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DRUG INTERACTIONS |
From the Merck Research Laboratories, West Point, Pennsylvania (Dr Li, Ms Panebianco, Dr Majumdar, Dr Rosen, Ms Ahmed, Dr Rushmore, Dr Murphy, Dr Petty); Thomas Jefferson University, Philadelphia, Pennsylvania (Mr Pequignot); Villanova University, Villanova, Pennsylvania (Dr Lupinacci); and West Pharmaceuticals Services, GFI Research, Evansville, Indiana (Dr Royalty).
Address for reprints: Laura Rosen, MD, PhD, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486; e-mail: laura_rosen{at}merck.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (
2.0) for clinical significance (AUC0-, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.
Key Words: Aprepitant • dolasetron • interaction • CYP3A4 • CYP2D6
Dolasetron is a prodrug that is rapidly converted to hydrodolasetron, which is believed to be responsible for the majority of clinical activity.8-11 Hydrodolasetron is metabolized largely via cytochrome P450 (CYP) D6.12 Less than 1% of hydrodolasetron undergoes CYP3A4 metabolism,12,13 although this has been presumably evaluated in subjects with normal CYP2D6 activity. For CYP2D6 poor metabolizers, it is possible that an alternate pathway, such as CYP3A4, plays a more important role in hydrodolasetron clearance. The extent to which CYP2D6 poor metabolizers might rely on an alternate pathway to metabolize hydrodolasetron is unknown, and if that alternate pathway were itself inhibited, the effect on hydrodolasetron exposure is unknown. Aprepitant is a moderate CYP3A4 inhibitor and can increase the plasma concentrations of some drugs metabolized by CYP3A4.14,15 We conducted this study to determine whether aprepitant affects the pharmacokinetics of hydrodolasetron when dolasetron is orally coadministered with aprepitant. It was of particular interest to determine if aprepitant, because it is a moderate inhibitor of CYP3A4, affects the pharmacokinetics of hydrodolasetron in CYP2D6 poor metabolizers, who might rely on CYP3A4 and, thus, be more susceptible to impaired hydrodolasetron clearance in the presence of CYP3A4 inhibitors.
In addition, dolasetron and other 5-HT3 receptor antagonists are known to have slight effects on electrocardiographic (ECG) parameters, such as increases in the PR and QRS intervals and QTc prolongation in particular.16-19 Because these effects are related to the plasma concentrations of hydrodolasetron, a pharmacokinetic interaction that increases the hydrodolasetron plasma level could increase the risk of ECG abnormalities. (Aprepitant itself does not affect ECG parameters, even at exposures up to 
5-fold greater than those achieved with the aprepitant regimen for CINV; Merck Research Laboratories, unpublished data, 2002). Therefore, another objective of this study was to compare the effect of dolasetron on ECG parameters when dolasetron is given with and without aprepitant.
We evaluated the potential effect of aprepitant on the plasma concentration profile of hydrodolasetron as well as on ECG parameters in CYP2D6 poor metabolizers and CYP2D6 extensive metabolizers. The CYP3A4-inhibitory effect of aprepitant is greater for orally administered CYP3A4-metabolized drugs; therefore, we used orally administered dolasetron to maximize any potential interaction with aprepitant.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects
Healthy adult volunteers were identified as CYP2D6 poor or extensive metabolizers via CYP2D6 genotyping as well as dextromethorphan phenotyping using a single oral dose of 30 mg dextromethorphan.20 Subjects carrying at least one copy of the CYP2D6 *1 allele and who had a urinary metabolic ratio of dextromethorphan to dextrorphan less than 0.1 were categorized as CYP2D6 extensive metabolizers. Subjects who were homozygous or heterozygous for the CYP2D6 *3, *4, or *5 alleles21,22 and who had a urinary metabolic ratio of dextromethorphan to dextrorphan greater than 0.3 were categorized as CYP2D6 poor metabolizers.
