis of in vitro data, with reasonable accuracy across a range of compounds that are metabolized by different enzymes. Prediction of the effects of obesity on drug clearance, normalized by various body size scalars, is of potential value in the design of clinical studies during drug development and in the introduction of dosage adjustments that are likely to be needed in clinical practice.

Agitation in the inpatient psychiatric setting: a review of clinical presentation, burden, and treatment.

Agitation among psychiatric inpatients (particularly those diagnosed with schizophrenia or bipolar disorder) is common and, unless recognized early and managed effectively, can rapidly escalate to potentially dangerous behaviors, including physical violence. Inpatient aggression and violence have substantial adverse psychological and physical consequences for both patients and providers, and they are costly to the healthcare system. In contrast to the commonly held view that inpatient violence occurs without warning or can be predicted by "static" risk factors, such as patient demographics or clinical characteristics, research indicates that violence is usually preceded by observable behaviors, especially non-violent agitation. When agitation is recognized, staff should employ nonpharmacological de-escalation strategies and, if the behavior continues, offer pharmacological treatment to calm patients rapidly. Given the poor therapeutic efficacy and potential for adverse events associated with physical restraint and seclusion, and the potential adverse sequelae of involuntary drug treatment, these interventions should be considered last resorts. Pharmacological agents used to treat agitation include benzodiazepines and first- and second-generation antipsychotic drugs. Although no currently available agent is ideal, recommendations for selecting among them are provided. There remains an unmet need for a non-invasive and rapidly acting agent that effectively calms without excessively sedating patients, addresses the patient's underlying psychiatric symptoms, and is reasonably safe and tolerable. A treatment with these characteristics could substantially reduce the clinical and economic burden of agitation in the inpatient psychiatric setting.

The impact of benzodiazepines on safe driving.

OBJECTIVE: Benzodiazepines are prescribed to relieve anxiety and aid sleep. Studies demonstrate that benzodiazepines increase odds of crash involvement, but little evidence exists regarding their impact on crash responsibility. We examined the impact of benzodiazepines on crash responsibility by drug half-life and driver age, using a case-control design with drivers aged 20 and over involved in fatal crashes in the United States from 1993-2006. METHODS: Drivers (all with BAC = 0) were classified as having no benzodiazepines detected versus short, intermediate, or long half-life benzodiazepines. Cases were drivers with at least one potentially unsafe driving action (UDA) in relation to the crash (e.g., speeding), a proxy measure for crash responsibility; controls had no UDAs recorded. Odds ratios (ORs) of any UDA by benzodiazepines half-life exposure were calculated, with adjustment for age, sex, other medication usage, and prior driving record. RESULTS: Compared with drivers not using benzodiazepines, drivers taking intermediate or long half-life benzodiazepines demonstrated increased odds of an UDA from ages 25 (intermediate OR: 1.59; 95% CI = 1.08, 2.33; long OR: 1.68; 95% CI = 1.34, 2.12) to 55 (intermediate OR: 1.50; 95% CI = 1.09, 2.06; long OR: 1.33; 95% CI = 1.12, 1.57). Drivers taking short half-life benzodiazepines did not demonstrate increased odds compared to drivers not using benzodiazepines. CONCLUSIONS: Given the potential impact of benzodiazepines on driver safety, further experimental research is needed to better understand the effect of benzodiazepines on crash responsibility.

In vitro metabolism of indiplon and an assessment of its drug interaction potential.

This study was designed to study the in vitro metabolism of indiplon, a novel hypnotic agent, and to assess its potential to cause drug interactions. In incubations with pooled human liver microsomes, indiplon was converted to two major, pharmacologically inactive metabolites, N-desmethyl-indiplon and N-desacetyl-indiplon. The N-deacetylation reaction did not require NADPH, and appeared to be catalyzed by organophosphate-sensitive microsomal carboxylesterases. The N-demethylation of indiplon was catalyzed by CYP3A4/5 based on the following observations: (1) the sample-to-sample variation in N-demethylation of indiplon ([S] = 100 microM) in a bank of human liver microsomes was strongly correlated with testosterone 6beta-hydroxylase (CYP3A4/5) activity (r(2) = 0.98), but not with any other CYP enzyme; (2) recombinant CYP1A1, CYP1A2, CYP3A4, CYP3A5 and CYP3A7 had the ability to catalyze this reaction; (3) the N-demethylation of indiplon was inhibited by CYP3A4/5 inhibitors (ketoconazole and troleandomycin), but not by a CYP1A2 inhibitor (furafylline). In pooled human liver microsomes, indiplon exhibited a weak capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5 and carboxylesterase (p-nitrophenylacetate hydrolysis) activities (IC50 >/= 20 microM). Clinical data available on indiplon support the conclusions of this paper that the in vitro metabolism of indiplon is catalyzed by multiple enzymes, and indiplon is a weak inhibitor of human CYP enzymes.

