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1.
Biomed Chromatogr ; 37(4): e5587, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36680551

RESUMO

Paxalisib is a pan-PI3K and mTOR inhibitor, currently entering into Phase II clinical trials as a potential drug to treat glioblastoma patients. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of paxalisib in mouse plasma as per the US Food and Drug Administration regulatory guidelines. From the mouse plasma, paxalisib and the internal standard (IS; filgotinib) were extracted using ethyl acetate as an extraction solvent. The chromatographic separation of paxalisib and the IS was accomplished on a Symmetry C18 (250 × 4.6 mm, 5.0 µm) column maintained at 40°C using 10 mm ammonium formate and acetonitrile in gradient conditions at a 0.8 ml/min flow-rate. The injection volume was 20 µl. The elution was monitored using a photo-diode array detector set at λmax 280 nm. Paxalisib and the IS eluted at 6.5 and 5.9 min, respectively with a total run time of 10 min. The calibration curve was linear over the range of 111-4,989 ng/ml. Inter- and intraday precision and accuracy, stability studies, dilution integrity and incurred sample reanalysis were investigated and the results met the acceptance criteria. The validated HPLC method was extended to assess the pharmacokinetic parameters of paxalisib in mice.


Assuntos
Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases , Camundongos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos Testes , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de MTOR , Serina-Treonina Quinases TOR
2.
Biomed Chromatogr ; 37(2): e5548, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36385469

RESUMO

Copanlisib is a dual PI3K-δ inhibitor, used in follicular lymphoma treatment. In this research, we report a validated LC-MS/MS method for quantifying copanlisib from a mouse dried blood spot (DBS). We validated the method in line with the guidelines of the US Food and Drug Administration. The liquid-liquid extraction technique was used to extract copanlisib from the DBS discs. We used an Atlantis dC18 column and isocratic mobile phase for the chromatographic separation of copanlisib and the internal standard (idelalisib). The flow was 0.90 ml/min. Under the optimized chromatographic conditions, the retentions of copanlisib and the internal standard were 0.98 and 0.93 min, respectively. Each injection total run time was 2.50 min. The MS/MS ion transitions monitored were m/z 481.31 â†’ 128.00 and 416.10 â†’ 176.10 for copanlisib and the internal standard (IS) idelalisib, respectively. We have used a broad calibration range (1.01-4,797 ng/ml) with a determination coefficient (r2 ) of 0.997. All of the evaluated parameters met the acceptance criteria. Hematocrit did not influence the DBS copanlisib concentrations. We have used the validated method to derive the intravenous pharmacokinetic parameters by quantifying copanlisib in mouse plasma.


Assuntos
Quinazolinas , Espectrometria de Massas em Tandem , Camundongos , Animais , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Pirimidinas , Inibidores de Fosfoinositídeo-3 Quinase , Reprodutibilidade dos Testes , Teste em Amostras de Sangue Seco/métodos
3.
Drug Res (Stuttg) ; 71(1): 36-42, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32992346

RESUMO

Idelalisib 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.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Purinas/análise , Quinazolinonas/análise , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Masculino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacocinética , Purinas/administração & dosagem , Purinas/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacocinética , Espectrometria de Massas em Tandem/métodos
4.
Biomed Chromatogr ; 35(4): e5015, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33125719

RESUMO

Phosphatidylinositol 3-kinase (PI3K) inhibitors are a novel class of anticancer drugs that are approved to treat various malignancies. We report the development and validation of a HPLC method for the simultaneous quantitation of three PI3K inhibitors, namely copanlisib, duvelisib and idelalisib, in rat plasma as per the regulatory guidelines of the United States Food and Drug Administration. The method involves extraction of copanlisib, duvelisib and idelalisib along with an internal standard (IS; filgotinib) from rat plasma (100 µL) using a liquid-liquid extraction process. The chromatographic separation of the analytes was achieved using step-wise gradient elution on a Hypersil Gold C18 column. The UV detection wavelength was set at λmax = 280 nm. Copanlisib, duvelisib, idelalisib and the IS eluted at 7.16, 12.6, 11.9 and 9.86 min, respectively, with a total run time of 15 min. The calibration curve ranged from 50 to 5000 ng/mL for all the analytes. Inter- and intra-day precision and accuracy, stability studies, dilution integrity and incurred sample reanalysis were investigated for all three analytes, and the results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Inibidores de Fosfoinositídeo-3 Quinase/sangue , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Antineoplásicos/farmacocinética , Isoquinolinas/sangue , Isoquinolinas/química , Isoquinolinas/farmacocinética , Modelos Lineares , Masculino , Inibidores de Fosfoinositídeo-3 Quinase/química , Purinas/sangue , Purinas/química , Purinas/farmacocinética , Pirimidinas/sangue , Pirimidinas/química , Pirimidinas/farmacocinética , Quinazolinas/sangue , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinonas/sangue , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
5.
Drug Res (Stuttg) ; 70(5): 233-238, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32289835