Women were required to have a negative serum beta human chorionic gonadotropin (ß-hCG) level and to agree to use appropriate contraception throughout the study. All subjects were to refrain from consuming herbal medicines (including St John's wort), grapefruit or grapefruit juice, and garlic supplements for 2 weeks before the administration of study drug and throughout the study. Subjects were excluded if they had a history of cardiac or vascular disorder, asthma or other pulmonary disease, major gastrointestinal abnormalities or peptic ulceration, or hepatic, neurologic, hematologic, endocrine, renal, or major genitourinary disease. Other exclusion criteria included habitual and heavy consumption of caffeine at the time of the study or regular use of prescription or nonprescription medicines that could not be discontinued at least 2 weeks before the study and for the duration of the study. Subjects with clinically significant abnormalities on physical or laboratory examination, performed within 3 weeks prior to the start of the study, were excluded. Other exclusion criteria included having a history of either prolonged cardiac conduction intervals, congenital QT syndrome, hypokalemia or hypomagnesemia, or use of diuretics with potential for inducing electrolyte abnormalities. Subjects were excluded if they had a prestudy resting heart rate less than 55 beats per minute or greater than 90 beats per minute, ECG PR interval greater than 185 milliseconds, QRS duration greater than 115 milliseconds, or QTc interval greater than 420 milliseconds. Subjects were excluded if they had a history of allergies or intolerance to aprepitant, 5-HT3 receptor antagonists, or dextromethorphan.
Treatments Administered
Treatment A consisted of a single oral dose of dolasetron 100 mg alone on day 1 (0 hours) and no study drugs on days 2 and 3. Treatment B consisted of a single oral dose of aprepitant 125 mg plus dolasetron 100 mg simultaneously on day 1 (0 hours), followed by aprepitant 80 mg orally on day 2 (24 hours) and day 3 (48 hours). Dolasetron and aprepitant were administered 30 minutes after a standard breakfast in the clinical research unit. For each subject, treatments A and B were given at least 21 days apart. Drug supplies were packaged in an open-label fashion by allocation number. A randomized allocation schedule was used to determine the order of treatments.
Sample Collection and Analytical Methods
Plasma samples were collected for hydrodolasetron assay at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hours after dolasetron administration. Blood was collected into chilled EDTA-containing tubes, which were immediately placed on wet ice and centrifuged at 4°C for 10 minutes. The plasma was transferred to cryotubes and immediately frozen at -20°C. The frozen samples were shipped on dry ice to Cephac Europe SA (Poitiers, France) for hydrodolasetron assay. Samples were analyzed using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) with a lower limit of quantitation of 0.5 ng/mL and ondansetron as the internal standard. The mass transition was 327.1 to 166.1. The assay was linear from 0.500 to 100 ng/mL using 0.5 mL of sample. For the low, middle, and high quality control samples, the interassay precision (% coefficient of variation) was 6.8% to 7.3%, and accuracy ranged from 99.3% to 102.6%.
In treatment B only, 5 mL blood was drawn at 24 hours after each aprepitant dose for aprepitant assay. Blood was collected into EDTA-containing tubes, and the samples were immediately placed on ice. Within 45 minutes of collection, samples were centrifuged at 0°C to 5°C at 3000 revolutions per minute for 15 minutes, and the plasma was separated into cryotubes, which were stored at -20°C until analysis. Samples were sent to Merck Research Laboratories (West Point, Pennsylvania) for aprepitant assay. The analytical methods used were liquid-liquid extraction for aprepitant, followed by LC-MS/MS detection with a lower limit of quantitation of 10 ng/mL.23 The internal standard was an analog of aprepitant. The mass transition was 535 to 277. For the low, middle, and high quality control samples in the initial interday and intraday assays, precision was 1.0% to 11.9% (% coefficient of variation), and accuracy was 99% to 101%.
For CYP2D6 phenotyping, subjects received dextromethorphan 30 mg orally on day -1, after which urine was collected over an 8-hour period and stored on ice. After thorough mixing, a 30-mL aliquot was transferred to a polypropylene vial and frozen at -20°C until analysis. PPD Development (Middleton, Wisc) conducted quantitation of dextromethorphan and dextrorphan by LC-MS/MS. Low, middle, and high quality control samples were run for both assays. For the quality control samples in the dextromethorphan assay, precision was 4.87% to 13.4% (% coefficient of variation), and accuracy ranged from 90.21% to 96.17%. For the quality control samples in the dextrorphan assay, precision ranged from 2.83% to5.49% (% coefficient of variation), and accuracy ranged from 87.1% to 98.16%.
