Quantitation of Ivosidenib, A Novel Mutant IDH1 Inhibitoron Mice DBS: Application to a Pharmacokinetic Study

Drug Research ◽  
2019 ◽  
Vol 69 (09) ◽  
pp. 505-511 ◽  
Author(s):  
Sreekanth Dittakavi ◽  
Rakesh Kumar Jat ◽  
Ramesh Mullangi
Keyword(s):  
Pharmacokinetic Study ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
Dried Blood Spots ◽  
Pharmacokinetic Analysis ◽  
Validation Parameters ◽  
Chromatographic Resolution ◽  
Mutant Idh1 ◽  
Intravenous And Oral Administration ◽  
Regulatory Guideline

AbstractIvosidenib is an approved drug for relapsed or refractory IDH1 mutant AML patients. The goal of the present work is to develop and validate an LC-MS/MS method for the quantitation of ivosidenib in mice dried blood spots (DBS) as per regulatory guideline in the linearity range of 1.10–3293 ng/mL. To date there is no bioanalytical method reported for quantitation of ivosidenib. The chromatographic resolution of ivosidenib and internal standard (warfarin) was achieved on a C18 column with an isocratic mobile phase. All validation parameters met the acceptance criteria. The intra- and inter-day precision was in the range of 2.79–10.5 and 5.76–9.02%, respectively. Ivosidenib was stable for 3 freeze/thaw cycles, up to 7 days at room temperature and for one month at −80°C. The applicability of the validated method is shown in a mice pharmacokinetic study. Ivosidenib was quantifiable up to 24 and 36 h following intravenous and oral administration to mice, respectively. The oral bioavailability was 48%. Comparison of DBS vs. plasma concentrations of ivosidenib showed excellent correlation, indicating DBS can be used as an alternative for plasma for pharmacokinetic analysis.

scholarly journals Validated DBS method for filgotinib quantitation in rat dried blood spots and its application to a pharmacokinetic study in rats

ADMET & DMPK ◽  
2020 ◽  
Author(s):  
Abhishek Dixit ◽  
Vinay Kiran ◽  
Bhavesh Babulal Gabani ◽  
Ramesh Mullangi
Keyword(s):  
Pharmacokinetic Study ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
Dried Blood Spots ◽  
Janus Kinase ◽  
Extraction Solvent ◽  
Validation Parameters ◽  
Carry Over ◽  
Development And Validation

<p class="ADMETabstracttext">Filgotinib is a selective JAK1 (Janus kinase) inhibitor, showed efficacy in patients suffering from moderate-to-severe rheumatoid arthritis. In this paper, we present the data on the development and validation of a sensitive, selective and high-throughput LC-MS/MS (liquid chromatography with tandem mass spectrometry) method for the quantitation of filgotinib from rat dried blood spot (DBS) cards. To the DBS disc cards, 0.2 % formic acid enriched with internal standard (IS) was added and sonicated. Thereafter the extraction of filgotinib and the IS (tofacitinib) was accomplished using ethyl acetate as an extraction solvent. The resolution of filgotinib and the IS was achieved on a Gemini C<sub>18</sub> column with an isocratic<strong> </strong>mobile phase, which is a mixture of 0.2 % formic acid:acetonitrile (20:80, v/v) at a flow-rate of 0.9 mL/min. The total run time was 2.90 min and the retention time of filgotinib and the IS was ~1.31 and 0.89 min, respectively. Filgotinib and the IS were analyzed using positive ion scan mode and parent-daughter mass to charge ion (m/z) transition of 426.3®291.3 and m/z 313.2®149.2, respectively, for quantitation. The calibration range was 1.37-1937 ng/mL. No matrix effect and carry over were observed. All the validation parameters met the acceptance criteria. The validated method has been applied to a pharmacokinetic study in rats. A good correlation between DBS and plasma concentrations for filgotinib was observed.</p>

Determination of Tofacitinib in Mice Whole Blood on Dried Blood Spots Using LC–ESI–MS/MS: Application to Pharmacokinetic Study in Mice

Drug Research ◽  
2018 ◽  
Vol 69 (06) ◽  
pp. 330-336 ◽  
Author(s):  
Abhishek Dixit ◽  
Sadanand Rangnathrao Mallurwar ◽  
Suresh P Sulochana ◽  
Mohd Zainuddin ◽  
Ramesh Mullangi
Keyword(s):  
Pharmacokinetic Study ◽  
Whole Blood ◽  
Internal Standard ◽  
Dried Blood Spots ◽  
Assay Method ◽  
Blood Spots ◽  
Novel Method ◽  
Positive Ion ◽  
Regulatory Guideline

