Bioavailability of three formulations of intravenous diazepam

Fee, J. P. H.; Collier, P. S.; Dundee, J. W.

doi:10.1111/j.1399-6576.1986.tb02426.x

Cited by 7 publications

(6 citation statements)

References 18 publications

(16 reference statements)

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“…There are examples of IV drugs in which the pharmacokinetic profiles have been significantly altered when a lipid emulsion was introduced as an emulsifier; known examples are propofol and diazepam [23, 56–58]. Taking this into account, the estimated within-subject CV was estimated to be 35 % when designing the study.…”

Section: Discussionmentioning

confidence: 99%

Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor® EL

Ehinger

Hansson

Sjövall

et al. 2012

Clinical Drug Investigation

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BackgroundCiclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro- and cardioprotection. The intravenous formulation currently on the market, Sandimmune® Injection (Sandimmune®), uses Cremophor® EL as emulsifying excipient. Cremophor® EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock.ObjectivesThe primary objective was to assess if CicloMulsion®, a Cremophor® EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune®, and the secondary objective was to compare the tolerability profiles of the two preparations.MethodsThis was a single-centre, open-label, subject-blind, laboratory-blind, single-dose, randomized, two-treatment, two-period, two-sequence crossover study of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according to current guidelines were performed.ResultsThe geometric mean ratios for CicloMulsion®/Sandimmune® (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC0–last (area under the blood concentration–time curve from time zero to time of last measurable concentration) and 0.95 (0.92, 0.97) for Cmax (maximum blood concentration). For all additional variables analysed, the 90 % CIs were also within the accepted bioequivalence range of 0.80–1.25. One anaphylactoid and one anaphylactic reaction, both classified as serious adverse events, were reported after treatment with Sandimmune®. No serious adverse events were recorded after treatment with CicloMulsion®.ConclusionWe have assessed the pharmacokinetics and tolerability of a new Cremophor® EL-free lipid emulsion of ciclosporin, CicloMulsion®, compared to Sandimmune®. The proportion of adverse events was significantly higher for the Cremophor® EL-based product Sandimmune®. We conclude that CicloMulsion® is bioequivalent to Sandimmune® and exhibits fewer adverse reactions.

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Section: Discussionmentioning

confidence: 99%

Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor® EL

Ehinger

Hansson

Sjövall

et al. 2012

Clinical Drug Investigation

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“…Nordiazepam concentrations adapted from Dhillon and Richens 35 and Greenblatt et al 36 . Population simulations of the PBPK model to 5‐mg 57 (c) and 10‐mg 58 (d) intravenous doses of diazepam. Mean (solid black lines) ± minimum‐maximum (dashed blue lines).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, the population unbound interstitial brain concentrations of diazepam and nordiazepam were calculated for this dose and schedule. Diazepam concentrations reach equilibrium by the seventh 36 Population simulations of the PBPK model to 5-mg 57 (c) and 10-mg 58 (d) intravenous doses of diazepam. Mean (solid black lines) ± minimum-maximum (dashed blue lines).…”

Section: Steady-state Brain Concentrationsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling of Diazepam: Unbound Interstitial Brain Concentrations Correspond to Clinical End Points

Burkat

2022

The Journal of Clinical Pharma

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Benzodiazepines induce a series of clinical effects by modulating subtypes of γ -aminobutyric acid type A receptors in the central nervous system. The brain concentration-time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4-benzodiazepines diazepam and nordiazepam was developed from plasma concentration-time courses with PK-Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration-time profiles correlated with diazepam pharmacodynamic end points. With a 30-mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant γ -aminobutyric acid type A receptors composed of α1β2γ 2s, α2β2γ 2s, and α5β2γ 2s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10-mg peroral administrations of diazepam delivered every 24 hours, steady-state peak and trough unbound interstitial brain diazepam concentrations are 22.3 ± 7.5 and 9.3 ± 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13-to 30-Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.

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“…sedation and amnesia, are elicited during the phase of drug distribution at higher Cps. After reaching blood-tissue pseudoequilibrium, the rate of elimination influences the time to recover from residual drowsiness, often regarded as a side-effect, pertaining at lower Cps (Reves, 1984 ethanol/propylene glycol or fat emulsion (Diazemuls') influences the bioavailability, resulting in a reduction using the latter (Fee & Dundee, 1985). In the present study, a biexponential equation adequately described the Cp-time data of both drugs when fitting the data from the three injections simultaneously, indicating linear kinetics.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that the solvents used in different preparations of diazepam, i.e. ethanol/propylene glycol or fat emulsion (Diazemuls') influences the bioavailability, resulting in a reduction using the latter (Fee & Dundee, 1985). The potency ratio 1:2 of midazolam and diazepam shown to be equipotent by other investigators is presumingly dependent on the different solvent in the preparation.…”

Section: Discussionmentioning

confidence: 99%

Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.

Sunzel

Paalzow

Berggren

et al. 1988

Brit J Clinical Pharma

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Bioavailability of three formulations of intravenous diazepam

Cited by 7 publications

References 18 publications

Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor® EL

Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor® EL

Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling of Diazepam: Unbound Interstitial Brain Concentrations Correspond to Clinical End Points

Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.

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