The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human

Wu, Yunhui; Loper, Alice E.; Landis, Elizabeth; Hettrick, Lisa; Novak, Linda; Lynn, Kari; Chen, Cindy; Thompson, Karen; Higgins, Ray; Batra, Udit; Shelukar, Suhas; Kwei, Gloria Y.; Storey, David

doi:10.1016/j.ijpharm.2004.08.001

Cited by 249 publications

(117 citation statements)

References 27 publications

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“…4,10,18) The low oral bioavailability of aprepitant was also reported to be attributed to its slow dissolution rate, poor permeability across the intestinal mucosa, or first-pass metabolism in the gut and liver. 5) Higher T-Bil was correlated with a higher plasma exposure to aprepitant in a univariate analysis. Multiple regression analysis also revealed that T-Bil affected the pharmacokinetics of aprepitant in the present study.…”

Section: Discussionmentioning

confidence: 92%

“…4) There are no restrictions in the administration of aprepitant with regard to feeding conditions. 4,5) Aprepitant penetrates the blood-brain barrier and binds to a high degree with brain NK 1 receptors, inhibiting emesis via the central nervous system. [6][7][8][9] A population pharmacokinetics study of aprepitant in Japan found that body weight, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and age affected the oral clearance of aprepitant.…”

Section: Interindividual Variations In Aprepitant Plasma Pharmacokinementioning

confidence: 99%

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Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Motohashi

Mino

Hori

et al. 2013

Biological & Pharmaceutical Bulletin

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The pharmacokinetics of aprepitant, a neurokinin-1 receptor antagonist, have not been fully evaluated in clinical settings. The aim of this study was to characterize the plasma pharmacokinetics of aprepitant and reveal their influence of laboratory tests and cytochrome P450 (CYP) 3A5 gene polymorphisms in cancer patients. Forty-four Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled. The patients did not have gastrointestinal disease and the clinical laboratory values were within their normal reference levels. The plasma concentrations of aprepitant 24 (day 2 predose), 72, and 120 h after the first aprepitant administration were determined using LC-MS/MS. The relationships between plasma exposure to aprepitant and body weight, clinical laboratory values, age, gender, or CYP3A5*3 were investigated. The median and interquartile ranges of the 120-h area under the plasma concentration time curve (AUC) 0-120 of aprepitant were 73215 and 55518-91121 ng h/mL. The coefficient of variation value for aprepitant AUC 0-120 was 53%. The AUC 0-120 of aprepitant was correlated with the levels of total bilirubin and serum albumin, respectively (r=0.454, p<0.01 and r=0.287, p=0.06), but not with other non-genetic factors and CYP3A5 genetic variants in a univariate analysis. The AUC 0-120 of aprepitant was significantly correlated with the level of total bilirubin (adjusted R 2 =0.187, p<0.01) in a multivariate analysis. In conclusion, the plasma pharmacokinetics of aprepitant varied markedly in cancer patients receiving cisplatin-based chemotherapy for the first time and were correlated with the level of total bilirubin. Key words aprepitant; pharmacokinetics; total bilirubin; serum albumin; cytochrome P450 3A5 Aprepitant is a highly selective antagonist of neurokinin-1 (NK 1 ) receptors and developed as a treatment for both acute (during the first 24 h postchemotherapy) and delayed (24 through 120 h postchemotherapy) chemotherapy-induced nausea and vomiting (CINV). The combination of aprepitant, dexamethasone, and a 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist has elevated the percentages of patients with a complete response (no vomiting and no rescue medication) during the 5 d after highly and moderately emetogenic chemotherapy by approximately 20% 1,2) and 10% 3) compared to non-aprepitant regimens, respectively.The bioavailability of oral aprepitant capsules is 59% for the 125 mg capsules and 67% for the 80 mg capsules.4) There are no restrictions in the administration of aprepitant with regard to feeding conditions. 4,5) Aprepitant penetrates the blood-brain barrier and binds to a high degree with brain NK 1 receptors, inhibiting emesis via the central nervous system. [6][7][8][9] A population pharmacokinetics study of aprepitant in Japan found that body weight, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and age affected the oral clearance of aprepitant.10) The authors reported that the ...