For CYP2D6 genotyping, a 5-mL sample of whole blood was collected in a sodium EDTA-containing tube, transferred to a cryotube, and stored at -70°C. Genomic DNA (gDNA) was isolated from each sample using a QiAmp DNA Mini Kit (Qiagen, Valencia, Calif). Genotyping of CYP2D6 was conducted by Merck Research Laboratories (West Point, Pennsylvania) using polymerase chain reaction (PCR). An allele-specific PCR method24,25 was used to monitor for the presence or absence of the most common alleles of the CYP2D6 gene: CYP2D6*1 (wild allele, ie, active allele) and CYP2D6*4 (variant/inactive allele). As well, a PCR method described by Mulder et al26 was used to monitor for CYP2D6*5 (deleted allele). All PCR reaction conditions were as described in each reference. All reactions contained 200 ng of gDNA.
Tolerability Assessments
A complete physical examination was performed at the prestudy clinic visit, which occurred within 2 weeks of the start of the study, and at the poststudy clinic visit, which occurred 2 weeks after the last dose of study drug. A 12-lead ECG with a 1-minute rhythm strip was obtained at prestudy and poststudy. In addition, 12-lead ECGs were performed at the following times: immediately following breakfast on day -1, predose (0 hour) and at 1, 2, 8, and 24 hours postdose in treatments A and B. The ECG on day -1 was obtained before dextromethorphan administration. The ECGs on day -1 and day 1 were obtained at the same time of day under the same conditions, and the results were averaged for use as the baseline for analysis of subsequent ECGs. Routine hematology, chemistry, and urinalysis evaluations were conducted at prestudy and poststudy. Additional assessments of electrolytes, including serum magnesium, were performed on day -1 in treatments A and B to ensure that those parameters were normal before obtaining ECGs. Subjects were observed for the occurrence of adverse experiences until the poststudy visit.
Pharmacokinetic Analyses
Individual plasma hydrodolasetron concentrations were used to estimate the following hydrodolasetron pharmacokinetic parameters: area under the concentration-versus-time curve (AUC0-), peak plasma concentration (Cmax), time to Cmax (tmax), and terminal half-life (t
) for each treatment. The commercial software WinNonlin (version 4.1; Pharsight Corp, Mountain View, Calif) was used to estimate these parameters. To obtain the first-order terminal rate constant (
z), 1/y was used for fitting the terminal log-linear portion of the plasma concentration curve. The terminal t was set at ln(2)/z. The linear trapezoidal rule is used anytime the concentration data are increasing, and the logarithmic trapezoidal rule is used anytime the concentration data are decreasing. Thus, the linear up/log down trapezoidal rule was used to calculate the AUClast up to the last measurable concentration (Clast). AUC0- was calculated from AUClast + Clast/z. For all hydrodolasetron pharmacokinetic calculations and hydrodolasetron plasma concentration-versus-time profiles, all values below the lower limit of detection were set to zero.
Statistical Methods
The primary hypothesis was that the AUC0- of hydrodolasetron would not be substantially greater after treatment B (dolasetron plus aprepitant) compared with that after treatment A (dolasetron alone). The secondary hypothesis was that the Cmax of hydrodolasetron would not be substantially greater after treatment B than after treatment A. Individual hydrodolasetron AUC0- values were natural log-transformed and evaluated in an analysis of variance (ANOVA) model with factors for treatment, period, treatment sequence, and subject within sequence. The geometric mean AUC0- ratio (treatment B/treatment A) and 90% confidence interval (CI) for the true ratio were calculated from the ANOVA. An upper limit of the CI 2.0 would support the hypothesis of no substantial effect of aprepitant on hydrodolasetron AUC. The limit of 2.0 was chosen because the ECG effects of hydrodolasetron have been observed at single doses above 200 mg, whereas the recommended dose of dolasetron is 100 mg. Therefore, a 2-fold increase in the plasma exposure of hydrodolasetron with a 100-mg dose of dolasetron (ie, that which would produce exposure equivalent to that of a 200-mg dose) can be considered clinically unimportant. Individual hydrodolasetron AUC0- values were also natural log-transformed and evaluated in an ANOVA model with factors for treatment, period, subject within population (CYP2D6 extensive or poor metabolizer), population, and treatment-by-population interaction. A 90% CI for the true AUC treatment ratio was obtained separately for extensive and poor metabolizers. Cmax of hydrodolasetron was analyzed similarly.
