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PHARMACOKINETICS |
From Merck Research Laboratories, West Point and Blue Bell, Pennsylvania (Dr Majumdar, Ms Howard, Dr Goldberg, Ms Hickey, Mr Constanzer, Dr Rothenberg, Ms Crumley, Ms Panebianco, Dr Bradstreet, Dr Bergman, Dr Petty), and Brussels, Belgium (Dr De Lepeleire, Ms Michiels); Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Waldman, Dr Greenberg, Dr Butler); and SGS Biopharma, Centrum Ziekenhuis Antwerpen, Campus Stuivenberg, Belgium (Dr Knops).
Address for reprints: Anup K. Majumdar, WP75B-100, Merck & Co, Sumneytown Pike, West Point, PA 19486.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSION/CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Key Words: Aprepitant • pharmacokinetics • bioavailability, food effect
The clinically effective dose of aprepitant for the treatment of CINV is a 125-mg capsule 1 hour prior to chemotherapy treatment (day 1) and an 80-mg capsule once daily in the morning on days 2 and 3. To define precisely the pharmacokinetics of the final marketed formulation of 125-mg and 80-mg aprepitant capsules, 2 studies were conducted. Study 1 evaluated the absolute bioavailability of the capsules and estimated the effect of food. Prior experience with various formulations of aprepitant in clinical subjects suggested some nonlinearity in the disposition of aprepitant. Because of this nonlinearity, bioavailability estimates could not be precisely made using traditional methods of separate intravenous (IV) and oral dosing. Therefore, in the first study, a 2-mg IV dose of stable isotope-labeled aprepitant was coadministered with oral capsules containing unlabeled drug to precisely estimate the oral bioavailability of different doses of aprepitant. The 2-mg IV dose of stable isotope-labeled aprepitant should minimally affect the disposition of the drug, relative to the 125- and 80-mg oral doses. The second study evaluated aprepitant pharmacokinetics following the 3-day oral regimen currently recommended for CINV.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSION/CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was a 2-part study. Part 1 was a single-period, double-blind, placebo-controlled study to investigate the safety and tolerability of aprepitant 2 mg IV and was completed prior to initiating part 2 of the study. An intravenous catheter was placed into a forearm vein for administration of 100 mL of aprepitant (2 mg, 20 µg/mL; treatment A) or matching placebo (treatment B) over 4 hours. Plasma samples were collected predose and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 30, 36, 48, and 72 hours after starting the IV.
Part 2 was an open-label, randomized, 4-period crossover study to quantify the absolute bioavailability of aprepitant 125-mg and 80-mg capsules and define the effects of food on the resultant drug pharmacokinetics. The 4 study drug treatments of part 2 were as follows:
The 4 treatment periods of part 2 were each separated by at least 7 days. In treatments C and D, the IV infusion of the stable isotope-labeled aprepitant was administered over 4 hours (the approximate Tmax value of oral aprepitant) to ensure that plasma levels of the IV drug paralleled that of the oral agent, to permit accurate quantification of bioavailability.
Two female subjects experienced flushing, cyanosis, dyspnea, and chest discomfort within 2 minutes of initiating the IV infusion of the stable isotope-labeled aprepitant in part 2. Consequently, the IV portion of treatments C and D was not administered to the remaining subjects, reflecting safety considerations. Of the 24 planned subjects in part 2, 16 had completed all treatments, including the IV dosing components of treatments C and D, prior to these adverse events. For subjects who had not received treatments C and/or D prior to these adverse events, those treatments were modified to eliminate the IV component: (1) 1 aprepitant 125-mg FMC capsule in the fasted state (treatment C) and (2) one 80-mg FMC capsule in the fasted state (treatment D).
Dosing of study drug in both parts of the study was completed in the CRU under supervision/observation of the investigator/study coordinator. For part 2, the dosing time remained consistent in each period for each subject throughout the study. Treatments C, D, E, and F oral doses were administered with 8 oz of water. On each day of dosing within treatments E and F of part 2, subjects received study drugs following a standard breakfast (2 scrambled eggs, 2 slices of toast with 2 pats of butter, 2 strips of bacon, 113 g of hash brown potatoes) that was consumed within 
15 minutes prior to dosing. All meals provided to the subjects during their sequestered stay in the CRU were standardized.
