Differences In Cmax Research Articles

1569 RECEPTOR BINDING ABILITY OF α1-AR ANTAGONISTS IS RESPONSIBLE FOR THERAPEUTIC EFFICIENCY WITH LONG-TERM USE IN BENIGN PROSTATIC HYPERPLASIA

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research1 Apr 20121569 RECEPTOR BINDING ABILITY OF α1-AR ANTAGONISTS IS RESPONSIBLE FOR THERAPEUTIC EFFICIENCY WITH LONG-TERM USE IN BENIGN PROSTATIC HYPERPLASIA Yoshiyuki Kojima, Shoichi Sasaki, Takashi Hamakawa, Yasuhiro Shibata, Makoto Imura, Yasue Kubota, Keiichi Tozawa, Yutaro Hayashi, and Kenjiro Kohri Yoshiyuki KojimaYoshiyuki Kojima Nagoya, Japan More articles by this author , Shoichi SasakiShoichi Sasaki Nagoya, Japan More articles by this author , Takashi HamakawaTakashi Hamakawa Nagoya, Japan More articles by this author , Yasuhiro ShibataYasuhiro Shibata Nagoya, Japan More articles by this author , Makoto ImuraMakoto Imura Nagoya, Japan More articles by this author , Yasue KubotaYasue Kubota Nagoya, Japan More articles by this author , Keiichi TozawaKeiichi Tozawa Nagoya, Japan More articles by this author , Yutaro HayashiYutaro Hayashi Nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri Nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1341AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The application of pharmacokinetics and pharmacodynamics has become an increasingly important aspect of contemporary clinical pharmacology. These techniques have been applied for the improved understanding of the clinical actions of drugs. In some patients, α1-AR antagonist monotherapy loses its efficiency after long-term use. We investigated whether the individual difference of pharmacokinetics and pharmacodynamics was responsible for the diverse responses to α1-AR antagonists in long-term use. METHODS We enrolled 61 patients with untreated BPH. Transperineal prostate needle biopsies were performed for patients with slightly elevated PSA. Four biopsy specimens were obtained from the transition zone to examine the expression levels of α1a-, α1b- and α1d-ARs mRNA. One month after biopsy, tamsulosin was given to patients for 12 weeks. A second biopsy was then performed. The patients continued to receive tamsulosin monotherapy after the second biopsy. TaqMan RT-PCR was performed using these specimens to assess each α1-AR subtype expression level. The expression levels were compared before and after 12-week tamsulosin treatment. All study subjects were also evaluated for serum tamsulosin concentration during the period of stable prescription. Serum tamsulosin concentration was determined by high performance liquid chromatography, and maximum plasma tamsulosin concentration (Cmax) was estimated. After up to 7 years of follow-up (average: 47.6±22.6 months), 4 patients developed AUR. We divided the patients into two groups, patients who did and did not develop AUR during long-term follow-up. RESULTS We examined the correlation between the change in α1-AR expression levels after the 12-week treatment period, and the long-term efficacy of tamsulosin. The α1a-AR expression level significantly increased after 12-week tamsulosin treatment in AUR (-) group, while no significant increase was observed in AUR (+) group. The α1d-AR expression level also increased after tamsulosin treatment in AUR (-) group, although no significant difference was observed. There was no significant difference in Cmax between AUR (+) (7.6±6.0 ng/ml) and AUR (-) (7.5±6.2 ng/ml) groups. CONCLUSIONS Our result suggests that maximum plasma tamsulosin concentration is not the main responsible factor for determining long-term efficacy. But patients with less receptor binding ability of tamsulosin have a lower adaptive response to chronic tamsulosin administration and, consequently, may lose therapeutic efficiency with long-term use. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e636 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshiyuki Kojima Nagoya, Japan More articles by this author Shoichi Sasaki Nagoya, Japan More articles by this author Takashi Hamakawa Nagoya, Japan More articles by this author Yasuhiro Shibata Nagoya, Japan More articles by this author Makoto Imura Nagoya, Japan More articles by this author Yasue Kubota Nagoya, Japan More articles by this author Keiichi Tozawa Nagoya, Japan More articles by this author Yutaro Hayashi Nagoya, Japan More articles by this author Kenjiro Kohri Nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A Single-Center, Randomized, Open-Label, Dose-Escalation Study to Evaluate the Pharmacokinetics of Tacrine Analogue Octahydrogenacridine Succinate Tablets in Healthy Chinese Subjects

