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PHARMACOKINETICS |
From MGI PHARMA, Bloomington, Minnesota (Dr Shah, Mr DeGroot) and The Ohio State University, Columbus (Dr Apseloff). Dr Apseloff is a Fellow of the American College of Clinical Pharmacology. Financial disclosures: Dr Apseloff has received research support from MGI PHARMA. Dr Shah and Mr DeGroot are employees of MGI PHARMA. This study was approved by the Western Institutional Review Board.
Address for reprints: Ajit Shah, PhD, MGI PHARMA, 5775 West Old Shakopee Road, Suite 100, Bloomington, MN 55437-3174; e-mail: ajit.shah{at}mgipharma.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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equivalent to a 30-second infusion.
Key Words: Pharmacokinetics • chemotherapy-induced nausea and vomiting • antiemetic • 5-HT3 receptor antagonist • palonosetron
Palonosetron hydrochloride is a novel, potent, and selective 5-HT3 receptor antagonist. Phase III active comparator studies have shown that a single dose of palonosetron 0.25 mg administered intravenously (IV) provides improved prevention of acute and delayed CINV versus early 5-HT3 receptor antagonists (ie, ondansetron and dolasetron).3 11-13 Palonosetron is currently approved for delivery via a rapid, 30-second, IV infusion. In practice, however, palonosetron is often premixed with dexamethasone and infused over approximately 15 minutes (the standard infusion time for dexamethasone). The ability to vary administration times for palonosetron may provide greater flexibility in drug administration and allow treatments to be tailored to a patient's individual needs. However, no study has been conducted to determine whether variations in the duration of an infusion result in any clinically relevant changes in the pharmacokinetics, efficacy, or safety of palonosetron. The objective of this study was to compare the pharmacokinetics and safety of palonosetron 0.25 mg delivered by a single IV infusion over 15 minutes with a rapid, 30-second IV infusion.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Exclusion criteria included a history of chronic disease or cardiovascular disease, any clinically significant illness within 3 months before the study, or a known contraindication to 5-HT3 receptor antagonists. Subjects also were excluded if any prescription medications were used within 2 weeks before study admission or if any nonprescription medications, nutritional supplements, vitamins, or herbal products were used within 72 hours before study admission. Subjects previously enrolled in any palonosetron study were excluded, as were lactating women and subjects who had donated blood within 30 days before study admission. The study was conducted in conformance with all applicable local and federal guidelines as described in the US Code of Federal Regulations and was approved by the Western Institutional Review Board. Written informed consent was obtained from all subjects before any procedures were undertaken.
Study Design
This was a phase I, single-center, open-label, randomized, 2-way crossover study to determine the pharmacokinetics and safety of palonosetron 0.25 mg in healthy subjects who received palonosetron as a 15-minute infusion compared with a 30-second infusion. The study consisted of a screening visit and 2 treatment periods separated by a 14-day washout period. Subjects were randomized to receive either the 15-minute infusion (treatment A) or the 30-second infusion (treatment B). Following the washout period, subjects were crossed over to the other study treatment. Drug infused over 15 minutes was diluted in a total volume of 50 mL of sterile normal saline and was delivered at a constant rate using a 60-mL syringe attached to a syringe pump (B-D 360 infuser, Becton Dickinson and Co), whereas the total volume of drug delivered over 30 seconds was 5 mL injected manually from a 5-mL syringe. Study drug was administered between 6:30 and 9:00 AM following an overnight fast of at least 8 hours. Subjects were required to fast for an additional 4 hours after completion of the infusion, although water was not restricted.
Pharmacokinetic Sampling
For each pharmacokinetics sample, 7 mL of blood was collected in a tube containing sodium heparin. At the following times on days 1 and 15, blood samples were drawn from a peripheral vein of the arm not used for drug administration:
Blood samples were centrifuged at 1000 to 1300 x g for 10 minutes at room temperature to separate the red cells from the plasma. The plasma was removed and transferred into two 5-mL labeled polypropylene tubes and immediately stored in an upright position at –20°C. Plasma tubes were kept frozen until assayed.
Safety Assessments
Adverse events were documented throughout the study, and 12-lead electrocardiographic (ECG) measurements were performed at screening (on any day from day –21 to day –2), on the day before dosing (days –1 and 14), and at the completion of each treatment period (days 8 and 22). Changes in physical examinations (performed at screening, on the day before dosing [days –1 and 14], and at the completion of each treatment period [days 8 and 22]) and vital signs and clinical laboratory tests of hematology, serum chemistry, and urinalysis (performed at screening, before dosing [days 1 and 15], and at the completion of each treatment period [days 8 and 22]) also were used to evaluate safety.