In part 2, dosing with the aprepitant oral capsule (125 or 80 mg) and the IV 2-mg dose of stable isotope-labeled aprepitant was initiated at the same time (8:00 AM). Plasma samples were obtained before dosing and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 30, 36, 48, 72, and 96 hours after initiating the IV. Samples were placed on ice, centrifuged within 45 minutes of collection, and resulting plasma samples immediately frozen at -20°C until analysis.
Aprepitant was labeled with 2 13C and 3 15N atoms, resulting in a molecular weight of the stable isotope-labeled drug that was 5 d higher than that of the unlabeled drug. The stable labeled [13C2 15N3] aprepitant was prepared by the Label Compound Synthesis Group (Department of Drug Metabolism, Merck Research Laboratories [MRL], Rahway, NJ). The other components of the stable isotope-labeled IV formulation were identical to those of the placebo IV formulation.
Safety Assessment
Safety and tolerability were assessed by physical examination, vital signs, 12-lead ECGs, routine laboratory tests (hematology, blood chemistry, and urinalysis), infusion site evaluations, and the recorded occurrences of adverse experiences.
Analytical Methods
Aprepitant in plasma samples was analyzed by the Department of Drug Metabolism (MRL, West Point, Pa).11 Analytical methods included liquid-liquid extraction for analyte isolation followed by liquid chromatography tandem mass spectrometry (LC/MS/MS) detection. The lower limit of quantitation (LOQ) for aprepitant in samples from part 1 of the study was 0.1 ng/mL. The intraday precision (percentage coefficient of variation [CV%]) of standard samples was within 3.3%, and the accuracy ranged between 94% and 103% of nominal concentrations. The LOQ for the stable isotope-labeled aprepitant in samples from part 2 of the study was 0.1 ng/mL. The intraday precision (CV%) was within 4.6%, and the accuracy ranged between 95% and 106% of nominal concentrations. The LOQ for unlabeled aprepitant in samples from part 2 of the study was 10 ng/mL of plasma. The intraday precision (CV%) was within 3.5%, and the accuracy ranged between 98% and 102% of nominal concentrations.
Because the doses of aprepitant in part 1 and those of stable labeled aprepitant in part 2 were only 2 mg as compared to the doses of 80- and 125-mg for the unlabeled aprepitant in part 2, the methods (LOQ = 0.1 ng/mL) developed to assay aprepitant in part 1 and the stable labeled aprepitant in part 2 were more sensitive (standard curve ranges from 0.1 ng/mL to 25 ng/mL) than that used to assay the unlabeled aprepitant in part 2 (standard curve range of 10 ng/mL to 5000 ng/mL).
Pharmacokinetic Methods
Individual aprepitant plasma concentrations were used to estimate aprepitant pharmacokinetic parameters AUC0-
, Cmax, Tmax, ClP, t1/2, and Vdss following the aprepitant single IV dose in part 1 of the study and following the aprepitant IV stable isotope-labeled doses in part 2 of the study. Also estimated were AUC0-, Cmax, Tmax, and t1/2 of aprepitant for the unlabeled oral capsule doses in part 2 of the study. The commercial software WinNonlin version 3 was used to calculate these parameters. A weight of 1/y was used for fitting the terminal log-linear portion of the plasma concentration-time curve to obtain the first-order terminal disposition rate constant (
Z). The apparent terminal half-life (t1/2) was ln(2)/Z. The trapezoidal rule was used to calculate the AUClast up to the last measurable concentration (Clast). AUC0- was calculated from [AUClast + Clast/Z]. The initial maximum concentration observed in plasma (Cmax) and its time of occurrence (Tmax) were obtained by inspection. The AUC0- and Cmax following IV doses were adjusted by the actual doses administered, obtained by multiplying the volume of infusion solution administered by the assayed concentration of the infusion solution. The volume of infusion solution administered was obtained by taking the difference in the weight of the infusion apparatus before and after dosing and using a specific gravity of 1.0 for the infusion solution. The assayed potencies of the capsules administered approximate (>99%) their nominal values, and hence, the AUC0- and Cmax following oral doses are based on nominal doses.