The objectives of the present study were to investigate the pharmacokinetics (PK) of tacrine analogue octahydrogenacridine (OHA) succinate tablets in healthy Chinese subjects. A single-center, randomized, open-label, dose-escalation study was conducted in 42 healthy Chinese subjects. Part I of the study (n=30, 16 male and 14 female) evaluated the PK profiles of OHA in healthy Chinese subjects (aged 18-45 years) after single and multiple doses of 2 mg, 4 mg and 8 mg. Part II (n=10) assessed food effect on PK characteristics of OHA. The 10 participants of 4 mg dose group in part I were given another single dose of 4 mg OHA under fed condition. Part III (n=12, 7 male and 5 female) investigate PK behavior of OHA in elderly (aged 65-75 years) Chinese healthy subjects. In Part I, following a single- and multiple-dose, octahydrogenacridine succinate was rapidly absorbed with a median t(max) of 0.67 to 1.00 h, and was eliminated with a mean t1/2 of 2.27 to 2.98 h in all dose groups and did not appear to be dose dependent. In Part II, there were no significant differences in Cmax, AUC0-tn or tmax between 4 mg single dose fasting group and fed group (p=0.257, 0.153, 0.098, respectively). In Part III, both in single-dose and multiple-dose treatment, the main PK parameters of OHA in the elderly healthy Chinese subjects showed no statistical difference with those of non-elderly group. All these results indicated that OHA might be a promising drug under development for Alzheimer's disease (AD) therapy.

Abstract B190: Pharmacokinetics of the AKT inhibitor CCT128930 from dried blood spots sampled from caudal bleeding compared with conventional cardiac puncture.

Abstract There has been much increase in the use of blood spots in recent years as a result of the ease of storage and transport of blood dried on cards compared with frozen plasma. In preclinical studies in oncology, mice are the model used for therapy experiments and blood spots allow full pharmacokinetic (PK) studies in 3–4 animals versus 21–27 for conventional plasma pharmacokinetics analysis, saving animals and decreasing compound usage. We here apply the blood spots technology to the early pharmacokinetic analysis of the AKT inhibitor CCT128930 dosed i.v. at 10mg/kg and bled from the tail vein. The PK are very reproducible between individual mice and the blood levels are not affected by the type of anticoagulant used (heparin or EDTA) or by use of the FTA-DMPK card. CCT128930 shows a blood clearance of 0.092L/h (<liver blood flow) and volume of distribution of 140mL. However, the PK parameters evaluated in blood water by conventional methods (cardiac puncture) differ significantly to those from the blood spot experiments. The overall blood clearance is 1.6-fold higher following blood measurement in samples taken by cardiac puncture versus serial tail bleed. The 6h post-dosing concentrations of CCT128930 following caudal sampling are 10-fold higher than that measured after cardiac puncture although there is no difference in Cmax. These data suggest that the serial bleeding from the tail vein affects the PK parameters of this compound compared with conventional bleeding. We have used blood spots extensively in our drug discovery programs checking the 6h sample versus conventional cardiac bleed and this strategy has allowed us to save over 50% of animals in the last year in our preclinical PK evaluations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B190.

A novel immunoassay to quantify paclitaxel in plasma using monoclonal antibody–coated nanoparticles.

e11544 Background: Paclitaxel (PTX) is used in first line treatment of patients having a variety of solid tumors including breast, ovarian, and NSCL carcinomas. Paclitaxel has substantial variability in PK parameters, with up to 10-fold inter-patient differences in Cmax and/or AUC. This variability has critical clinical consequences for severe toxicities at high concentrations and decreased efficacy at low concentrations. The time above a critical paclitaxel plasma concentration of 0.05 µmol/L (Tc>0.05, 42 ng/mL) is correlated to toxicity and efficacy in many clinical studies. The current chromatographic methods for measuring paclitaxel blood levels are time-consuming and expensive. A new nanoparticle-based automated assay provides a rapid, simple and cost-effective measurement of PTX levels in patients undergoing treatment to allow timely personalized dose adjustment. Methods: A prototype automated homogenous immunoassay to quantify PTX, requiring less than 10μL plasma, was developed for use on the Beckm...

