Granisetron In Plasma Research Articles

Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials.

BackgroundDespite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy.MethodsIn C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated.ResultsAPF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in ≤20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in ≥80% and ≥75% of patients in both trials with the 250 and 500 mg doses, respectively.ConclusionAfter a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron levels for ≥5 days.

Pharmacokinetics (PK), tolerability, and efficacy of APF530 in patients receiving moderately (MEC) and highly (HEC) emetogenic chemotherapy: Phase II trial results.

e20518 Background: Up to 30% of patients continue to have chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 PK, tolerability, and efficacy were studied in two open-label, single-dose trials (1 US, 1 EU) in patients receiving MEC or HEC. Methods: In the US study, 45 patients received 250, 500, or 750 mg APF530 SC (5, 10, or 15 mg granisetron, respectively). In the EU study, 35 patients were randomized to 250 or 500 mg APF530 SC. Injections were given 30 to 60 minutes before single-day MEC or HEC. Plasma granisetron was measured from pre-dose to 168 hours. Safety, tolerability, and efficacy were also evaluated. Results: APF530 PK was dose proportional with slow absorption and elimination of granisetron after a single SC dose. Median tmax, exposure, and t1/2were similar for 250 and 500 mg APF530 in both trials, with no differences between MEC and HEC groups. Adverse events in both trials were as expected for granisetron; injection-site reactions (eg, erythema, induration), predominantly mild, were seen in ≤ 20% of patients. Complete responses (no emesis, no rescue medication) were obtained in ≥ 80% and ≥ 75% of patients in both trials with the 250- and 500-mg doses, respectively. Conclusions: APF530 showed dose-proportional PK and sustained concentrations of granisetron over 168 hours. The 250- and 500-mg doses were carried into phase III; both were well tolerated, and maintained therapeutic granisetron levels for ≥ 5 days. Clinical trial information: 2007-005068-29. [Table: see text]

High percutaneous bioavailability of granisetron by dissolving microneedleswe

High percutaneous absorption efficiency of granisetron (GST) was sought by formulating GST into two-layered dissolving microneedles containing 10.0 ± 0.12 g GST (low dosage) and 37.6 ± 2.31 g GST (high dosage). The GST-loaded microneedles were administered percutaneously to rat skin. Plasma GST concentrations were measured using LC/MS/MS. The GST bioavailabilities (BAs) were, respectively, 97.6 ± 9.7% (low dosage) and 93.1 ± 14.9% (high dosage). No skin irritation or damage to the skin was observed where it was administered. GST was stable with 100.6-101.4% in microneedles in within three months at 4–40 °C. Results show that dissolving microneedles are a good percutaneous delivery system for GST.

Nasal absorption studies of granisetron in rats using a validated high-performance liquid chromatographic method with mass spectrometric detection

Granisetron is a selective 5-HT3 receptor antagonist that is used therapeutically for the prevention of vomiting and nausea associated with emetogenic cancer chemotherapy. Although forms of the drug are commercially available for intravenous and oral dosage, there is a need for intranasal delivery formulations in specific patient populations in which the use of these dosage forms may be unfeasible and/or inconvenient. A rapid and specific high-performance liq uid chromatography method with mass spectrometric detection (LC-MS) was developed and validated for the analysis of granisetron in plasma after nasal administration in rats. Granisetron was separated in a reverse-phase C-18 column without interference from other components of plasma. This method involves a rapid assay for the determination of granisetron in a small volume of plasma with a run time of 12 min using ondansetron as an internal standard. Data were acquired in the electrospray ionization (ESI) mode with positive ion detection and application of single ion recording (SIR). Granisetron and ondansetron were detected at m/z values of 313.2 and 294.2, respectively. The method described was found to be suitable for the analysis of all samples collected during preclinical pharmacokinetic investigations of granisetron in rats after nasal administration. To date, the first pharmacokinetic study after intranasal administration of granisetron was performed and some pharmacokinetic parameters were presented in this paper. Granisetron was found to be well absorbed through nasal route and the bioavailability of this drug following nasal administration was comparable with that of intravenous administration.