The apparent plasma clearance following IV doses was quantified by dividing the actual doses by the corresponding AUCs. The apparent volume of distribution (Vdss) following the IV doses was estimated by Vdss = [(AUMC0-/AUC0-)-
/2] x Dose/AUC0-, where AUMC0- was the area under the plasma concentration-moment curve and was the length of infusion. The AUMC0- was estimated by AUMClast + Tlast x Clast/Z + Clast/2Z, where Tlast is the time of the last measurable concentration and AUMClast is the area under the plasma concentration-moment curve up to the last measurable concentration (Clast). The above expression for Vdss assumes linear kinetics.
The bioavailability of the capsule formulations was determined by comparing the dose-standardized AUC0- value (AUC/dose) following the capsule dose to the dose-standardized AUC0- value (AUC/dose) following the simultaneously administered IV stable isotope-labeled [13C2 15N3] aprepitant dose. The effect of food on the capsule formulations was determined by comparing the AUC0- of the capsule dose administered in the fed state to the AUC0- of the capsule dose administered in the fasted state.
Statistical Analysis
Part 1. Seven of 9 subjects completed part 1 of the study, and all 6 subjects who received active aprepitant had complete data sets and were included in the pharmacokinetic analysis. All 9 subjects who entered part 1 of the study were included in the safety analysis.
For the IV 2-mg dose of aprepitant, geometric means and 95% confidence intervals (CIs) were calculated for the pharmacokinetic parameters AUC0-, Cmax, clearance (ClP), and volume of distribution (Vdss). The median was calculated for Tmax, and harmonic mean and 95% CI (using jack-knife methodology) was calculated for half-life.
Part 2. In part 2, 16 subjects had complete data sets, and the remaining subjects had partial data sets that were included in analyses. Subjects were included in the absolute bioavailability analysis if they had a bioavailability ratio (oral/IV) for either the 125-mg or 80-mg dose. Subjects were included in the fed versus fasted analysis if they had pharmacokinetic data available for at least 3 of the 4 oral treatments. All 25 subjects who entered part 2 of the study were included in the safety analysis.
To examine the effect of food on aprepitant pharmacokinetics, the relative bioavailability of aprepitant capsules (fed/fasted) was estimated by performing a normal theory analysis of variance (ANOVA) with the response variable natural log-transformed oral AUC0- with factors for gender, subject within gender, carryover, period, treatment, gender-by-treatment interaction, and within-subject error. The carryover and gender-by-treatment interaction terms were tested at 
= .05. The gender term was tested against the subject-within-gender term at = .10. A reduced ANOVA model reflecting deletion of the non-statistically significant carryover and interaction terms was used to complete the statistical analysis. To further evaluate the possibility of a food effect, a 90% CI for the true difference in mean natural log-transformed AUC0- (fed vs fasted) was calculated for each oral dose using the reduced ANOVA model mean square error and referencing a t-distribution. For each oral dose, these confidence limits were exponentiated to obtain the 90% CI for the geometric mean AUC0- ratio (fed/fasted). Cmax was analyzed for food effect in a manner similar to AUC0-. For Tmax, the Hodges-Lehmann point estimate of median difference (fed minus fasted) and exact 95% CI were calculated to compare the fed versus fasted treatments.
Since the IV doses of aprepitant were administered to each subject in only 2 of the 4 treatment periods (since subjects were randomized to treatment sequence, the sequence of the 2 periods of IV treatment were not the same for all subjects), some of the ANOVA effects could not be properly evaluated in an analysis estimating the absolute bioavailability of aprepitant. Therefore, the terms of carryover, period, and treatment-by-period interaction were assessed in the fed versus fasted comparison, and the study was carried out under the assumption that these effects are similar for the aprepitant oral and IV doses.