AbstractA simple, sensitive and rapid assay method has been developed and validated as per regulatory guideline for the estimation of tofacitinib on mice dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. The method employs liquid extraction of tofacitinib from DBS disk of mice whole blood followed by chromatographic separation using 5 mM ammonium acetate (pH 6.5):acetonitrile (20:80, v/v) at a flow rate of 0.60 mL/min on an X-Terra Phenyl column with a total run time 2.5 min. The MS/MS ion transitions monitored were m/z 313→149 for tofacitinib and m/z 316→149 for the internal standard (13C3, 15N-tofacitinib). The assay was linear in the range of 0.99–1980 ng/mL. The intra- and inter-day precision was in the range of 1.17–10.3 and 3.37–10.9%, respectively. Stability studies showed that tofacitinib was stable on DBS cards for one month. This novel method has been applied to analyze the DBS samples of tofacitinib obtained from a pharmacokinetic study in mice.

Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study

Drug Research ◽  
2019 ◽  
Vol 70 (01) ◽  
pp. 41-48
Author(s):  
Sreekanth Dittakavi ◽  
Gurulingappa Hallur ◽  
Buchi Reddy Purra ◽  
Vinay Kiran ◽  
Ashok Zakkula ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Active Metabolite ◽  
Myeloid Leukemia ◽  
Internal Standard ◽  
Precipitation Method ◽  
Isocitrate Dehydrogenase 2 ◽  
Refractory Acute Myeloid Leukemia ◽  
Chromatographic Resolution ◽  
Regulatory Guideline

AbstractEnasidenib is a selective mutant isocitrate dehydrogenase 2 inhibitor approved for the treatment of relapsed and refractory acute myeloid leukemia patients. A sensitive and rapid method has been developed and validated as per regulatory guideline for the simultaneous quantitation of enasidenib and its active metabolite, AGI-16903 in mice plasma using an LC-MS/MS. Enasidenib and AGI-16903 along with internal standard were extracted from mice plasma using simple protein precipitation method. Chromatographic resolution of enasidenib, AGI-16903 and the internal standard (close analogue of AGI-16903) was achieved on a Chromolith RP-18e column using 0.2% formic acid:acetonitrile (15:85, v/v) as an eluent, which was delivered at a flow-rate of 1.2 mL/min. The MS/MS ion transitions monitored were m/z 474.1→267.2, 402.1→188.1 and 421.0→146.1 for enasidenib, AGI-16903 and the internal standard, respectively. The linearity range was 1.01–3023 ng/mL for both enasidenib and AGI-16903. The within-run and between-run accuracy and within-run and between-run precision were in the range of − 2.29 to 2.72 (as one value is in negative side). and 4.65–9.82%, respectively for enasidenib; 0.19–10.3 and 3.22–9.22%, respectively for AGI-16903. Both enasidenib and AGI-16903 were found to be stable in stability (up to three freeze-thaw cycles and for long-term at −80°C for 30 days) and processed (bench-top for 6 h and in in-injector for 24 h) samples. Application of the validated method was shown in a pharmacokinetic study in mice.

Validated LC-MS/MS Method for Simultaneous Quantitation of SAFit-1 and SAFit-2 in Mice Plasma: Application to a Pharmacokinetic Study

Drug Research ◽  
2020 ◽  
Vol 70 (07) ◽  
pp. 325-332
Author(s):  
Bhavesh Babulal Gabani ◽  
Suresh Ponnayyan Sulochana ◽  
Anup H.A. Siddesh ◽  
Vinay Kiran ◽  
Neeraj Kumar Saini ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Internal Standard ◽  
Stability Studies ◽  
Validation Data ◽  
Fk506 Binding Protein ◽  
Liquid Liquid Extraction ◽  
Chromatographic Resolution ◽  
Development And Validation ◽  
Regulatory Guideline