흰쥐를 이용한 Granisetron함유 경비 투여제제의 평가 및 그 적용

Granisetron is a selective 5-HT3 receptor antagonist that is used therapeutically for the prevention of vomiting and nausea associated with emetogenic cancer chemotherapy. Although this drug is commercially available for intravenous and oral dosage, there is a need for intranasal delivery formulations in specific patient populations in which the use of these dosage forms may be unfeasible and/or inconvenient. A rapid and specific high-performance liquid chromatography method with mass spectrometric detection(LC-MS) was developed and validated for the analysis of granisetron in plasma after nasal administration in rats. This method has been validated for concentrations ranging from 5 to 1000 ng/ml with simple treatment. This technique has high level reproducibility, accuracy, and sensitivity. The method described was found to be suitable for the analysis of all samples collected during preclinical pharmacokinetic investigations of granisetron in rats after nasal administration. This study was aimed to investigate the feasibility of nasal delivery of granisetron for the elimination of vomiting. The effects of osmolarity, dosage volume at the same dose and applied dose on the nasal absorption of granisetron in rats were observed. No significant difference in the effect of osmolarity and dosage volume at the same dose was observed. As the applied dose of granisetron in nasal formulation increased, the absorption increased linearly. Based on these results it appears that only the applied dose(drug mass) determines the nasal absorption of granisetron. The bioavailability of granisetron on nasal administration of 4 mg/kg appeared to be comparable to that of intravenous administration of the same dose. These results suggest that granisetron can be efficiently delivered nasally and the development of nasal formulation will be feasible.

Periodic modulation-based stochastic resonance algorithm applied to quantitative analysis for weak liquid chromatography–mass spectrometry signal of granisetron in plasma

The periodic modulation-based stochastic resonance algorithm (PSRA) was used to amplify and detect the weak liquid chromatography–mass spectrometry (LC–MS) signal of granisetron in plasma. In the algorithm, the stochastic resonance (SR) was achieved by introducing an external periodic force to the nonlinear system. The optimization of parameters was carried out in two steps to give attention to both the signal-to-noise ratio (S/N) and the peak shape of output signal. By applying PSRA with the optimized parameters, the signal-to-noise ratio of LC–MS peak was enhanced significantly and distorted peak shape that often appeared in the traditional stochastic resonance algorithm was corrected by the added periodic force. Using the signals enhanced by PSRA, this method extended the limit of detection (LOD) and limit of quantification (LOQ) of granisetron in plasma from 0.05 and 0.2 ng/mL, respectively, to 0.01 and 0.02 ng/mL, and exhibited good linearity, accuracy and precision, which ensure accurate determination of the target analyte.

High-performance liquid chromatographic determination of granisetron in human plasma

This paper describes a high-performance liquid chromatographic method (HPLC) with fluorometric detection for the analysis of granisetron in plasma. The detection is performed at 305 nm for excitation and 365 n, for emission. The method involves sample clean-up by liquid-liquid extraction. N-(1-Naphthyl) ethylenediamine dihydrochloride is used as internal standard. Toluene and phosphate buffer were added to 0.5 ml of plasma added to the internal standard. After extraction, the organic layer was separated and then evaporated to dryness. The residue was reconstituted in eluent mixture. An aliquot was injected onto the HPLC column, Spherisorb CN, equilibrated with an eluent mixture constituted by acetonitrile-phosphate buffer (pH 4.5) (15:85). The proposed technique is reproducible, selective, reliable, and sensitive. Linear detector responses were observed for the calibration curve standards in the range of 0.50 to 100 ng/ml. Extraction recovery from plasma proved to be more than 90%. Precision expressed as C.V. was in the range 2 to 8%. As low as 0.3 ng of granisetron per ml of plasma can be measured with good accuracy. The method has been validated, and stability testsunder various conditions have been performed. Its sensitivity is adequate for pharmacokinetic studies.

Evaluation of the Bioequivalence of Tablet and Capsule Formulations of Granisetron in Patients Undergoing Cytotoxic Chemotherapy for Malignant Disease

Granisetron is a novel, highly specific 5-hydroxytryptamine receptor antagonist given prophylactically to patients undergoing chemotherapy. An open, randomized, crossover trial was performed with 37 patients (24 females and 13 males) undergoing cytotoxic chemotherapy for malignant disease to compare an oral tablet (1-mg tablet given twice daily) with a clinical-trial capsule (1-mg capsule given twice daily). Complete pharmacokinetic data were determined for 24 patients (14 females and 10 males). The concentration of granisetron in plasma was measured by HPLC; the limit of quantitation was 0.2 ng/mL. The bioavailability evaluation was based mainly on the area under the curve (AUC) (mean values: 52.1 ng.h/mL for the capsule and 54.2 ng.h/mL for the tablet) and the maximum concentration (Cmax) (mean values: 7.42 ng/mL for the capsule and 8.18 ng/mL for the tablet) measured at the steady state after 7 days of continuous therapy. Wide interpatient variability in plasma granisetron levels after oral administration was observed. The 90% standard confidence interval for the geometric mean ratio overlapped the critical range, 0.8-1.25. Point estimates for AUC and Cmax based on two one-sided t tests and log-transformed data showed that the upper limit of the confidence interval was not within 20% of the mean for the capsule; the corresponding power analysis values for AUC and Cmax were 0.89 and 0.81, respectively. Despite bioequivalence not being proven, any differences that exist between the two formulations are likely to be small. There was no difference in efficacy or safety between the two formulations assessed.