A Two-way Randomized Cross-over Pharmacokinetic and Pharmacodynamic Study of an Innovative Oral Solution of Midazolam (ADV6209).

PURPOSE: The objective of this study was to assess the bioavailability and the sedative effect of a single-dose administration of an innovative oral solution of midazolam containing γ-cyclodextrins (ADV6209). METHODS: A bioavailability study with a standard two-sequences, two-periods, and crossover design was conducted. Subjects randomly received 15 mg of ADV6209 by oral route followed by 5 mg of the reference drug (midazolam hydrochloride intravenous solution (Hypnovel®, Roche) by intravenous route or vice versa. Blood samples were drawn at different time points to measure midazolam and its metabolite α-hydroxymidazolam concentrations. Non-compartmental pharmacokinetic methods were used to calculate main pharmacokinetic parameters and absolute bioavailability. RESULTS: Caucasian healthy subjects (n = 12) were included in the study. ADV6209 had a bioavailability of 39.6%. The oral elimination half-life with ADV6209 was slightly shorter than with the reference i.v. form (2.66 h versus 2.99 h). The sedative effect was observed 27.5 ± 15.5 min after oral administration for a duration of 48.5 ± 35.4 min. Double peak phenomenon was observed in 5 patients. CONCLUSIONS: Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.

Rapid Study on Mefloquine Hydrochloride Complexation with Hydroxypropyl-ß-Cyclodextrin and Randomly Methylated ß-Cyclodextrin: Phase Diagrams, Nuclear Magnetic Resonance Analysis, and Stability Assessment.

This study investigates the complexation of mefloquine hydrochloride by cyclodextrins to improve its solubility in order to design an oral solution. This approach may enhance the effectiveness of mefloquine, a drug which can be used for malaria prophylaxis and treatment in children. Mefloquine hydrochloride's solubility was assessed in different buffer solutions, and its quantification was achieved through high-performance liquid chromatography. The complexation efficiency with cyclodextrins was evaluated, and nuclear magnetic resonance (NMR) methods were employed to determine the interactions between mefloquine and cyclodextrins. Mefloquine's solubility increased when combined with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and randomly methylated ß-cyclodextrin (RAMEB), with RAMEB being more effective. The drug's solubility varied across different pH buffers, being higher in acidic buffers. Interestingly, mefloquine's solubility decreased with a citrate buffer, possibly due to precipitation. The NMR studies highlighted non-covalent interactions between RAMEB, HP-ß-CD, and mefloquine, explaining the solubilizing effect via complexation phenomena. Furthermore, the NMR experiments indicated the complexation of mefloquine by all the studied cyclodextrins, forming diastereoisomeric complexes. Cyclodextrin complexation improved mefloquine's solubility, potentially impacting its bioavailability.

Cyclodextrin Complexation as a Way of Increasing the Aqueous Solubility and Stability of Carvedilol.

We studied the effect of several CDs on carvedilol's solubility and chemical stability in various aqueous media. Our present results show that it is possible to achieve a carvedilol concentration of 5 mg/mL (12.3 mM) in the presence of 5 eq of γCD or RAMEB in an aqueous medium with an acceptable acid pH (between 3.5 and 4.7). Carvedilol formed 1:1 inclusion complexes but those with RAMEB appear to be stronger (K = 317 M-1 at 298 K) than that with γCD (K = 225 M-1 at 298 K). The complexation of carvedilol by RAMEB significantly increased the drug's photochemical stability in aqueous solution. These results might constitute a first step towards the development of a novel oral formulation of carvedilol.

Population pharmacokinetic evaluation of ADV6209, an innovative oral solution of midazolam containing cyclodextrin.

INTRODUCTION: In the absence of a licensed formulation in many countries worldwide, ADV6209, an innovative 2mg/ml oral solution of midazolam containing cyclodextrin, has been developed for moderate sedation in paediatric patients. Population pharmacokinetics for ADV6209 is reported. METHODS: Plasma concentration data were collected from 37 paediatric patients and 12 healthy adults recruited in a single dose, open-label phase II pharmacokinetic study and in a single dose, randomised, open-label two-period crossover bioavailability study, respectively. Data were analysed using non-linear mixed effect modelling. Plasma concentrations of midazolam were described by a two-compartment model. An additional one-compartment model was added for α- hydroxymidazolam. RESULTS: The body weight covariate was found to have a significant impact on midazolam and α-hydroxymidazolam clearance, and on midazolam volume of distribution. The population pharmacokinetic model indicated that 77% of the midazolam dose was absorbed within 30min after oral administration. Parameter estimations for a subject of 34kg indicated values of midazolam clearance of 34.7l·h-1, a central volume of distribution of 27.9l and a peripheral volume of distribution of 413l. A higher metabolic ratio and a higher midazolam clearance per body weight were observed in the youngest group of subjects, in accordance with literature data. The clearance per body weight of α-hydroxymidazolam remained constant over the different age groups. CONCLUSION: Pharmacokinetic parameters were close to those reported in the literature with midazolam extemporaneous oral solutions or syrups, demonstrating that cyclodextrin had no significant effect on measured parameters.

Determinants of amikacin first peak concentration in critically ill patients.