A phase I study evaluating the pharmacokinetics of components of S-1 in pts with varying degrees of renal function.

e13089 Background: S‐1 is an oral fluoropyrimidine that combines tegafur with two modulators, gimeracil and oteracil potassium. This study was designed to evaluate the PK of S-1 components (FT, CDHP, and Oxo) and the metabolites (5-FU, FBAL, CA) after single and multiple doses of S-1 administered to pts with renal impairment. Methods: This phase I study was conducted in 2 parts (PK Phase and Extension Phase). During the PK Phase, pts were stratified into 4 cohorts: Normal (CrCL >80 mL/min); Mild (CrCL of 51 to 80 mL/min); Moderate (CrCL of 30 to 50 mL/min); Severe (CrCL <30 mL/min). S-1 dosing was determined by degree of renal impairment: 20 mg/m2 QD (severe); 20 mg/m2 BID (moderate); 30 mg/m2 BID (mild), and 30 mg/m2 BID (normal) for 14 days followed by a 1‐week off period. 6 pts were enrolled into each cohort. Plasma and urine were collected to measure the concentrations of S-1 components and its metabolites on day -2 through 48 hrs after the first administration of a single dose of S-1, day 7 and 14. Results: There was no DLTs in the normal (n=7) or moderate(n=6) cohorts. One of 6 pts in the mild cohort experienced 4 DLTs: Gr 3 diarrhea, Gr 3 mucosal inflammation, Gr 3 dehydration, and Gr 3 blood creatinine increased. For the single dose 5-FU and CDHP data, there was statistically significant increase in AUC0-inf value for the mild cohort relative to the normal cohort. For the multiple dose 5-FU, CDHP, Oxo, FBAL, CA, and uracil data, there were no statistically significant differences in Cmax or AUC 0-12 values for the mild or moderate cohort relative to the normal cohort. As compared to normal cohort, there was no evidence of increased accumulation of S-1 components or metabolites following multiple-dose administration in mild or moderate cohort. Conclusions: Based on the results from the single dose PK, a dose reduction from 30 mg/m2 BID to 25 mg/m2 BID for pts with mild renal impairment, 20 mg/m2 BID for pts with moderate renal impairment should be considered for S-1 monotherapy. Data on the severe cohort will be presented at the meeting. S-1 was generally well tolerated in this population with normal renal function, and mild or moderate renal impairment.

Metformin IR versus XR Pharmacokinetics in Humans

Pharmacokinetics of metformin extended release (XR) formulation were studied under fasting and fed conditions and compared to those of immediate release (IR) under fasting conditions in humans. 78 healthy human volunteers participated in 3 independent studies (26 subjects per study) were given either 1000 mg oral dose metformin IR or 750 mg metformin XR. Plasma samples were obtained up to 24 hours after dosing. Pharmacokinetic parameters in plasma were calculated by non compartmental analysis using Kinetica program. Results have shown increased XR bioavailability and delayed time to reach the maximum concentration (Cmax ) in the fed state as compared to fasted state, with no significant difference in Cmax and half life values. On the other hand, the IR formulation showed significant differences in all parameters as compared to XR formulation, yet the half life was similar. In conclusion, XR formulation was shown similar to IR formulation with less possible side effects.

Effect of the Cytochrome P450 3A4 Inducers, Rifampicin and Dexamethasone, on the Pharmacokinetic, Pharmacodynamic and Safety Profile of Bortezomib In Patients with Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

AbstractAbstract 3983Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures:Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 2770: An open-label comparative study of the pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with mild, moderate, or severe hepatic impairment, or normal hepatic function

Abstract Zibotentan (ZD4054) is a small-molecule, specific endothelin A (ETA) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer. Zibotentan is eliminated by both renal (58%) and metabolic clearance. The current study investigated whether hepatic impairment has a clinically relevant effect on exposure to zibotentan. This open-label, two-centre study investigated the PK and tolerability of zibotentan in subjects with hepatic impairment, compared with subjects with normal hepatic function. Subjects were divided into four categories using the Child-Pugh (CP) classification: mild hepatic impairment (CP A), moderate hepatic impairment (CP B), severe hepatic impairment (CP C) and normal hepatic function. Each subject received a single oral dose of zibotentan 10 mg. AUC and Cmax are expressed as the ratio (R) of geometric means and 90% confidence intervals (CI) for each hepatic impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure of zibotentan was considered if the upper 90% CI for the ratio exceeded two. Thirty-seven subjects were enrolled and 32 subjects (eight per group) received zibotentan and completed the study. Compared with the normal function group, zibotentan Cmax was 7% (R 0.93; 90% CI 0.75-1.15), 11% (R 0.89; 90% CI 0.72-1.1) and 5% (R 0.95; 90% CI 0.77-1.17) lower in subjects with CP A, CP B and CP C hepatic impairment, respectively. Zibotentan AUC was 40% (R 1.40; 90% CI 0.91-2.17), 45% (R 1.45; 90% CI 0.94-2.24) and 190% (R 2.90; 90% CI 1.88-4.49) higher in subjects with CP A, CP B and CP C hepatic impairment, respectively, compared with those with normal function. Mean t½ was 9.28 h, 13.0 h, 14.6 h and 24.8 h for the normal function, CP A, CP B and CP C hepatic impairment groups, respectively. Compared with the normal function group, CL/F was approximately 25%, 29% and 64% lower, respectively, in the CP A, CP B and CP C hepatic impairment groups. Zibotentan was well tolerated by all subjects, with headache (CTC Grade 1-2) being the most common adverse event in each group. Despite increased exposure to zibotentan with increased hepatic impairment, there were no differences in the type or severity of adverse events. In conclusion, following a single oral dose of zibotentan 10 mg, there was no significant difference in Cmax with degree of hepatic impairment, indicating that hepatic impairment did not affect the absorption of zibotentan. AUC was higher and t½ longer in subjects with hepatic impairment than in those with normal function due to the slower clearance of zibotentan, with the extent of the difference being related to the degree of impairment. Trial sponsored by AstraZeneca (NCT00672581; AZ code D4320C00025). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2770.

Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration

In the US, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the generic formulation provides the same rate and extent of absorption as (ie, is bioequivalent to) the innovator drug product. Thus, most orally administered generic drug products in the US are approved based on results of one or more clinical bioequivalence studies. To evaluate how well the bioequivalence measures of generic drugs approved in the US over a 12-year period compare with those of their corresponding innovator counterparts. This retrospective analysis compared the generic and innovator bioequivalence measures from 2070 single-dose clinical bioequivalence studies of orally administered generic drug products approved by the Food and Drug Administration (FDA) from 1996 to 2007 (12 y). Bioequivalence measures evaluated were drug peak plasma concentration (C(max)) and area under the plasma drug concentration versus time curve (AUC), representing drug rate and extent of absorption, respectively. The generic/innovator C(max) and AUC geometric mean ratios (GMRs) were determined from each of the bioequivalence studies, which used from 12 to 170 subjects. The GMRs from the 2070 studies were averaged. In addition, the distribution of differences between generic means and innovator means was determined for both C(max) and AUC. The mean +/- SD of the GMRs from the 2070 studies was 1.00 +/- 0.06 for C(max) and 1.00 +/- 0.04 for AUC. The average difference in C(max) and AUC between generic and innovator products was 4.35% and 3.56%, respectively. In addition, in nearly 98% of the bioequivalence studies conducted during this period, the generic product AUC differed from that of the innovator product by less than 10%. The criteria used to evaluate generic drug bioequivalence studies support the FDA's objective of approving generic drug formulations that are therapeutically equivalent to their innovator counterparts.

Intraindividual comparison between gadopentetate dimeglumine and gadobutrol for magnetic resonance perfusion in normal brain and intracranial tumors at 3 tesla

In vitro studies have shown that the 3-Tesla (T) magnetic resonance (MR) characteristics of high- and standard-molar gadolinium-based contrast agents differ. Such differences may indicate that high-molar (1.0 M) agents offer advantages for perfusion-weighted imaging (PWI) at 3T, as has been previously reported at 1.5 T. To investigate possible intraindividual differences of high- versus low-molar contrast agents on PWI at 3T in patients with intracranial space-occupying lesions. Six patients with intraaxial and five patients with extraaxial tumors underwent two MR examinations at 3T, separated by at least 48 hours. On each occasion, an exogenous contrast-based, T2*-weighted, gradient-recalled echo-planar imaging (EPI) technique was used to determine the intracranial perfusion characteristics using one of two intravenous contrast agents: either 5 ml of 1.0 M gadobutrol or 10 ml of 0.5 M gadopentetate dimeglumine. The primary PWI outcome measure was region-of-interest maximal signal change (C(max)). The difference in C(max) for gray and white matter (Delta C(max)) was significantly higher for gadobutrol compared to gadopentetate dimeglumine (P<0.01). The ratio of C(max) between gray and white matter (rC(max) = C(maxGray)/C(maxWhite)) was also significantly higher (median 24.6%, range 13.7-36.5%) for gadobutrol (P<0.01). The ratio of C(max) between the whole tumor and whole normal side hemisphere was higher in five out of the six intraaxial tumor cases. A significantly higher ratio (Delta C(max)/C(max)) in the difference between C(max) of gray and white matter (from hemisphere without brain lesion) compared to C(max) for the hemisphere containing the neoplasm (hemisphere with brain lesion) was demonstrated for gadobutrol in intraaxial tumors (P<0.05). Higher-concentration 1.0 M gadobutrol can offer advantages over standard 0.5 M gadopentetate dimeglumine, particularly with respect to delineation between gray and white matter and for the demarcation of highly vascularized tumor tissue on brain PWI performed at 3T.