Development and validation of a sensitive liquid chromatography/electrospray tandem mass spectrometry assay for the quantification of olanzapine in human plasma.

A simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the quantification of olanzapine, atypical antipsychotic drug, in human plasma using loratadine as internal standard (IS). Following liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a reverse phase C18 column and analyzed by MS in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 313/256 for olanzapine and m/z 383/337 for the IS. The assay exhibited a linear dynamic range of 0.1-30 ng/mL for olanzapine in human plasma. The lower limit of quantification was 100 pg/mL with a relative standard deviation of less than 10%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The average absolute recovery of olanzapine from spiked plasma samples was 85.5+/-1.9%. A run time of 2.0 min for each sample made it possible to analyze more than 400 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability or bioequivalence studies.

A 5-year prospective assessment of the risk associated with individual benzodiazepines and doses in new elderly users.

OBJECTIVES: To determine the risk of injury associated with the new use of individual benzodiazepines and dosage regimens in the elderly. DESIGN: Prospective database cohort study with 5 years of follow-up. SETTING: Quebec, Canada. PARTICIPANTS: Two hundred fifty-three thousand two hundred forty-four persons aged 65 and older who were nonusers of benzodiazepines in the year before follow-up. MEASUREMENTS: Population-based hospitalization and prescription and medical services claims databases were used to compare the risk of injury during periods of benzodiazepine use with those of nonuse. Periods of use were measured for 10 insured benzodiazepines by drug and dose as time-dependent covariates. Injury was defined as the first occurrence of a nonvertebral fracture, soft-tissue injury, or accident-related hospital admission. Patient age, sex, previous injury history, concomitant medication use, and comorbidity were measured as fixed and time-dependent confounders. Cox proportional hazards models were used to estimate the risk of injury with benzodiazepine use and to determine the extent to which patient characteristics, differences in dosage, or in the effect of increasing dosage for individual drugs explained differences between drugs. RESULTS: More than one-quarter (27.6%) of 253,244 elderly were dispensed at least one prescription for a benzodiazepine, and 17.7% of elderly were treated for at least one injury during follow-up, of which fractures were the most common. Patient characteristics, systematic differences in the risk of injury in elderly prescribed different benzodiazepines, and differences in dosage prescribed for individual drugs confounded the risk of injury with benzodiazepine use. The risk of injury with increasing dosage varied by drug from a hazard ratio of 0.92 (95% confidence interval (CI)=0.60, 1.42) for alprazolam to 2.20 (95% CI=1.39, 3.47) for flurazepam per 1 standardized adult dose increase. CONCLUSION: The risk of injury varied by benzodiazepine, independent of half-life, as did the risk associated with increasing dosage for individual products. Higher doses of oxazepam, flurazepam, and chlordiazepoxide are associated with the greatest risk of injury in the elderly.

Olanzapine: a review of its use in the management of bipolar I disorder.

Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder, and for maintenance therapy to prevent recurrence in responders. Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics, such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders, and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated, and although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms (EPS). Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.

In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions.

The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with Ki values of 8.40, 0.08 and 0.39 microM, respectively. However, the Ki for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ.

The costs of benzodiazepine-associated hospital-treated fall Injuries in the EU: a Pharmo study.

OBJECTIVE: To estimate the hospitalisation costs of accidental fall injuries in the EU resulting from the use of benzodiazepines. METHODS: Risk and exposure data were obtained from the Dutch Pharmo system, a population-based register of drug-dispensing records and hospital records. The population attributable risk (PAR) was calculated using the age-specific prevalence estimates of benzodiazepine use and the corresponding relative risk (RR), obtained from a case-control study in community-dwelling inhabitants over 55 years of age in defined areas of The Netherlands covering the period 1985-2000. Annual hospitalisation costs of benzodiazepine-related fall injuries were based on the age-specific PARs and extrapolated to the European population using accident and demographic data of the EU. All analyses were performed from the perspective of a third-party payer. RESULTS: Fall injuries in the study population were significantly associated with benzodiazepine use (RR 1.6, 95% CI 1.4-1.7), especially in those aged over 85 years (RR 3.6, 95% CI 2.9-4.5). The total annual hospital direct medical costs in 2000 of fall-related injuries attributable to benzodiazepine use were Euro 1.8 billion (95% CI Euro 1.5-2.2 billion) in the EU. CONCLUSIONS: The estimated costs of hospitalisations of accidental-fall injuries related to benzodiazepine use in the EU varied between Euro 1.5 and Euro 2.2 billion each year. More than 90% of these costs were in the elderly, with hip fractures as the major contributor. Discontinuing benzodiazepines in the elderly and/or substituting them with other drugs not associated with the risk of falls in the elderly will to a large extent prevent these accidents.