Amikacin antimicrobial effect has been correlated with the ratio of the peak concentration (Cmax ) to the minimum inhibitory concentration. A target Cmax ≥ 60-80 mg/L has been suggested. It has been shown that such target is not achieved in a large proportion of critically ill patients in intensive care units. A retrospective analysis was performed to examine the determinants of Cmax ≥ 80 mg/L on the first peak in 339 critically ill patients treated by amikacin. The influence of available variables on Cmax target attainment was analyzed using a classification and regression tree (CART) and logistic regression. Mean Cmax in the 339 patients was 73.0 ± 23.9 mg/L, with a target attainment rate (TAR, Cmax ≥ 80 mg/L) of 37.5%. In CART analysis, the strongest predictor of amikacin target peak attainment was dose per kilogram of lean body weight (dose/LBW). TAR was 60.1% in patients with dose/LBW ≥ 37.8 vs. 19.9% in patients with lower dose/LBW (OR = 6.0 (95% CI: 3.6-10.2)). Renal function was a secondary predictor of Cmax . Logistic regression analysis identified dose per kilogram of ideal body weight (OR = 1.13 (95% CI: 1.09-1.17)) and creatinine clearance (OR = 0.993 (95% CI: 0.988-0.998)) as predictors of target peak achievement. Based on our results, an amikacin dose ≥ 37.8 mg/kg of LBW should be used to optimize the attainment of Cmax ≥ 80 mg/L after the first dose in critically ill patients. An even higher dose may be necessary in patients with normal renal function.

Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations.

Midazolam (MDZ) is a benzodiazepine commonly administered in preanesthesia of children by oral or by sublingual routes. To mask its bitter taste and enhance its aqueous solubility, we already developed a 0.2% (w/v) MDZ oral solution containing γ-cyclodextrin (γ-CD), which proves to be better accepted by children in pediatrics at University Hospital of Amiens. To improve the MDZ solubility, its closed form proportion in acidobasic equilibrium and its chemical stability, nuclear magnetic resonance, liquid chromatography-electrospray-high-resolution mass spectrometry, and tandem mass spectrometry methods were used to highlight the advantages of using partially methylated CD (2,6 di-O-methyl-ß-cyclodextrin) and randomized methylated-ß-cyclodextrin (RAMEB). The formation of 1:1 inclusion complex offered an improvement of the MDZ solubility and an increase of the closed and pharmacologically active form with a 33% gain when compared with the aqueous solution without CD. It was also demonstrated that RAMEB had a protecting effect on the MDZ degradation because it was found in almost 95% of remaining MDZ solution after 3 months at 40°C.

Farnesyltransferase inhibitor R115777 protects against vascular disease in uremic mice.

BACKGROUND: Atherosclerosis and vascular calcification are major contributors to cardiovascular morbidity and mortality among chronic kidney disease patients. The mevalonate pathway may play a role in this vascular pathology. Farnesyltransferase inhibitors such as R115777 block one branch of mevalonate pathway. We studied the effects of farnesyltransferase inhibitor R115777 on vascular disease in apolipoprotein E deficient mice with chronic renal failure and on mineral deposition in vitro. METHODS AND RESULTS: Female uremic and non-uremic apolipoprotein E deficient mice were randomly assigned to four groups and treated with either farnesyltransferase inhibitor R115777 or vehicle. Farnesyltransferase inhibitor R115777 inhibited protein prenylation in mice with chronic renal failure. It decreased aortic atheromatous lesion area and calcification in these animals, and reduced vascular nitrotyrosine expression and total collagen as well as collagen type I content. Proteomic analysis revealed that farnesyltransferase inhibitor corrected the chronic renal failure-associated increase in serum apolipoprotein IV and α globin, and the chronic renal failure-associated decrease in serum fetuin A. Farnesyltransferase inhibitor further inhibited type I collagen synthesis and reduced mineral deposition in vascular smooth muscle cells in vitro, probably involving Ras-Raf pathway. CONCLUSIONS: We show for the first time that farnesyltransferase inhibition slows vascular disease progression in chronic renal failure by both indirect systemic and direct local actions. This beneficial effect was mediated via a reduction in oxidative stress and favorable changes in vasoprotective peptides.

Development and formulation of a 0.2% oral solution of midazolam containing gamma-cyclodextrin.

In absence of dedicated children formulation, intravenous formulations of midazolam, which exhibit strong bitterness, are occasionally used for oral or sublingual administration. In order to improve the quality and the acceptance by children of a midazolam anesthesia premedication, a new 0.2% (w/v) aqueous solution for oral administration has been prepared. The final formulation was obtained by the adjunction of a sweetener (sucralose), an aroma (orange aroma) and gamma-cyclodextrin to a citric acid solution of midazolam. The gamma-cyclodextrin forms an inclusion complex with the hydrophobic midazolam as evidenced using nuclear magnetic resonance spectroscopy (stoichiometry 1:1, K=283 M(-1)). A sterile filtration method was selected for the formulation microbial preservation using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). Finally, a routine high performance liquid chromatography (HPLC) method is proposed for the quantitative determination of global midazolam amount in the pharmaceutical preparation.