AbstractSAFit-1 and SAFit-2 are selective FKBP51 (FK506-binding protein 51) ligands. In this paper, we present the development and validation data of an LC-MS/MS method for the simultaneous quantitation of SAFit-1 and SAFit-2 in mice plasma as per FDA regulatory guideline. SAFit-1 and SAFit-2 along with internal standard were extracted from mice plasma using liquid-liquid extraction method. Chromatographic resolution of SAFit-1, SAFit-2 and the internal standard (warfarin) was achieved on an X-Terra phenyl column using 0.2% formic acid:acetonitrile (20:80, v/v) as an eluent, which was delivered at a flow-rate of 0.9 mL/min. The MS/MS ion transitions monitored were m/z 748.4→420.4, 803.7→384.3 and 309.2 →163.2 for SAFit-1, SAFit-2 and the internal standard, respectively. The linearity range was 2.45–2446 ng/mL for both SAFit-1 and SAFit-2. The intra- and inter-day accuracy and intra- and inter-day precision were in the range of 0.90–1.07 and 2.38–10.8%, respectively for SAFit-1; 0.97–1.15 and 0.23–12.5%, respectively for SAFit-2. Both SAFit-1 and SAFit-2 were found to be stable in stability studies (up to three freeze-thaw cycles and for long-term at −80°C for 30 days) and processed (bench-top for 3 h and in in-injector for 16 h) samples. The application of the validated method was shown in a pharmacokinetic study in mice.

A Validated DBS Method for Quantitation of a Novel Mutant IDH1/2 Inhibitor, Vorasidenib Using 10 μL Mice Blood: Application to a Pharmacokinetic Study in Mice

2020 ◽  
Vol 16 (8) ◽  
pp. 1140-1147
Author(s):  
Sreekanth Dittakavi ◽  
Rakesh Kumar Jat ◽  
Ramesh Mullangi
Keyword(s):  
Oral Administration ◽  
Method Validation ◽  
Pharmacokinetic Study ◽  
Internal Standard ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Bioanalytical Method Validation ◽  
Extraction Solvent ◽  
Validation Parameters ◽  
Intravenous And Oral Administration

Background: Vorasidenib is a pan-IDH inhibitor, undergoing clinical trials for the treatment of acute myeloid leukemia. Methods: In this paper, we present the data of method validation to quantify vorasidenib in the mice blood mice using dried blood spot (DBS) method on LC-MS/MS as per FDA bioanalytical method validation guideline. Using methanol (enriched with internal standard) as an extraction solvent followed by sonication, vorasidenib was extracted from DBS quality control samples, calibration curve samples and pharmacokinetic study samples. Baseline separation of vorasidenib and the IS in a 2.0 μL injected sample was accomplished by delivering 0.2% formic acid and acetonitrile (25:75, v/v) at a constant flowrate (1.00 mL/min) on a C18 column. The total run time was 2.0 min. Using the transition pair of m/z 415.4→260.4 for vorasidenib and m/z 583.1→186.1 for the IS, the quantitation was performed. The method linearity range was 1.00-3008.00 ng/mL. Results: The recovery of vorasidenib ranged between 71.28%-78.14% across the tested concentrations. No matrix effect was seen. Intra- and inter-day precisions were ≤7.23% and intra- and inter-accuracies ranged between 97.1%-107%. Vorasidenib was stable for three freeze/thaw cycles, up to 7 days at room temperature and for one month at -80°C. Following intravenous and oral administration of vorasidenib to mice, it was quantifiable up to 72 h. The oral bioavailability was 51.6%. Conclusions: All the validation parameters met the acceptance criteria as specified in the FDA regulatory guideline. The results suggest that validated DBS method can be used for pharmacokinetic studies in mice to characterize the pharmacokinetic parameters of vorasidenib post intravenous and oral administration.

Determination of tigecycline in turkey plasma by LC-MS/MS: validation and application in a pharmacokinetic study

2017 ◽  
Vol 20 (2) ◽  
pp. 241-249 ◽  
Author(s):  
A. Jasiecka-Mikołajczyk ◽  
J.J. Jaroszewski
Keyword(s):  
Pharmacokinetic Study ◽  
High Performance ◽  
Limit Of Detection ◽  
Internal Standard ◽  
Reversed Phase ◽  
Selected Reaction Monitoring ◽  
Limit Of Quantification ◽  
Complicated Skin ◽  
Intravenous And Oral Administration