For ECG PR interval, QTc interval, and QRS interval, separately, change from baseline (mean of day -1 and day 1 predose measurements) was calculated for each subject in each treatment period at each time point (1, 2, 8, and 24 hours postdose) and evaluated in an ANOVA model as described previously for AUC, except that the model also included a factor for treatment-by-time interaction. This model was used to calculate 95% CIs for mean change from baseline for each treatment and for the mean between-treatment differences in change from baseline.
Given a sample size of 12 subjects and a true within-subject variance of 0.0112 for natural log-AUC, there would be 0.99 probability that the upper bound of the 90% CI would be 2.0 if the true geometric mean AUC0- ratio (treatment B/treatment A) is 1.0. Given a sample size of 12 subjects and a true within-subject variance of 0.0514 for natural log-Cmax, there would be 0.99 probability that the upper bound of the 90% CI would be 2.0 if the true geometric mean Cmax ratio (treatment B/treatment A) is 1.0.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Dolasetron Pharmacokinetics
Figure 1 shows the plasma hydrodolasetron concentration profiles separately for CYP2D6 extensive metabolizers and CYP2D6 poor metabolizers after they received dolasetron alone and after they received dolasetron with aprepitant. Table I summarizes the results for the comparisons of the pharmacokinetic variables of hydrodolasetron after administration of dolasetron alone versus dolasetron with aprepitant for all subjects and for CYP2D6 poor and extensive metabolizers separately.
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For all subjects combined, the 90% CIs of the treatment ratios for both hydrodolasetron AUC0- and hydrodolasetron Cmax fell completely below the predefined limit of 2.0 (Table I), supporting the hypothesis that the AUC0- and Cmax values of hydrodolasetron would not be substantially higher after coadministration of aprepitant plus dolasetron compared with administration of dolasetron alone. These findings were true regardless of CYP2D6 metabolizer type (Table I). For the CYP2D6 poor metabolizer type, the geometric mean hydrodolasetron AUC0- was 2913.3 ng·h/mL after administration of dolasetron alone and 3223.7 ng·h/mL after dolasetron with aprepitant, and the 90% CI of the treatment ratio was0.98 to 1.25. Similarly, for hydrodolasetron Cmax in the poor metabolizer type, geometric mean values were 356.1 ng/mL after administration of dolasetron alone and 401.1 ng/mL after dolasetron with aprepitant, and the 90% CI of the ratio was 0.92 to 1.38. CYP2D6 extensive metabolizers followed a similar pattern.
After administration of dolasetron alone and dolasetron with aprepitant, respectively, the harmonic mean t values of hydrodolasetron were 11.7 and 10.3 hours in all subjects, 11.4 and 9.0 hours in CYP2D6 extensive metabolizers, and 11.9 and 12.1 hours in CYP2D6 poor metabolizers.
Aprepitant Concentrations
Plasma trough concentrations of aprepitant were generally comparable with those observed previously in healthy subjects receiving aprepitant. After the first dose of aprepitant on day 1 of treatment B, mean (SD) plasma trough concentrations of aprepitant at 24, 48, and 72 hours, respectively, were 1013.1 (805.7), 1214.1 (1164.9), and 1796.1 (2083.0) ng/mL. At 24, 48, and 72 hours, respectively, the mean values were 724.2 (210.4), 844.5 (280.5), and 1096.2 (557.8) ng/mL for CYP2D6 extensive metabolizers, and 1302.0 (1087.9), 1583.7 (1605.9), and 2496.0 (2838.8) ng/mL for poor metabolizers. The means for poor metabolizers were inflated because of one outlier with aprepitant concentrations about 5-fold higher than average. With the exception of this subject, aprepitant trough concentrations were similar between CYP2D6 extensive and poor metabolizers. [Excluding the outlier, the mean (SD) values of aprepitant at 24, 48, and 72 hours, respectively, were 878.5 (366.5), 933.0 (220.2), and 1359.1 (617.3).] The reason for the outlier is unclear, but it is well established that the variability of aprepitant pharmacokinetics profiles between persons is large, as previous data have shown up to 10-fold differences in the trough concentrations in different persons given the same dose.