RESUMO

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of filgotinib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of filgotinib along with internal standard (IS, tofacitinib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic analysis was performed using an isocratic mobile phase comprising 10 mM ammonium acetate (pH 4.5) and acetonitrile (70:30, v/v) at a flow-rate of 0.8 mL/min on a Hypersil Gold C18 column. The UV detection wavelength was set at λmax 300 nm. Filgotinib and the IS eluted at 5.56 and 4.28 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.05 to 5.00 µg/mL (r 2+=≥0.992). The intra- and inter-day precision and accuracy results were within the acceptable limits. Results of stability studies indicated that filgotinib 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.


Assuntos
Monitoramento de Medicamentos/métodos , Inibidores de Proteínas Quinases/sangue , Piridinas/sangue , Triazóis/sangue , Administração Oral , Animais , Artrite Reumatoide/tratamento farmacológico , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Monitoramento de Medicamentos/normas , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos , Modelos Animais , Piperidinas/sangue , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/administração & dosagem , Piridinas/química , Piridinas/farmacocinética , Pirimidinas/sangue , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Triazóis/administração & dosagem , Triazóis/química , Triazóis/farmacocinética
6.
Drug Dev Ind Pharm ; 46(3): 498-504, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32067499

RESUMO

Objective: The objective of the current research was to prepare self-micro-emulsifying drug delivery systems (SMEDDS) for BCS class II drug, nilotinib to enhance its oral bioavailability.Methodology: Different types of excipients like oil, surfactant, and co-surfactant were evaluated for drug solubility. Among the screened excipients, Capryol 90, Transcutol HP, and Tween 80 were selected as oil, co-surfactant, and surfactant, respectively, to construct a ternary phase diagram to identify a homogenous mixture. Characterization performed for the prepared SMEDDS for its particle size/droplet size, emulsification time, phase separation, droplet morphology, in vitro drug release, and oral bioavailability.Results: Prepared SMEDDS showed the highest of 87% drug release in in vitro drug release experiment. SMEDDS drug release was superior over suspension formulation, which could be attributed to oil/surfactant ratios and particle size of the SMEDDS. The acquired pharmacokinetic parameters indicate that twofold increase in systemic exposure of SMEDDS compared with nilotinib suspension formulation. A similar twofold increase in relative oral bioavailability was also observed when compared SMEDDS formulation with suspension formulation. Delayed Tmax (time to reach peak plasma concentrations) was observed with SMEDDS over suspension formulation, which was evident by slow rate of absorption of nilotinib from SMEDDS.Conclusion: This research demonstrated that SMEDDS could be an effective approach to improve solubility and oral bioavailability for the BCS class II poorly soluble nilotinib.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Excipientes/química , Pirimidinas/administração & dosagem , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Química Farmacêutica , Liberação Controlada de Fármacos , Emulsões , Masculino , Tamanho da Partícula , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
7.
Drug Res (Stuttg) ; 70(2-03): 101-106, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31931548

RESUMO

Larotrectinib, 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.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Proteínas Quinases/análise , Pirazóis/análise , Pirimidinas/análise , Animais , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Reprodutibilidade dos Testes , Temperatura
8.
ADMET DMPK ; 8(1): 113-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-35299776

RESUMO

Copanlisib is a pan phosphatidylinositol 3-kinase (PI3K) inhibitor approved for follicular lymphoma. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of copanlisib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of copanlisib along with internal standard (IS, enasidenib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic resolution of copanlisib and the IS was achieved on a Hypersil Gold C18 column maintained at 40 °C using a binary gradient mobile phase [10 mM ammonium formate (pH 4.0) and acetonitrile]. The flow-rate was 0.8 mL/min. For the detection of copanlisib and the IS, the photo-diode array detector was set at λmax 310 nm. Copanlisib and the IS eluted at 6.60 and 7.80 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 50 to 5000 ng/mL for copanlisib (r2≥ 0.998). The results of intra- and inter-day accuracy and precision studies were within the acceptable limits. Copanlisib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycle and long-term storage at -80 °C. The application of the validated method was shown in a mice pharmacokinetic study.