From the food effect ANOVA above, the gender-by-treatment interaction, carryover, and period effects were assessed. Among these potential effects, only the period term was statistically significant and only in the reduced ANOVA model. Since the response variable for the estimation of bioavailability was the individual AUC0- dose-standardized oral/IV ratio and each subject's oral and IV value for a particular dose was obtained from the same period, the period effect seen in the food effect analysis should not have been of concern in the absolute bioavailability analysis, assuming any period effect was proportional among the oral and IV treatments. Since the gender-by-treatment interaction was not notable from the food effect ANOVA above and the carryover and period effects were not of concern, estimates of absolute bioavailability for the MK-0869 125-mg and 80-mg oral doses were calculated as follows.
For each dosing regimen (oral or IV), each subject's AUC0- values were dose standardized to 1 mg prior to analysis. Considering each oral dose (125 mg and 80 mg) separately, subjects with both oral and IV data were included in an ANOVA with the response variable natural log-transformed dose-standardized AUC0- ratio (oral/IV). The factors gender and period were included in the ANOVA, and they were tested at the = .10 level. A gender comparison was made by comparing the 90% CI for the ratio (female/male) of geometric means for the AUC0- bioavailability ratio (oral/IV) to the (0.70, 1.43) target interval. If the 90% CI did not fall completely within the target interval, the estimates of absolute bioavailability were explored by gender. Then, a 95% CI for the mean natural log-transformed ratio (oral/IV) was calculated using the appropriate standard error from the ANOVA and referencing a t-distribution. Finally, the confidence limits were exponentiated to obtain the 95% CI for absolute bioavailability (oral/IV).
Summary statistics for the IV pharmacokinetic parameters AUC0-, Cmax, apparent clearance (Cl), and volume of distribution (Vd), as well as for the oral parameters AUC0-, Cmax, half-life, and Tmax were computed. In addition, a formal comparison was made between the treatment groups to explore any change in apparent plasma clearance of aprepitant. The comparisons of treatment C (part 2) versus treatment A (part 1) and treatment D (part 2) versus treatment A (part 1) were accomplished using a 2-sample t test. The P value was computed for each of the 2 comparisons, and ratios of geometric means (treatment C/treatment A and treatment D/treatment A) and corresponding 95% CIs were computed. A similar comparison between treatment D and treatment C was performed using a paired t test. A comparison between treatment D and treatment C was made by gender also using a paired t test.
Study 2: The Pharmacokinetic Profile of the 3-Day Aprepitant Regimen
Subjects
Six men and 6 women with a mean age of 44 years (range, 31-53) and within 30% of their ideal body weight were enrolled in the study. Subjects were in good health based on medical history, physical examination (including vital signs and ECG), and routine laboratory tests (routine hematology and blood chemistry). The use of nonstudy drugs, including herbal/organic remedies, was prohibited for at least 2 weeks prior to and during the study unless approved by the investigator. Subjects agreed to refrain from grapefruit products and charcoal-broiled foods for at least 2 weeks prior to the study and throughout the study and could not consume >6 cups of caffeinated beverages per day. Serum ß-hCG tests confirmed that women were not pregnant prior to study initiation, and a negative urine ß-hCG test immediately prior to the first dose of study drug was required. Women of childbearing potential were required to use double-barrier contraception. Women taking oral contraceptives were not enrolled. The study was approved by the local institutional review board, and all subjects gave written informed consent before study participation. The study was conducted at the SGS Biopharma, Centrum Ziekenhuis Antwerpen, Campus Stuivenberg, Belgium. All 12 subjects completed the study and were included in the pharmacokinetic and safety analysis.
Study Design
In this open-label study, each subject was administered a single oral dose of one 125-mg capsule of aprepitant on day 1 and a single oral dose of one 80-mg capsule of aprepitant on each of days 2 and 3 between 8:30 AM and 9:30 AM each day. All doses were administered in the CRU 15 minutes following completion of a standard light breakfast. On days 1 and 3, subjects remained in the CRU overnight and plasma samples (5 mL) were collected before the first dose and at 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours (ie, day 2 predose) after the 125-mg dose on day 1. Also, plasma was collected predose and after the day 3 80-mg dose at 1, 2, 3, 4, 6, 8, 12, 16, 24 (ie, day 4), 36, 48 (ie, day 5), 72 (ie, day 6), and 96 hours (ie, day 7). Samples were placed on ice, centrifuged within 45 minutes of collection, and resulting plasma samples immediately frozen at -20°C until analysis.