Abstract Tigecycline (TIG), a novel glycylcycline antibiotic, plays an important role in the management of complicated skin and intra-abdominal infections. The available data lack any description of a method for determination of TIG in avian plasma. In our study, a selective, accurate and reversed-phase high performance liquid chromatography-tandem mass spectrometry method was developed for the determination of TIG in turkey plasma. Sample preparation was based on protein precipitation and liquid-liquid extraction using 1,2-dichloroethane. Chromatographic separation of TIG and minocycline (internal standard, IS) was achieved on an Atlantis T3 column (150 mm × 3.0 mm, 3.0 μm) using gradient elution. The selected reaction monitoring transitions were performed at 293.60 m/z → 257.10 m/z for TIG and 458.00 m/z → 441.20 m/z for IS. The developed method was validated in terms of specificity, selectivity, linearity, lowest limit of quantification, limit of detection, precision, accuracy, matrix effect, carry-over effect, extraction recovery and stability. All parameters of the method submitted to validation met the acceptance criteria. The assay was linear over the concentration range of 0.01-100 μg/ml. This validated method was successfully applied to a TIG pharmacokinetic study in turkey after intravenous and oral administration at a dose of 10 mg/kg at various time-points.

scholarly journals Determination of sarecycline by UPLC-MS/MS and its application to pharmacokinetic study in rats

2020 ◽  
Author(s):  
Yonghui Shen ◽  
Deru Meng ◽  
Feifei Chen ◽  
Hui Jiang ◽  
Liming Hu ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Plasma ◽  
Chronic Inflammatory Disease ◽  
Linear Calibration ◽  
Limit Of Quantification ◽  
Acquity Uplc ◽  
Intravenous And Oral Administration

AbstractSarecycline is a narrow-spectrum antibiotic for the treatment of acne, which is a chronic inflammatory disease of the hair follicle sebaceous glands. In the study, UPLC-MS/MS was used to establish a rapid and accurate analytical method. The sarecycline was determined with poziotinib as internal standard (IS) in rat plasma. An ACQUITY UPLC HSS T3 column (2.1 × 100 mm, 1.8 μm) could performe chromatographic separation with the mobile phase (methanol: water of 0.1% formic acid) with gradient elution. The ions of target fragment were m/z 488.19→410.14 for sarecycline and m/z 492.06→354.55 for poziotinib, which could quantify the electrospray ionization of positive multiple reaction monitoring (MRM) mode. The linear calibration curve of the concentration range was 1–1,000 ng/mL for sarecycline with a lower limit of quantification (LLOQ) of 1 ng/mL. The mean recovery was between 82.46 and 95.85% for sarecycline and poziotinib in rat plasma. RSD for precision of inter-day and intra-day were between 3.24 and 13.36%, and the accuracy ranged from 105.26 to 109.75%. The developed and validated method was perfectly used in the pharmacokinetic study and bioavailability of sarecycline after intravenous and oral administration in rats.

Validated HPLC Method for Quantification of a Novel Trk Inhibitor, Larotrectinib in Mice Plasma: Application to a Pharmacokinetic Study

Drug Research ◽  
2020 ◽  
Vol 70 (02/03) ◽  
pp. 101-106
Author(s):  
Harsha K. Tripathy ◽  
S.V. Nair Manju ◽  
Ashok Zakkula ◽  
Ram Murthi Bestha ◽  
Sreekanth Dittakavi ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
High Performance ◽  
Wave Length ◽  
Internal Standard ◽  
Hplc Method ◽  
Long Term Storage ◽  
Development And Validation ◽  
Orally Active ◽  
Regulatory Guideline

AbstractLarotrectinib, is an orally active novel small molecule approved for the treatment of solid tumors in pediatrics and adult patients. It acts by inhibiting tropomyosin receptor kinase. In this paper, we report the development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of larotrectinib in mice plasma as per the FDA regulatory guideline. Plasma samples processing was accomplished through simple protein precipitation using acetonitrile enriched with internal standard (IS, enasidenib). The chromatographic analysis was performed using a gradient mobile phase comprising 10 mM ammonium acetate and acetonitrile at a flow-rate of 0.8 mL/min on an X-Terra Phenyl column. The UV detection wave length was set at λmax 262 nm. Larotrectinib and the IS eluted at 3.85 and 6.60 min, respectively with a total run time of 8.0 min. The calibration curve was linear over a concentration range of 0.20–5.00 μg/mL (r2=≥0.992). The intra- and inter-day precision and accuracy results were within the acceptable limits. Results of stability studies indicated that larotrectinib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycles and long-term storage at −80°C. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.