Glucose tolerance in fish: Is the daily feeding time important?

Daily rhythms in glucose tolerance have been reported for several species of mammals, which seem to be linked to factors such as daily rhythms of insulin resistance and feeding habits. In this paper, we studied entrainment to a daily scheduled meal of blood glucose after carbohydrate intake (dextrin or glucose). After a meal containing dextrin, blood glucose showed different maximum concentrations (Cmax) and time to peak (Tmax) depending on mealtime, the greatest differences in Cmax being found 2 h after feeding. The highest Cmax (8.22 mmol/l) was obtained when mealtime was set in the middle of the light phase (ML), and the lowest Cmax (3.46 mmol/l) when goldfish were fed in the middle of the dark phase (MD). Cosinor analysis revealed a significant daily rhythm in dextrin tolerance with its acrophase around ML, amplitude of 1.99 mmol/l, and a mesor of 5.49 mmol/l. However, when the carbohydrate source in the meal was glucose, an inverse pattern was observed: higher blood glucose in goldfish fed at MD compared with ML (6.98 vs 4.32 mmol/l, respectively). Similar results were obtained when glucose was administered intraperitoneally, with higher values at MD than at ML (13.82 vs 9.54 mmol/l, respectively). Finally, no differences in amylase activity were observed in the gut after dextrin load at ML and MD (522 vs 446 U/mg protein), discarding the effect of digestive factors in the daily rhythm of tolerance. In conclusion, our results described for the first time a daily rhythm in tolerance to carbohydrate in a teleost fish, highlighting the impact of the time of day in glucose metabolism.

427 POSTER Pharmacokinetics (PK) of EZN-2208, a novel anticancer agent, in patients (pts) with advanced malignancies: a phase I dose-escalation study

It has been reported that pomegranate juice significantly increased the AUC of orally administered carbamazepine in rats, which suggests that pomegranate may inhibit the cytochrome P450 3A (CYP3A)–mediated carbamazepine metabolism.The aim of the present study was to clarify the effect of repeated consumption of pomegranate juice on CYP3A activity by assessing the pharmacokinetics of midazolam, a typical CYP3A probe drug, and its metabolites in healthy volunteers.An open-label, randomized, single-center, 2-period crossover study was conducted on healthy Japanese volunteers. Each subject received 200 mL of pomegranate juice twice daily for 2 weeks. On day 14, they were administered 15 μg/kg midazolam orally with either pomegranate juice or water. Plasma concentrations and urinary excretions of midazolam, 1′-hydroxymidazolam, and 4-hydroxymidazolam were determined up to 24 hours using LC/MS/MS and analyzed by a noncompartmental method.Sixteen subjects (11 men and 5 women) were enrolled and completed the study. The mean (SD) age was 24.1 (4.8) years (range 22–40), mean body weight was 62.9 (8.8) kg (range 45.6–79.9). Differences in the mean AUC0–∞ were 12.7 (4.4) and 14.2 (6.6) ng/mL/h in pomegranate juice and control groups, respectively (geometric mean ratio: 1.02 [95% CI, 0.95–1.09]; P = 0.40). Differences in Cmax for midazolam did not reach the level of statistical significance (5.1 [1.7] vs 5.0 [2.0] ng/mL, geometric mean ratio: 0.95 [95% CI, 0.79–1.11]; P = 0.68). Excretions of 1′-hydroxymidazolam (P = 0.34) and 4-hydroxymidazolam (P = 0.32) were not significantly altered by ingestion of pomegranate juice.In this small Japanese adult volunteer population receiving single subtherapeutic doses of midazolam, 2 weeks' consumption of pomegranate juice did not significantly alter the pharmacokinetic profile of midazolam compared with that of the control. Protocol identifier: UMIN000004459.