Safety Assessments
Safety was assessed by measurement of vital signs, physical examinations, 12-lead ECGs, and routine hematology, blood chemistry, and urinalysis tests. The subjects were monitored throughout the study for adverse experiences.
Analytical Methods
Plasma samples collected were analyzed by the Department of Drug Metabolism, MRL, West Point, Pennsylvania.11 Analytical methods included liquid-liquid extraction for analyte isolation followed by LC/MS/MS detection. The LOQ was 10 ng/mL, the intraday precision (CV%) of standard samples was within 4.6%, and the accuracy ranged between 95% and 106% of nominal concentrations.
Pharmacokinetic Methods
The commercial software WinNonlin version 3 was used to calculate the AUC0-24h, Cmax, and Tmax following the day 1 (125 mg) and day 3 (80 mg) doses. In addition, the apparent terminal elimination half-life (apparent t1/2) was determined following the day 3 dose.
Statistical Analysis
Geometric means were calculated for aprepitant AUC0-24h and Cmax on days 1 and 3. Also, the geometric mean AUC0-24h ratio (day 3/day 1) was calculated. Median Tmax was calculated for days 1 and 3. Harmonic mean half-life was calculated on day 3. A 95% CI was calculated for each pharmacokinetic parameter.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSION/CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Absolute bioavailability of the 125-mg and 80-mg FMC capsules under fasting condition. The single 2-mg IV dose produced plasma concentrations of aprepitant that were adequate to assess the absolute bioavailabilities of the 125-mg and 80-mg capsules in part 2. The geometric means (95% CIs) absolute bioavailability (oral dose-standardized AUC0-/IV dose-standardized AUC0-) of aprepitant 125-mg and 80-mg FMC capsules in the fasted state were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively (Table II). The geometric means (95% CIs) bioavailability in women and men were 0.52 (0.45, 0.62) and 0.65 (0.57, 0.75), respectively, following the 125-mg capsule and 0.65 (0.57, 0.74) and 0.70 (0.63, 0.77), respectively, following the 80-mg capsule. The ratio (female absolute bioavailability/male absolute bioavailability) of geometric means and 90% CIs were 0.80 (0.67, 0.96) and 0.93 (0.81, 1.06) for the 125-mg and 80-mg capsules, respectively. While there was a statistically significant difference in absolute bioavailability between men and women for the 125-mg dose, the difference is not clinically significant.
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ratios (fed/fasted) and 90% CIs were 1.20 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg doses, respectively. Based on tolerability and clinical activity of aprepitant, a difference of <2-fold between fasted and fed AUC would indicate that specific instructions with respect to food are not necessary. Since both CIs were fully contained in this prespecified target interval (0.5, 2.0) for clinical significance, these results suggest that food (standard breakfast) does not affect the relative bioavailability of aprepitant 125-mg and 80-mg capsules to a clinically important extent.
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Dose proportionality of aprepitant 125-mg and 80-mg FMC capsule doses. The geometric mean dose-standardized AUC0- ratios (125 mg/80 mg) and 90% CIs were 1.14 (1.05, 1.24) and 1.26 (1.16, 1.36) for the fasted and fed states, respectively (Table IV). Similarly, the geometric mean dose-standardized Cmax ratios (125 mg/80 mg) and 90% CIs were 0.98 (0.87, 1.10) and 1.07 (0.95, 1.21) for the fasted and fed states, respectively (Table IV).