DBS Assay with LC-MS/MS for the Determination of Idelalisib, A Selective PI3K-δ Inhibitor in Mice Blood and Its Application to a Pharmacokinetic Study

Drug Research ◽  
2020 ◽  
Vol 71 (01) ◽  
pp. 36-42
Author(s):  
Harsha K. Tripathy ◽  
Nair S.V. Manju ◽  
Sreekanth Dittakavi ◽  
Ashok Zakkula ◽  
Ramesh Mullangi
Keyword(s):  
Pharmacokinetic Study ◽  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Lymphocytic Leukemia ◽  
Extraction Solvent ◽  
Non Hodgkin Lymphoma ◽  
Validation Parameters ◽  
Multiple Reaction Monitoring Mode ◽  
Carry Over

AbstractIdelalisib is a selective and second-generation PI3K-δ inhibitor, approved for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia. In this paper, we present a fully validated dried blood spot (DBS) method for the quantitation of idelalisib from mice blood using an LC-MS/MS, which was operated under multiple reaction monitoring mode. To the punched DBS discs, acidified methanol enriched with internal standard (IS; larotrectinib) was added and extracted using tert-butyl methyl ether as an extraction solvent with sonication. Chromatographic separation of idelalisib and the IS was achieved on an Atlantis dC18 column using a mixture of 10 mM ammonium formate:acetonitrile (25:75, v/v). The flow-rate and injection volume were 0.80 mL/min and 2.0 µL, respectively. Idelalisib and the IS were eluted at ~0.98 and 0.93 min, respectively and the total run time was 2.00 min. Idelalisib and the IS were analyzed using positive ion scan mode and parent-daughter mass to charge ion (m/z) transition of 416.1→176.1 and 429.1→342.1, respectively was used for the quantitation. The calibration range was 1.01−4 797 ng/mL. No matrix effect and carry over were observed. Haematocrit did not influence DBS idelalisib concentrations. All the validation parameters met the acceptance criteria. The applicability of the validated method was shown in a mice pharmacokinetic study.

scholarly journals HIGHLY SENSITIVE AND RAPID EVALUATION OF PYRIDOSTIGMINE IMPURITY B IN HUMAN PLASMA BY LIQUID CHROMATOGRAPHY COUPLED WITH TANDEM MASS SPECTROMETER AFTER ADMINISTRATION OF PYRIDOSTIGMINE TO HEALTHY VOLUNTEERS IN A PHARMACOKINETIC STUDY

2018 ◽  
Vol 11 (6) ◽  
pp. 353
Author(s):  
Sambasiva Rao Puram ◽  
Raman Batheja ◽  
G Nithya
Keyword(s):  
Liquid Chromatography ◽  
Mass Spectrometer ◽  
Solid Phase ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
Linear Calibration ◽  
Test Formulation ◽  
System Suitability ◽  
Validation Parameters ◽  
Incurred Sample Reanalysis

Objective: Objective of this work is to evaluate the levels in plasma of pyridostigmine impurity B (metabolite of pyridostigmine) in humans after administration of pyridostigmine formulations.Methods: Plasma concentrations of pyridostigmine impurity B were estimated using by liquid chromatography coupled with electron spray ionization triple quad mass spectrometer technique, lamivudine is used as an internal standard. Multiple reaction at 109.9/95.2 (pyridostigmine impurity B) and 230.2/112.2 (lamivudine) were monitored. Chromatography was optimized using acetonitrile: Buffer (10 millimolar ammonium acetate) (85:15) on an Inertsil C18, 150 mm×4.6 mm, 5 μ analytical column. Linear Calibration curve set between 1.434 ng/ml and 39.637 ng/ml. Sample extraction was conducted using solid phase extraction method using mixed mode cation exchange cartridges. The method was developed on API 4000.Results: Method was developed, tested for system suitability, carryover, selectivity, matrix effect, intra-inter precision and accuracy, recovery, linearity, and various stabilities in aqueous as well as plasma as matrix. The method was validated for all the above validation parameters mentioned as per European medical agency guideline on method validation.Conclusions: The method is successfully applied to analyze 1890 subject samples after administration of pyridostigmine 180 mg as per Independent Ethics Committee approved protocol. Incurred sample reanalysis was revealed a great reproducibility of method. Statistical analysis was also conducted to compare test formulation with innovator formulation. Test formulation concentrations of pyridostigmine impurity B are similar to those obtained from innovator formulation.

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