Incorporating measures of variability and uncertainty into the prediction of in vivo hepatic clearance from in vitro data.

The existing procedures for quantitative in vitro-in vivo clearance prediction can be significantly biased either by totally neglecting the existing variability and uncertainty by using mean parameter values or by implementing Monte Carlo simulation with statistical distribution of the parameters reconstructed from very small sets of data. The aim of the present study is to develop a methodology for the prediction of in vivo hepatic clearance in the presence of semiquantitative or qualitative data and accounting for the existing uncertainty and variability. The method consists of two steps: 1) transformation of the information available into fuzzy sets (fuzzification); and 2) computation of the in vivo clearance using arithmetic operations with fuzzy sets. To illustrate the approach, rat hepatocyte and microsomal data for eight benzodiazepine compounds are used. A comparison with a standard Monte Carlo procedure is made. The methodology proposed can be used when Monte Carlo simulation may be biased or cannot be implemented. The obtained fuzzy in vivo clearance can be used subsequently in fuzzy simulations of pharmacokinetic models.

Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture.

OBJECTIVE: While benzodiazepine treatment is known to increase the risk of hip fracture in older populations, controversy persists over which characteristics of benzodiazepine use (e.g., elimination half-life, dosage, duration of use) are most associated with such risks. METHOD: The authors reviewed the health care utilization data of 1,222 hip fracture patients and 4,888 comparison patients frequency matched on the basis of age and gender (all were at least 65 years old). Patients were enrolled in Medicare as well as in the New Jersey Medicaid or Pharmaceutical Assistance to the Aged and Disabled programs. Benzodiazepine use, as well as other covariates, were assessed before the index date (which was either the date of hospital admission for hip fracture surgical repair or, for the comparison subjects, a randomly assigned, frequency-matched date). RESULTS: All benzodiazepine doses > or =3 mg/day in diazepam equivalents significantly increased the adjusted risk of hip fracture by 50%. Significantly increased adjusted risks of hip fracture were seen during the initial 2 weeks of use (60% increase) and after more than 1 month of continuous use (80% increase) but not for 2-4 weeks of continuous use. Use of benzodiazepines other than long-acting agents significantly increased the risk of hip fracture by 50%. CONCLUSIONS: Even at modest doses, including some low doses currently advocated in prescribing guidelines for older patients, treatment with benzodiazepines appears to increase the risk of hip fracture. Patients appear to be particularly vulnerable immediately after initiating therapy and after more than 1 month of continuous use. Benzodiazepines with shorter half-lives appear to be no safer than longer half-life agents. Clinicians should be aware of these risks and weigh them against potential benefits when prescribing for elderly patients.

Sedation in the intensive care unit: an overview.

Sedation in the critically ill patient is essential to ensure maximal quality of life in the high-stress environment of the intensive care unit. The main goals of sedation include augmentation of pain control, management of agitation and psychological distress, and improvement of patient tolerance and acceptance of the endotracheal tube and ventilatory support. Ideally, the sedated patient should be asleep yet easily rousable. This is most commonly achieved in practice with a combination of morphine and benzodiazepines although a variety of combinations of drugs have been utilized. Other agents which have been employed include, other opiates such as fentanyl and sufentanil, butyrophenones such as haloperidol, and anesthetics such as propofol. These agents will be reviewed with respect to their role in sedating the critically ill patient.

Practical considerations in anticonvulsant therapy--Part 2.

Epilepsy is, for many patients, a lifelong condition that requires treatment with powerful drugs whose doses must be carefully titrated to avoid both breakthrough seizures and toxicity. The medication regimens used to treat epilepsy are further complicated by the fact that most seizure medications are metabolized in the liver and have the potential for serious pharmacokinetic drug-drug interactions with many other medications. Successful management of epilepsy requires a high degree of cooperation among the patient, the pharmacist, and the treating physician. Such cooperation can ensure that the appropriate treatment and drug preparation are selected, compliance is maintained, and dangerous drug-drug interactions are avoided.