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Section: Discussionmentioning

confidence: 92%

Section: Interindividual Variations In Aprepitant Plasma Pharmacokinementioning

confidence: 99%

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Motohashi

Mino

Hori

et al. 2013

Biological & Pharmaceutical Bulletin

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“…The use of the wet mill, NanoCrystal, brought about a remarkable improvement in bioavailability by reducing the size of the particles to the nanometer range. 12,13) Conventional beads milling is timeconsuming and requires a large amount of beads for pulverizing a given compound in the grinding chamber. Moreover, troublesome tasks such as the cleaning of balls and machine have to be carried out after the pulverization.…”

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confidence: 99%

Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

Takatsuka¹,

Endo²,

Yao³

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Synthesis of water soluble compounds with high pharmacological activity is becoming increasingly difficult. Pulverization is one of the methods that can be used to enhance the dissolution rate of poorly water soluble compounds and improve their bioavailability. 1) Pulverization is an important process, especially during the discovery, clinical, and developmental stages of a drug to salvage from the dropout of compound.Phenytoin is a highly crystalline compound with a high melting point of 295-298°C and poor solubility in water. Because of its poor solubility in water, there are very few cases where the concentration of phenytoin in blood reaches the desired levels when administered at a conventional dosage. 2,3) According to a few reports, however, the dissolution rate of phenytoin was improved by reducing its particle size, thereby increasing its concentration in blood to the desired level. [4][5][6] Reducing the particle size makes the increase of surface area and as a result of it, dissolution rate of drug increases according to the Nernst-Brunner and Levich modification of the Noyes-Whitney model of dissolution. 7,8) Solubility problem could be solved by reducing particle size to nanometer range. 9)There are different techniques for pulverizing compounds to obtain nanoparticles-wet-grinding in agitated media milling, stirred media milling, wet co-grinding.10,11) However, in most cases, these techniques are difficult to be carried out. Wet milling is one of the various methods used to obtain nanoparticles of a given compound. The use of the wet mill, NanoCrystal, brought about a remarkable improvement in bioavailability by reducing the size of the particles to the nanometer range.12,13) Conventional beads milling is timeconsuming and requires a large amount of beads for pulverizing a given compound in the grinding chamber. Moreover, troublesome tasks such as the cleaning of balls and machine have to be carried out after the pulverization. The rotation/revolution mixer is used to homogenize materials such as epoxy resins, silicone resins, acrylic resins, metal pastes, inks, cosmetics, pastes, and foodstuff. In the pharmaceutical field, beads milling is used for preparing oral formulations for preclinical safety studies.14) Beads milling helps improve product quality and reduce its manufacturing process. Rotation/revolution mixer does not need much amount of compounds and can pulverize a small amount of them (mg order). It can easily scale up from very small volume to large volume. This paper reports on a method to reduce the size of the particles to the nanometer range by using a rotation/revolution mixer and zirconia balls. ExperimentalManufacturing Instruments A rotation/revolution mixer (Nano Pulverizer NP-100, Thinky Co., Ltd., Tokyo, Japan) was used to pulverize the compounds. Two types of vessels made of polyacetal were used-one was convex and the other was circular, as shown in Figs. 3a, b. Zirconia (zirconium oxide) balls with diameters of 0.05 mm, 0.1 mm, 0.3 mm, 0.5 mm, and 1 mm (YTZ-0.05, -0.1, -0.3...

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“…This again highlights the limitation of a preclinical animal model to accurately predict outcome of a human study. Nevertheless, preclinical animal studies to guide formulation development still remain a useful biopharmaceutical tool (19,20).…”

Section: General Strategies For Fdc Developmentmentioning

confidence: 99%

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

Mitra

2012

AAPS J

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Abstract. Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.

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The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human

Cited by 249 publications

References 27 publications

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

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