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Study 2
The plasma profile of aprepitant on day 3 following the second 80-mg dose was similar to that on day 1 following the first 125-mg dose (Figure 4). On day 1, following the 125-mg dose, the geometric mean AUC0-24h was 19 455 ng•h/mL, Cmax was 1539 ng/mL, and median Tmax was 4 hours (Table V). On day 3, the mean AUC0-24h was 20 149 ng•h/mL, Cmax was 1356 ng/mL, and median Tmax was 4 hours (Table V). The harmonic mean apparent half-life following the day 3 dose was 8.6 hours (Table V). Thus, consistent daily plasma exposures of aprepitant were obtained with a loading dose of 125 mg on day 1 followed by an 80-mg dose on days 2 and 3.
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Safety
Overall, single doses and the 3-day aprepitant regimen for CINV were generally well tolerated by healthy subjects participating in this study. Of the 34 subjects enrolled in study 1, 1 subject discontinued due to an IV apparatus malfunction, 2 due to clinical adverse experiences (apparent hypersensitivity reactions possibly due to polysorbate 80 in the IV formulation12), and 3 were lost to follow-up. Of the 34 subjects, 19 (56%) reported a total of 52 clinical adverse experiences. Overall, 29 of the 52 clinical adverse experiences (14 of the 34 subjects) were rated by the investigator as drug related (possibly, probably, or definitely) and were generally mild in intensity. The 12 subjects in study 2 reported a total of 41 clinical adverse experiences, none of which were serious or resulted in discontinuation. Ten subjects reported a total of 24 adverse experiences that were considered "possibly" drug related by the investigator, the most common of these being headache (12), diarrhea or loose stools (5), and asthenia/tiredness (4).
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DISCUSSION/CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSION/CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The study estimated the geometric mean absolute bioavailability of oral aprepitant capsules in the fasted state, 0.59 for the 125-mg capsule and 0.67 for the 80-mg capsule. Despite a higher dose-standardized AUC0- of aprepitant following the 125-mg dose compared with the 80-mg dose, the bioavailability was slightly less for the 125-mg capsule compared to the 80-mg capsule because, as noted above, the higher AUC0- of aprepitant following the 125-mg compared to the 80-mg dose reflects the lower apparent plasma clearance of higher doses of aprepitant. Conversely, the slightly lower bioavailability of the 125-mg aprepitant capsule compared with 80-mg capsule is consistent with a slightly decreased extent of absorption with increased dose but is not of clinical importance.
The systemic exposure (AUC0-) of aprepitant from a 125-mg capsule is increased 20% when administered with a high-fat meal. Similarly, aprepitant exposure is increased 9% when an 80-mg capsule is administered with food. A higher food effect but lower bioavailability in the fasting state for 125-mg compared to 80-mg capsules is consistent with a small effect of food on drug absorption. Based on tolerability and clinical activity of aprepitant, a difference of <2-fold between fasted and fed AUC is considered clinically insignificant. Thus, this study confirms that for the 125-mg and 80-mg aprepitant FMC capsules, the effect of food on bioavailability is clinically insignificant (
20% mean increase in plasma AUC0- with food), supporting the conclusion that this formulation at these doses can be administered independently of food.
The pharmacokinetics of aprepitant oral capsules appears to be slightly nonlinear, especially when administered after food intake. The dose proportionality of the pharmacokinetics of the capsule doses used in this study was assessed both while fasting and shortly after food intake. The plasma AUC0- of aprepitant increased in a slightly greater than dose-proportional fashion (ie, 14% and 26% greater than if kinetics were linear following fasted and fed administration, respectively) following the 125-mg compared to the 80-mg dose. In vitro data13 as well as clinical drug interaction studies with a CYP3A4 substrate (eg, midazolam)14 and inhibitor (eg, ketoconazole) indicate that aprepitant is a substrate as well as an inhibitor of CYP3A4. The slight nonlinearity noted above would be consistent with saturation of metabolism via CYP3A4.
Part 2 of this study characterized the plasma pharmacokinetic profile of the 3-day regimen for CINV. The daily plasma concentrations of aprepitant were well maintained, with a loading dose of 125 mg on day 1 followed by an 80-mg dose on days 2 and 3. Moreover, administration of the 3-day aprepitant regimen for CINV was well tolerated.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSION/CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSION/CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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