Clinical and Laboratory Tolerability Assessments
The numbers of subjects with at least one clinical adverse experience were similar between treatments (6 dolasetron alone, 6 dolasetron plus aprepitant), as were the numbers of subjects with adverse experiences considered by the investigator to be drug related (3 dolasetron alone, 4 dolasetron plus aprepitant). For CYP2D6 poor metabolizers considered separately, the numbers of patients with clinical adverse experiences were also similar between treatments (4 dolasetron alone, 3 dolasetron plus aprepitant). The same pattern followed for CYP2D6 extensive metabolizers (2 dolasetron alone, 3 dolasetron plus aprepitant). All clinical adverse experiences were mild or moderate; none were rated by the investigator as severe. The most commonly reported clinical adverse experiences during treatment with dolasetron and dolasetron with aprepitant were fatigue (2 and 3 subjects, respectively), headache (2 and 2 subjects, respectively), somnolence (2 and 3 subjects, respectively), dry mouth (1 and 1 subject, respectively), and dizziness (2 and 0 subjects, respectively). There were no serious clinical adverse experiences during the study, and no subjects discontinued because of clinical adverse experiences. There were no laboratory adverse experiences in this study.
Electrocardiographic Assessments
Table II summarizes the mean change from baseline QTc interval for all subjects and for CYP2D6 extensive and CYP2D6 poor metabolizers separately. Baseline mean QTc intervals were similar for the 2 treatments. CYP2D6 poor metabolizers had no statistically significant increases in QTc interval during coadministration of aprepitant and dolasetron. They also had no statistically significant between-treatment differences in change from baseline at any time point, except for at the 8-hour time point. This difference at 8 hours was not due to a QTc increase during coadministration of aprepitant and dolasetron but rather to a QTc decrease during dolasetron administration. The CYP2D6 extensive metabolizers had no QTc interval increases during coadministration of aprepitant and dolasetron, and they had no statistically significant between-treatment differences in change from baseline at any time point.
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Baseline mean values for PR and QRS intervals were similar for the 2 treatments (data not shown). For the overall group of subjects, as well as for CYP2D6 extensive and poor metabolizers considered separately, there were no significant increases in PR or QRS during treatment with aprepitant plus dolasetron that led to significant differences between treatments.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Doses of dolasetron as high as 400 mg have been reported to be well tolerated in healthy subjects and cancer patients. The ECG effects of hydrodolasetron are dose dependent and were observed at single doses greater than 200 mg. The recommended oral dose of dolasetron is 100 mg. Therefore, up to a 2-fold increase in plasma concentration of hydrodolasetron (ie, exposure equivalent to a 200-mg dose) can be considered clinically unimportant for the recommended 100-mg oral dose of dolasetron. Consequently, an increase in hydrodolasetron AUC up to 2-fold (AUC ratio 2.0) is clinically unimportant.
The subjects received dolasetron alone (treatment A: dolasetron 100 mg on day 1) and dolasetron with aprepitant (treatment B: dolasetron 100 mg plus aprepitant 125 mg on day 1, and aprepitant 80 mg on days 2 and 3) in a crossover fashion. The treatment B/treatment A ratios were very close to 1 for both AUC0- (1.09) and Cmax (1.08), indicating little difference between the 2 treatments on these parameters. The upper bounds of the 90% CIs were less than 1.4, considerably below the requirement of 2.0 needed to satisfy the primary and secondary hypotheses that these parameters would not be substantially changed by the coadministration of dolasetron with aprepitant. Such was also the case for the treatment ratios of AUC0- and of Cmax for CYP2D6 extensive and, importantly, poor metabolizers, again with the upper bounds of the 90% CIs of the ratios falling below 1.4. Clearly, aprepitant had no substantial effect on the AUC0- and Cmax of hydrodolasetron, even in the CYP2D6 poor metabolizer type in whom an effect might be anticipated. Aprepitant administration had no clinically important effect on the tmax or t of hydrodolasetron. Because aprepitant plasma concentrations were similar to those observed in healthy subjects in previous studies, the lack of effect of aprepitant on hydrodolasetron pharmacokinetics cannot be attributed to insufficient exposure to aprepitant (manuscript in preparation).
