Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole‐cyclodextrin formulations

Buchanan, Charles M.; Buchanan, Norma L.; Edgar, Kevin J.; Klein, Sandra; Little, James L.; Ramsey, Michael G.; Ruble, Karen M.; Wacher, Vincent J.; Wempe, Michael F.

doi:10.1002/jps.20878

Cited by 51 publications

(66 citation statements)

References 35 publications

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“…Using moderate renal insufficiency as the worst case, the exposure to HPβCD after administration of HPβCD‐diclofenac was still estimated to be 7.9‐fold lower based on AUC 0–t and 3.9‐fold lower based on the average concentration than in healthy subjects administered intravenous itraconazole. Notably, the PK profile of HPβCD following administration of intravenous itraconazole has previously been studied in subjects with mild, moderate, and severe renal insufficiency, with results similar to those observed in the present study — a 2.3‐fold decrease in CL and a 3.7‐fold increase in t ½ were observed for subjects with mild or moderate renal insufficiency, whereas a 6‐fold decrease in CL and a 6‐fold increase in t ½ were observed for subjects with severe renal insufficiency versus healthy subjects 33, 34…”

Section: Discussionsupporting

confidence: 89%

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Hamilton

Ernst

Kramer

et al. 2017

Clinical Pharm in Drug Dev

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Given their established analgesic properties, nonsteroidal anti‐inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half‐life, t½) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½. There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPβCD‐diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

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Section: Discussionsupporting

confidence: 89%

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Hamilton

Ernst

Kramer

et al. 2017

Clinical Pharm in Drug Dev

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“…At predetermined time intervals, 0.4 ml of blood was collected from the right femoral artery and centrifuged at 3000 g for 10 min using a centrifuge 5415C (Eppendorf, U.S.A.). 15,35) Blood Sample Analysis Plasma (0.1 ml) was mixed with 0.1 ml of mobile phase solution containing domperidone (100 ng/ml), as an internal standard. Then, 0.01 ml of 1 M NaOH was added and followed by liquid-liquid extraction for 10 min with 1.5 ml of diethyl ether : n-hexane (4 : 1 v/v).…”

Section: )mentioning

confidence: 99%

“…Various oral formulations of sibutramine such as another salt form such as sibutramine mesylate 9,10) and sibutramine tartrate, 11) solid dispersions with poloxamer [12][13][14] and inclusion complex. 15) One of the well established method for increasing the solubility and bioavailability of poorly water-soluble drugs is solid dispersion. 16) Several conventional methods such as melting, solvent evaporation and solvent wetting were reported to prepare solid dispersions.…”

mentioning

confidence: 99%

Enhanced Solubility and Bioavailability of Sibutramine Base by Solid Dispersion System with Aqueous Medium

Jang

Kang

et al. 2010

Biological & Pharmaceutical Bulletin

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Sibutramine [1-(4-chlorophynyl)-N,N-dimethyl-a-(2-methylpropyl)cyclobutane methane amine] is a newer antiobesity drug with a novel mechanism of action.1) It contains a potent inhibitor of the reuptake of noradrenaline (NA), serotonin (5-HT) and may stimulate thermogenesis by its activation of b 3 -adrenoceptors in brown adipose tissue. [2][3][4] In human subjects, sibutramine is rapidly metabolized to an Nmono-desmethyl metabolite (desmethylsibutramine [Metabolite I]) and an N,N-didesmethyl metabolite (didesmethylsibutramine [Metabolite II]). The in vivo effects of sibutramine are predominantly the results of the action of the above 2 metabolites. 4-7)Sibutramine hydrochloride monohydrate is the commercially available formulation of sibutramine with the relatively high solubility of 2.9 mg/ml at pH 5.2 and melting point of 190°C. 4,8) However, sibutramine base with low solubility has not been used in commercial formulation. Various oral formulations of sibutramine such as another salt form such as sibutramine mesylate 9,10) and sibutramine tartrate, 11) solid dispersions with poloxamer [12][13][14] and inclusion complex. 15)One of the well established method for increasing the solubility and bioavailability of poorly water-soluble drugs is solid dispersion.16) Several conventional methods such as melting, solvent evaporation and solvent wetting were reported to prepare solid dispersions. 17,18) However, the solid dispersion prepared by melting method with high temperature might chemically decompose the drugs. 19,20) In the case of solvent evaporation and solvent wetting method, the drug in the solid dispersions changed to amorphous form, resulting that the drug might be unstable. 18) Furthermore, a large amount of hydrophilic carriers against drug in these conventional solid dispersions must be needed to improve the solubility of poorly water-soluble drugs. 21,22) In this study, to improve the bioavailability of poorly water-soluble sibutramine base, various sibutramine baseloaded solid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acid using spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibutramine was then investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloride monohydrate-loaded commercial product (Reductil ® ). This commercial product is a conventional capsule which contains 100 mg sibutramine hydrochloride monohydrate and is usually taken multiple times a day. Poloxamer has been employed to enhance the solubility and bioavailability of poorly water-soluble drugs. 19,23) HPMC is frequently used in the preparation of conventional pharmaceutical oral dosage form due to its hydrophilic and soft property. 24,25) To develop a novel sibutramine base-...