Bioanalyses
Plasma samples were assayed for palonosetron using a validated method with liquid chromatography coupled to tandem mass spectrometry (MS/MS) as previously described.14 In summary, palonosetron, its N-oxide metabolite (metabolite M9), and internal standard (quinidine) were extracted from plasma using solid-phase extraction (SPE). The SPE cartridges (Varian C2, 1CC) were first primed with methanol and centrifuged for 1 minute, then primed with 1 mL of deionized water and centrifuged. A premixed sample containing 0.5 mL of plasma, 0.5 mL of water, and 100 µL of internal standard solution (
2800 pg of quinidine) was added to the SPE cartridges. Following vortexing, a 1-mL aliquot was loaded on the cartridge, and the cartridges were centrifuged 10 minutes later and washed with 1 mL of deionized water. After this process was repeated twice, the cartridges were transferred to 10-mL conical glass tubes and eluted using 0.25 mL of a solution of ammonium acetate (1 g) dissolved in a mixture of water (500 mL), acetonitrile (1500 mL), and formic acid (1 mL).
A second elution was performed to ensure all bound material was recovered. The resulting samples were concentrated under vacuum for 15 minutes and analyzed by reverse-phase high-performance liquid chromatography (Jasco 1500, with Waters NovaPack Phenyl column [150 mm x 3.9 mm]) interfaced with tandem mass spectrometry (MS/MS detection [Quatro Ultima, micromass]) in a positive electrospray ionization mode. After the remaining eluate was transferred into glass inserts and placed in autosampler vials, 20 to 30 µL was injected onto the column. The mobile phase consisted of 1000 mL of water, 1000 mL of acetonitrile, 17 mL of formic acid, and 2 g of ammonium acetate. The flow rate was 0.5 mL/min. The typical MS parameters were cone voltage 75 V, collision energy 28 eV, amplifier voltage 650 V, and desolvation temperature 500°C. The positive ions were detected in the multiple-reaction monitoring mode with pre-cursor to product ion pairs as 297.56 
110.13 (for palonosetron), 313.55 126.13 (for metabolite M9), and 325.58 184.22 (for internal standard). The runtime was approximately 5 minutes, with retention times of internal standard, palonosetron, and metabolite M9 of 3.5, 4.0, and 4.0 minutes, respectively.
The assay had a dynamic range of approximately 45 to 2100 ng/L for palonosetron and 11 to 507 ng/L for metabolite M9. The precision and accuracy of calibration standards and quality control samples (low, medium, and high) for palonosetron were better than 13% and –6%, respectively; for metabolite M9, precision and accuracy were better than 29% and –8%, respectively.
Pharmacokinetic Analyses
Pharmacokinetic parameters were calculated from plasma palonosetron concentration-time data using noncompartmental methods by WinNonlin version 3.3. The maximum observed plasma concentration (Cmax) and the time at which Cmax was first observed (tmax) were determined by visual inspection of the individual data. The terminal phase rate constant, Kel, was estimated from the slope of the concentration-time data during the log-linear terminal phase using a least squares regression analysis. The terminal phase half-life (t1/2) was calculated as 0.693/Kel. The area under the plasma concentration-time curve from time 0 to the last measurable concentration at time t (AUC0-t) was calculated using the linear trapezoidal method, and AUC0- was computed as AUC0-t plus the extrapolation from the last time point to infinity using Ct/Kel, where Ct is the last quantifiable concentration. For palonosetron, total body clearance (CLp) was calculated as dose/AUC0-. Volume of distribution at steady state was calculated as CLp x mean resident time (MRT), where MRT was calculated as [AUMC/AUC0- – 
/2], where is the duration of infusion. The area under the first moment curve (AUMC) was determined using the linear trapezoidal rule and extrapolated to infinity as AUMC0-t + t x Ct/Kel + Ct/(Kel)2.
Plasma concentrations below the lower limit of quantitation (BLLQ) were treated as 0.0 ng/L for purposes of calculating pharmacokinetic parameters. Actual times after the start of drug administration were used in the calculations of pharmacokinetic parameters.
Statistics
A descriptive statistical analysis was performed on the pharmacokinetic parameters. Natural log-transformed AUC and Cmax and untransformed (or raw) CLp, apparent volume of distribution at steady state (Vdss), and t1/2 were analyzed using an analysis of variance (ANOVA) model containing sequence, period, and treatment as fixed effects and subject within sequence as a random effect. A 5% level of significance was used to test for these effects.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
Mean palonosetron plasma concentration-time plots after a 15-minute IV infusion and a 30-second IV infusion are shown in Figure 1. After 30-second and 15-minute infusions, plasma concentrations of palonosetron declined with an initial rapid distribution followed by a slower elimination; in some subjects, concentrations were measurable up to 120 hours after the start of drug administration. Metabolite M9 concentrations generally were low and near the lower limit of quantitation.