These findings are consistent with observations by Dimmitt et al of a single healthy adult identified as a CYP2D6 poor metabolizer in a group of 17 healthy subjects.27 Hydrodolasetron Cmax for this subject was in the same range as values for the 16 subjects without CYP2D6 deficiency. In this subject, the single-dose and steady-state plasma AUC values for hydrodolasetron were within or just above the upper range of values for the other subjects. However, compared with the mean values for the other subjects, the individual plasma AUC values for this subject showed a 1.5- to 2-fold increase, which the authors believed was caused by decreased transformation of hydrodolasetron to 5'OH- and 6'OH-hydrodolasetron as a result of CYP2D6 deficiency.
The safety profile of dolasetron is generally similar to that of other 5-HT3 receptor antagonists, and the most common adverse experiences reported for dolasetron are headache, fatigue, diarrhea, hypotension, and dizziness.16,28 In the current study, subjects experienced clinical adverse experiences consistent with those expected from the clinical experiences with aprepitant and dolasetron,3,16 and the overall pattern of adverse experiences was similar for dolasetron given alone and with aprepitant. The numbers of subjects with adverse experiences and drug-related adverse experiences were similar between CYP2D6 poor and extensive metabolizers. Notably, similar numbers of CYP2D6 poor metabolizers had clinical adverse experiences during aprepitant coadministration as during administration of dolasetron alone, providing further support that aprepitant does not have a clinically important interaction with dolasetron at the CYP3A4 pathway.
As with other 5-HT3 receptor antagonists, dolasetron has cardiac effects manifesting as small changes in ECG intervals, including increases in QTc, QRS, and PR intervals.16,29 These acute and generally reversible changes are related to plasma hydrodolasetron concentrations. Thus, a pharmacokinetic drug interaction that would increase plasma hydrodolasetron levels could increase the risk for ECG abnormalities. In this study, there were no clinically meaningful effects on QTc or other ECG parameters in either CYP2D6 extensive or poor metabolizers who received dolasetron alone or coadministered with aprepitant. Importantly during coadministration of aprepitant with dolasetron, poor and extensive metabolizers had no significant increases in QTc interval at any time point, including the time points associated with maximum hydrodolasetron exposures, that is, 2 hours, or in the time frame encompassing maximum aprepitant exposure, that is, 4 hours.3 For CYP2D6 poor metabolizers, there was a significant between-treatment difference in change from baseline at 8 hours, but this finding was only because there was a significant mean decrease of the QTc interval at 8 hours after administration of dolasetron alone (-11.2 milliseconds). The mean 5.2-millisecond increase after administration of dolasetron with aprepitant was not a significant change from baseline, but when combined with the significant decrease of QTc with dolasetron alone, the result was a significant between-treatment difference of 16.3 milliseconds (95% CI, 6.78-25.89) (Table II). Therefore, the only significant between-treatment difference was due to a QTc decrease in subjects administered dolasetron alone and, importantly, was not due to prolongation of the QTc in the presence of aprepitant. The lack of a significant aprepitant effect on this pharmacodynamic end point is consistent with its minimal effects on dolasetron pharmacokinetics.
In conclusion, aprepitant did not affect the pharmacokinetics of hydrodolasetron in either CYP2D6 poor or extensive metabolizers and was generally well tolerated when coadministered with dolasetron in healthy subjects.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Dr Li, Ms Panebianco, Dr Majumdar, Dr Rosen, Ms Ahmed, Dr Rushmore, Dr Murphy, and Dr Petty are or were employees of Merck & Co Inc, the manufacturer of aprepitant. Dr Royalty, the principal investigator, received funding from Merck to conduct the study. A portion of the salaries for Mr Pequignot and Dr Lupinacci at Thomas Jefferson University was paid by a contract between the University and Merck.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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