Comparative pharmacokinetics of ivermectin alone and a novel formulation of ivermectin and rafoxanide in calves and sheep

This study investigated the comparative serum disposition kinetics of ivermectin (IVM) after a single subcutaneous dose of 200 microg/kg body weight of IVM alone or in combination with an anthelmintic consisting of ivermectin and rafoxanide (200 microg/kg of IVM and 2.5 mg/kg rafoxanide) for use in calves and sheep. The IVM concentrations in serum samples were analyzed by high-performance liquid chromatography with fluorescence detection. In sheep serum, rafoxanide induced a rapid absorption of IVM when given in combined form manifested by a shorter absorption half-life time of IVM by 68.49% when given in combination as compared with IVM when given alone. In addition, there is an increase in the value of the area under the concentration curve (AUC) by 15.48% while the value of elimination rate constant was decreased by 38.2% and significantly increased the half-life time of elimination from 2.04 days for IVM alone to 3.3 days when given in combination with rafoxanide. In calves serum, the mean t1/2ab for IVM/rafoxanide was 0.131 days and for the control formulation 0.16 days, and t1/2el was 5.78 and 4.95, respectively. IVM Cmax for IVM/rafoxanide was 22.4 ng/ml and for the control formulation 19.1 ng/ml. T (max) values were 0.99 and 1.12 days, and the mean AUC values were 188.9 and 165.4 ng/ml/day. The difference in Cmax, AUC, Kab, K el, and t1/2el was significant. However, there was no statistical difference between the Tmax and t1/2ab. These findings revealed that the combination of rafoxanide with IVM in sheep and calves increased the absorption of IVM and delayed its elimination.

Circadian Time‐Effect of Orally Administered Loratadine on Plasma Pharmacokinetics in Mice

Little is known about the chronopharmacokinetics of loratadine, a long‐acting tricyclic antihistamine H1 widely used in the treatment of allergic diseases. Hence, the pharmacokinetics of loratadine and its major metabolite, desloratadine, were investigated after a 20 mg/kg dose of loratadine had been orally administered to comparable groups of mice (n=33), synchronized for three weeks to 12 h light (rest span)/12 h dark (activity span). The drug was administered at three different circadian times (1, 9, and 17 h after light onset [HALO]). Multiple blood samples were collected over 48 h, and plasma concentrations of loratadine and desloratadine were determined by high performance liquid chromatography. There were no significant differences in Tmax of loratadine and desloratadine between treatment‐time different groups. However, the elimination half‐life (t1/2) of the parent compound and its metabolite was significantly longer (p<0.01) following administration at 9 HALO (t1/2 loratadine and desloratadine 5.62 and 4.08 h at 9 HALO vs. 4.29 and 2.6 h at 17 HALO vs. 3.26 and 3.27 at 1 HALO). There were relevant (p<0.05) differences in Cmax between the three treated groups for loratadine and desloratadine; 133.05±3.55 and 258.07±14.45 ng/mL at 9 HALO vs. 104.5±2.61 and 188.62±7.20 ng/mL at 1 HALO vs. 94.33±20 and 187.75±10.79 ng/mL at 17 HALO. Drug dosing at 17 HALO resulted in highest loratadine and desloratadine total apparent clearance values: 61.46 and 15.97 L/h/kg, respectively, whereas loratadine and desloratadine clearances (CL) were significantly slower (p<0.05) at the other administration times (loratadine and desloratadine CL was 57.3 and 14.22 L/h/kg at 1 HALO vs. 43.79 and 12.89 L/h/kg at 9 HALO, respectively). The area under the concentration‐time curve (AUC) of loratadine and desloratadine was significantly (p<0.05) greater following drug administration at 9 HALO (456.75 and 1550.57 (ng/mL) · h, respectively); it was lowest following treatment at 17 HALO (325.39 and 1252.53 (ng/mL) · h, respectively). These pharmacokinetic data indicate that the administration time of loratadine significantly affected its pharmacokinetics: the elimination of loratadine and its major metabolite desloratadine.