9.
Xenobiotica ; 50(3): 339-345, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31144563

RESUMO

Cefuroxime is one of the widely used antibiotics. The objective of this study was to determine pharmacokinetics and disposition in various ocular tissues following topical (TOP), intracameral (IC) and intravitreal (IVT) administration of cefuroxime to rabbits.Following TOP, IC and IVT dosing plasma and various ocular tissues (aqueous humor (AH), vitreous humor (VH), conjunctiva, trabecular mesh (TM), lens and retina-choroid (RC)) were collected and analyzed to understand the disposition of cefuroxime. Postintravenous administration plasma samples were collected to determine the systemic pharmacokinetics.Post-TOP dosing cefuroxime concentrations were observed only in conjunctiva up to 48 h. IC administration showed cefuroxime concentrations in AH up to 8 h; in conjunctiva, TM and plasma, the concentration lasted up to 4 h and in RC and VH till 1 h. IVT administration of cefuroxime showed concentrations in all ocular tissues (up to 8 h) and lasted up to 48 h except in conjunctiva and RC.There was evidence that the mechanism(s) of cefuroxime entry into the eye by via IVT, IC and TOP routes is clearly different. The present ocular tissue data may aid clinicians for considering appropriate choice in the treatment of post-operative ocular complications due to bacterial infections including endophthalmitis.


Assuntos
Cefuroxima/farmacocinética , Animais , Cefuroxima/administração & dosagem , Humanos , Injeções Intraoculares , Coelhos , Distribuição Tecidual
10.
Drug Res (Stuttg) ; 70(1): 41-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31652462

RESUMO

Enasidenib 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.


Assuntos
Aminopiridinas/farmacocinética , Antineoplásicos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazinas/farmacocinética , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/isolamento & purificação , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Modelos Animais , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/normas , Triazinas/administração & dosagem , Triazinas/isolamento & purificação
11.
Biomed Chromatogr ; 33(11): e4658, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325170

RESUMO

Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2  = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Diaminas/sangue , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Triazinas/sangue , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Diaminas/química , Diaminas/farmacocinética , Estabilidade de Medicamentos , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazinas/química , Triazinas/farmacocinética
12.
Drug Res (Stuttg) ; 69(10): 537-544, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30536259

RESUMO

A simple, specific and reproducible high-performance liquid chromatography (HPLC) assay method has been developed and validated for the quantitation of second generation antiandrogens and their active metabolites namely apalutamide, enzalutamide, N-desmethylenzalutamide (active metabolite of enzalutamide), darolutamide and ORM-15341 (active metabolite of darolutamide) in mice plasma. The method involves extraction of apalutamide, enzalutamide, N-desmethylenzalutamide, darolutamide and ORM-15341 along with internal standard (IS) from 100 µL mice plasma through a simple protein precipitation process. The chromatographic analysis was performed on a Waters Alliance HPLC system using a gradient mobile phase (comprising 10 mM ammonium acetate and acetonitrile in a flow-gradient) and X-Terra Phenyl column. The UV detection wave length was set at λmax 250 nm. Apalutamide, enzalutamide, N-desmethylenzalutamide, darolutamide and ORM-15341 and the IS eluted at 13.6, 11.4, 9.68, 6.11, 6.93 and 4.69 min, respectively with a total run time of 15 min. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 209 - 5215 ng/mL (r 2=0.998). The intra- and inter-day precisions were in the range of 0.56-13.5 and 1.04-13.9%, respectively. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Antagonistas de Androgênios/sangue , Monitoramento de Medicamentos/métodos , Administração Oral , Antagonistas de Androgênios/isolamento & purificação , Antagonistas de Androgênios/farmacologia , Animais , Benzamidas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Masculino , Camundongos , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/sangue , Feniltioidantoína/isolamento & purificação , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/sangue , Pirazóis/isolamento & purificação , Pirazóis/farmacologia , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
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