Mean pharmacokinetic parameters are presented in Table I. For 15-minute and 30-second IV infusion treatments, the observed mean Cmax values were 919 and 1650 ng/L, respectively, with coefficients of variation (CVs) of 44% and 60%, respectively. The observed median tmax values were 15 and 3 minutes for 15-minute and 30-second IV infusion treatments, respectively. Mean AUC0- values were the same (20 700 ng·h/L) for the 15-minute and 30-second IV infusion treatments, with CVs of 25% and 21%, respectively. The ratio of geometric least squares mean values for 15-minute to 30-second IV infusion treatments was 60.2% for Cmax (90% CI: 40.4%-89.8%) and 99.3% for AUC0- (CI: 91.9%-107%), as shown in Table I. These results indicate that the 15-minute IV infusion resulted in a predictable pharmacokinetic profile with equivalent AUC0- and lower Cmax compared with a 30-second infusion.
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As presented in Table I, the mean plasma elimination half-life was 37.0 and 33.3 hours (least squares mean difference: 3.62 h, P = .283) for 15-minute and 30-second IV infusions, respectively, with CVs of 24% and 30%. The mean total body clearance was 214 and 209 mL/min (least squares mean difference: 3.92 mL/min, P = .711) for 15-minute and 30-second IV infusions, respectively. Mean volume of distribution at steady state was 611 and 554 L (least squares mean difference: 53.2 L, P = .260) for 15-minute and 30-second IV infusions, respectively. The observed differences in these pharmacokinetic parameters were not statistically significant. Metabolite M9 levels were low and near the lower limit of quantitation; therefore, no pharmacokinetic analysis could be performed. The pharmacokinetic parameters of palonosetron in this study are consistent with previous studies in healthy subjects and in patients.14-16
Safety
Eleven of the 15 enrolled study subjects received 2 doses of palonosetron 0.25 mg IV on day 1 and day 15, separated by a 14-day washout period, for a total exposure of 0.50 mg of palonosetron for each subject. One subject discontinued participation after the 15-minute infusion. For the 3 subjects who experienced extravasation during the 15-minute treatment, the infusion was stopped after 1, 3, and 4 minutes. Two of these subjects had previously received a 30-second infusion (treatment B).
There were no serious adverse events, and no subject discontinued because of an adverse event. The total number of treatment-emergent adverse events was similar between treatment groups. Overall, 8 subjects (8/15; 53.3%) reported 16 treatment-emergent adverse events, including 9 events (reported in 8 subjects) following the 15-minute infusion and 7 events (reported in 4 subjects) following the 30-second infusion (Table II). More subjects reported adverse events following the 15-minute infusion (8/15; 53.3%) than the 30-second infusion (4/13; 30.8%), although this includes the 3 subjects who experienced extravasation (associated with the infusion procedure). Only headache and injection site extravasation were reported by more than 1 subject. Most adverse events were considered mild to moderate in severity, and all adverse events were considered not related to palonosetron, with the exception of dyspepsia and headache (both considered possibly related).
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No laboratory findings were considered clinically significant, except for those indicating mild anemia in 1 subject on day 22 (hematocrit, 33.5%-35% [normal range, 36%-50%]; hemoglobin, 10.9-11.6 g/dL [normal range, 12.5-17 g/dL]). This subject had baseline hematocrit and hemoglobin levels of 39% and 13.0 g/dL, respectively, at screening and 42% and 13.8 g/dL, respectively, before dosing on day 1. Mean corpuscular hemoglobin and mean corpuscular volume values were below normal, and red cell distribution width values were above normal before dosing and remained fairly constant during the study. On day 22, however, the subject was considered by the investigator to have mild anemia, unlikely related to palonosetron, and was referred for follow-up care.
There were no clinically significant changes in vital signs or ECG results during the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Other than the expected differences in Cmax, the plasma concentration-time profiles of palonosetron following a 15-minute or 30-second infusion were superimposable. The pharmacokinetic profiles of palonosetron in this study also were similar to those observed previously,14,16 reinforcing the conclusion that altering infusion time for the delivery of palonosetron does not significantly alter the pharmacokinetics of the drug.
Results of the safety assessments indicate that palonosetron is safe and well tolerated when administered to healthy adults via either a rapid (30-second) or longer (15-minute) duration of IV infusion. Most adverse events were considered mild to moderate in intensity and not related to palonosetron. In addition, there were no serious adverse events, and no subject discontinued the study because of an adverse event.
In summary, the results of this study indicate that palonosetron has a predictable pharmacokinetic profile and that a 15-minute infusion of palonosetron results in a pharmacokinetic profile similar to that of a 30-second infusion. A longer infusion time does not appear to be associated with adverse safety issues. Therefore, it appears that a 15-minute infusion of palonosetron may be used clinically as an alternative to the standard 30-second infusion, based on pharmacokinetic considerations. Additional clinical studies to determine the effects of the 15-minute infusion on the efficacy of palonosetron are warranted.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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