700 POSTER Outcome of the Clinical Trials Directive on clinical cancer research in Europe: a 3-years'-follow-up analysis

Sildenafil citrate is indicated for the treatment of erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate has been developed for the benefit of patients who have difficulty swallowing solid dosage forms.The main goal of this study was to evaluate the bioequivalence of sildenafil ODT with and without water versus marketed sildenafil oral film-coated tablets. A secondary objective was to evaluate the effects of a high-fat meal on the pharmacokinetics of sildenafil ODT.The bioequivalence study of sildenafil ODT given with and without water versus marketed sildenafil citrate film-coated oral tablets was conducted in 36 subjects. In a food-effect study, the effect of a standard high-fat meal on the pharmacokinetics of sildenafil ODT was evaluated in 12 subjects. Both studies were randomized, open-label, crossover, single-dose (50 mg) studies in healthy men aged ≥45 years. Plasma samples were collected for 14 hours postdose, and pharmacokinetics were determined by using noncompartmental analyses.All subjects in both studies were Asian males between the ages of 45 and 69 years. Sildenafil ODT without water was bioequivalent to the marketed sildenafil film-coated oral tablet as the 90% CI for the ratio of geometric means of Cmax, AUC0–∞, and AUC0–last were contained within equivalence limits (80%–125%). When sildenafil ODTs were given with water, the 90% CIs for sildenafil AUC0–∞ and AUC0–last were contained within the range of 80% to 125%; however, the 90% CI for sildenafil Cmax was not (79.76–92.78). This difference in Cmax is unlikely to have any clinically meaningful impact. High-fat meals reduced the rate but not the extent of absorption of sildenafil. Mean Cmax was reduced by 59%, and median Tmax was delayed from 0.625 hour (fasting) to 4 hours (high-fat meal). However, AUC values were comparable between fed and fasted treatments.Sildenafil ODT, given with or without water, provides equivalent systemic exposure compared with marketed sildenafil film-coated oral tablets, thus offering a convenient alternative method of administration. Considering the results of the food-effect study, sildenafil ODT should be taken on an empty stomach. ClinicalTrials.gov identifiers: NCT01254383 (bioequivalence) and NCT01254396 (food effect).

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.

Pharmacokinetics and bioavailability of spectinomycin after i.v., i.m., s.c. and oral administration in broiler chickens

A pharmacokinetic and bioavailability study of spectinomycin was conducted in healthy broiler chickens following administration of a single (50 mg/kg bw) intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) dose and oral doses of 50 and 100 mg/kg bw. Following i.v. administration, the elimination half-life (t1/2beta), mean residence time (MRT), volume of distribution at steady-state (Vd(ss)), volume of distribution based on the terminal phase (Vd(z)) and total body clearance (ClB) were 1.46+/-1.10 h, 1.61+/-1.05 h, 0.26+/-0.009 L/kg, 0.34 (0.30-0.38) L/kg and 2.68+/-0.017 mL/min/kg respectively. After i.m. and s.c. dosing, the Cmax was 152.76+/-1.08 and 99.77+/-1.04 microg/mL, achieved at 0.25 (0.25-0.50) and 0.25 (0.25-1.00) h, the t1/2beta was 1.65+/-1.07 and 2.03+/-1.06 h and the absolute bioavailability (F) was 136.1% and 128.8% respectively. A significant difference in Cmax (5.13+/-0.10, 14.26+/-1.12 microg/mL), t1/2beta (3.74+/-1.07, 8.93+/-1.13 h) and ClB/F (22.69+/-0.018, 10.14+/-0.018 mL/min/kg) were found between the two oral doses (50 and 100 mg/kg bw respectively), but there were no differences in the tmax [2.00 (2.00-4.00), 2.00 (2.00-2.00) h] and Vd(z)/F [6.95 (6.34-9.06), 7.98 (4.75-10.62) L/kg). The absolute bioavailability (F) of spectinomycin was 11.8% and 26.4% after oral administration of 50 and 100 mg/kg bw respectively.

Pharmacokinetics of two generic fixed-dose combinations for HIV-infected children (Pedimune Baby &amp; Pedimune Junior) are similar to the branded products in healthy adults

Cipla Pharmaceuticals have developed generic fixed-dose combinations of stavudine, lamivudine and nevirapine for HIV-infected children (Pedimune Baby and Junior). We determined the pharmacokinetic profiles of stavudine, lamivudine and nevirapine in Pedimune and compared these with the branded products. This Phase I, comparative, single-centre, open-label, three-period, single-dose study was designed as a pilot study to exclude large differences in pharmacokinetics. Six healthy males were randomized to the following regimen sequences: ABC; ACB; BCA; BAC; CAB; CBA (A = reference, B = Pedimune Baby, C = Pedimune Junior). Single doses of medication were administered at 3 time points 4 weeks apart. An 8 h pharmacokinetic curve was recorded at day 1 of every cycle after medication intake. In addition, blood samples were taken on days 2, 3, 4, 8 and 15. Non-parametric statistical tests revealed no statistically significant differences in Cmax (0.173 < or = P < or = 0.753) and Tmax (0.317 < or = P < or = 1.000) of stavudine, lamivudine and nevirapine between the two Pedimune formulations and the branded drugs. Also, there were no significant differences in AUC(0-infinity) of stavudine, lamivudine and nevirapine between Pedimune Junior and the branded drugs (0.345 < or = P < or = 0.600) and between Pedimune Baby and the branded drug for nevirapine (P = 0.463). In contrast, the AUC(0-infinity) of stavudine (mean change: +21%; P = 0.046) and lamivudine (mean change: +14%; P = 0.028) differed significantly between Pedimune Baby and the branded drugs, but these changes were considered not clinically significant. The pharmacokinetic profiles of stavudine, lamivudine and nevirapine in Pedimune Baby and Junior are comparable to the branded products. Based on these results, it is acceptable to test the pharmacokinetics and dosing requirements of Pedimune in HIV-infected children.