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“…3.7) were used as model drugs. Experiments were performed in the course of screening the in vitro performance of hydroxybutenyl-β-cyclodextrin (HBenBCD) complexes of these compounds (8,9) and were designed to simulate the oral administration of a single dose of 200 mg itraconazole or 20 mg tamoxifen, respectively. HBenBCD complexes of the drugs were used since, particularly with itraconazole, it would not have been possible to dissolve a single dose in simulated gastric medium because of its very poor solubility even in acidic media.…”

Section: Methodsmentioning

confidence: 99%

“…Flow rate was set at 1.2 mL/min, resulting in the elution of itraconazole at ∼3 min. The amount of released drug was determined at a wavelength of 260 nm (9). The tamoxifen samples were diluted by factor 2 using also the methanol/30 mM hydrochloric acid 75:25 mixture.…”

Section: Mini-paddle Transfer Modelmentioning

confidence: 99%

Miniaturized Transfer Models to Predict the Precipitation of Poorly Soluble Weak Bases upon Entry into the Small Intestine

Klein

Buchanan

2012

AAPS PharmSciTech

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Abstract. For poorly soluble weak bases, the possibility of drug precipitation upon entry into the small intestine may affect the amount of drug available for uptake through the intestinal mucosa. A few years ago, a transfer model was introduced which has been developed to simulate the transfer of a dissolved drug out of the stomach into the small intestine. However, this setup requires the use of clinically relevant doses of the drug, which are typically not available in the early stages of formulation development. The present series of tests was performed to check whether it is possible to create a miniaturized but physiologically relevant transfer model that can be applied in the early formulation development. Experiments were performed with two miniaturized setups: a 96-well plate model and a mini-paddle transfer system. Itraconazole and tamoxifen were used as model drugs. An appropriate amount of each drug formulation was dissolved in simulated gastric fluid and then transferred into an acceptor phase consisting of fasted/fed state simulated small intestinal fluid. The amount of drug dissolved in the acceptor phase was monitored over a period of 4 h. Results from both setups were very similar. The tamoxifen preformulation did not precipitate, whereas the itraconazole formulation precipitated to the same extent in both setups. Due to the possibility of generating physiologically relevant results but using smaller sample sizes and smaller volumes of media, both miniaturized transfer systems offer various advantages in terms of substance and analytical and material cost savings when evaluating the precipitation potential of poorly soluble weakly basic drug candidates.

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Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole‐cyclodextrin formulations

Cited by 51 publications

References 35 publications

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Pharmacokinetics of Diclofenac and Hydroxypropyl‐β‐Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD‐Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment

Enhanced Solubility and Bioavailability of Sibutramine Base by Solid Dispersion System with Aqueous Medium

Miniaturized Transfer Models to Predict the Precipitation of Poorly Soluble Weak Bases upon Entry into the Small Intestine

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