A phase I clinical and pharmacokinetic study of flavopiridol administered concurrently with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced solid tumors

13515 Background: Flavopiridol, a potent cyclin-dependent kinase inhibitor, enhances oxaliplatin-induced apoptosis in HCT116 colon cancer cells in vitro, especially with concurrent therapy. Significant tumor regressions were also observed in HCT116 xenografts treated with flavopiridol and oxaliplatin therapy versus either therapy alone. Methods: Therefore, an ongoing phase I trial in advanced solid tumors was designed in which flavopiridol at a fixed dose (40 mg/m2 over 1 hour) was administered concurrently with escalating doses of oxaliplatin (60 mg/m2 -&gt; 80 mg/m2 over 2 hours), given as part of a modified FOLFOX6 regimen at standard doses every 14 days. Patients then received escalating doses of infusional 5-fluorouracil over 48 hours (900 mg/m2/day -&gt; 1200 mg/m2/day). Standard phase I eligibility criteria apply. Prior FOLFOX or oxaliplatin was allowed. Results: Median characteristics of nineteen evaluable patients: age 54 (39–77), KPS 80% (70–90), 9 males/10 females, 3 prior regimens (range 1 to 10). The combination has been well-tolerated, with 1 dose limiting toxicity occurring with oxaliplatin at 85 mg/m2 and infusional 5-fluorouracil at 1200 mg/m2/day (grade 3 hyponatremia and grade 3 syncope). Pharmacokinetic studies for flavopiridol indicate no appreciable difference in Cmax despite escalation of oxaliplatin dose. We have observed 1 partial response to treatment in pancreatic cancer. Stable disease has been seen in 5 patients, including 1 breast cancer (3 months), 1 gastric cancer (2 months), 1 anal cancer (7 months) and 2 colorectal cancers (5+ months), with one patient previously treated with oxaliplatin. Conclusions: The combination of flavopiridol and modified FOLFOX6 can be given safely without a significant increase in toxicity. The pharmacokinetic data for flavopiridol remains unchanged despite escalating doses of oxaliplatin. Activity has been observed in several tumor types, with promising activity noted for colorectal cancers even with prior oxaliplatin chemotherapy. Therefore, further dose escalation of flavopiridol is currently planned. No significant financial relationships to disclose.

Effect of food intake on the bioavailability of almotriptan, an antimigraine compound, in healthy volunteers: an open, randomized, crossover, single-dose clinical trial

This open, randomized, crossover, single-dose clinical trial evaluated the possible pharmacokinetic interaction between a single oral dose of almotriptan 25 mg, a 5-HT1B/1D receptor agonist for the acute treatment of migraine, and food intake in healthy volunteers. The influence of food intake in the rate and extent of almotriptan absorption was evaluated by bioequivalence criteria. Tolerability and safety of treatment were also assessed. 16 healthy volunteers (8 men and 8 women, aged 19-27 years) received a crossed single oral dose of almotriptan 25 mg under fasting and fed conditions, separated by a 7-day washout period. The treatment given under fasting condition was considered as reference. Plasma levels of almotriptan were analyzed using high-performance liquid chromatography (HPLC) and UV detection at 227 nm. The 90% confidence intervals (CI) for the logarithmically transformed Cmax and AUC0-infinity, values of almotriptan under fasting and fed conditions (97.8 - 124% and 102.9 - 108.2%, respectively) fell into the predetermined accepted range of 80 - 125%. No statistically significant differences in Cmax, tmax, AUC0-infinity, MRT and t1/2 were observed under fasting and fed conditions between men and women. Tolerability of treatments was good throughout the whole study period. In conclusion, administration of almotriptan 25 mg is bioequivalent under fasting and fed conditions in healthy men and women. Therefore, it is unlikely that concomitant food intake would produce clinially relevant differences in therapeutic effect with almotriptan at the dose studied here.