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1.
Anal Methods ; 16(20): 3287-3296, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38738631

RESUMO

This study introduces a novel approach for the simultaneous determination of topotecan (TOP) and pantoprazole (PNT), two drugs whose interaction is critical in clinical applications. The significance of this study originates from the need to understand the pharmacokinetic changes of TOP after PNT administration, which can inform necessary dose adjustments of TOP. To achieve this, nitrogen blue emissive carbon dots (B@NCDs) were produced and employed due to their unique fluorescent properties. When TOP is added to B@NCDs, it exhibits strong native fluorescence at 545 nm without influencing the B@NCDs' fluorescence at 447 nm. Conversely, PNT causes quenching of B@NCDs fluorescence, a property that enables the distinct detection of both drugs. The B@NCDs were fully characterized using different techniques, including ultraviolet-visible spectrophotometry, fluorescence analysis, X-ray diffraction (XRD), transmission electron microscopy (TEM), and FTIR spectroscopy. The proposed method demonstrated excellent linearity, selectivity, and sensitivity, with low detection limits (LOD, S/N = 3); 0.0016 µg mL-1 for TOP and 0.36 µg mL-1 for PNT. Applied to spiked rabbit plasma samples, this method offers a new approach for evaluating the pharmacokinetic interaction between TOP and PNT. It enables the determination of all pharmacokinetic parameters of TOP before and after coadministration with PNT, providing essential insights into whether dose adjustments are necessary. This research not only contributes to the field of drug monitoring and interaction studies but also exemplifies the potential of B@NCDs in complex biological matrices, paving the way for further pharmacological and therapeutic applications.


Assuntos
Carbono , Pantoprazol , Pontos Quânticos , Topotecan , Pantoprazol/farmacocinética , Pantoprazol/química , Topotecan/farmacocinética , Topotecan/química , Topotecan/análise , Carbono/química , Pontos Quânticos/química , Espectrometria de Fluorescência/métodos , Animais , Limite de Detecção , Corantes Fluorescentes/química
2.
Pharm Res ; 41(4): 795-806, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38536615

RESUMO

PURPOSE: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen. METHODS: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration-time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model. RESULTS: FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage. CONCLUSIONS: Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Camundongos , Animais , Topotecan/farmacocinética , Inibidores da Topoisomerase I/farmacocinética , Lipossomos , Neoplasias/tratamento farmacológico , Modelos Animais de Doenças , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
3.
Expert Opin Drug Discov ; 17(6): 581-601, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35321631

RESUMO

INTRODUCTION: Cancer has been identified as one of the leading causes of death worldwide. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds with antiproliferative effect and behaving as topoisomerase I inhibitors has become an active field of research. Depending on their mechanism of inhibition, they can be classified as catalytic inhibitors or poisons. AREAS COVERED: This review article summarizes the state of the art for the development of selective topoisomerase I inhibitors. Collected compounds showed inhibition of the enzyme, highlighting those approved for clinical use, the combination therapies developed, as well as related drawbacks and future focus. EXPERT OPINION: Research related to topoisomerase I inhibitors in cancer therapy started with camptothecin (CPT). This compound was first selected as a good anticancer agent and then topoisomerase I was identified as its therapeutic target. Derivatives of CPT irinotecan, topotecan, and belotecan are the only clinically approved inhibitors. Currently, their limitations are being addressed by different stretegies. Future studies should focus not only on developing other active molecules but also on improving the bioavailability and pharmacokinetics of potent synthetic derivatives.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/uso terapêutico , Inibidores Enzimáticos/farmacologia , Humanos , Irinotecano/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/farmacocinética , Topotecan/uso terapêutico
4.
J Clin Oncol ; 39(32): 3546-3560, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34347542

RESUMO

PURPOSE: AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS: Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS: Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) and ribociclib 175 mg/m2 once a day and everolimus 2.5 mg/m2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION: Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.


Assuntos
Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Everolimo/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Temozolomida/uso terapêutico , Topotecan/uso terapêutico , Adolescente , Fatores Etários , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Criança , Pré-Escolar , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Everolimo/efeitos adversos , Everolimo/farmacocinética , Feminino , Humanos , Lactente , Masculino , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Purinas/efeitos adversos , Purinas/farmacocinética , Temozolomida/efeitos adversos , Temozolomida/farmacocinética , Fatores de Tempo , Topotecan/efeitos adversos , Topotecan/farmacocinética , Resultado do Tratamento
5.
Biomed Res Int ; 2021: 9968602, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34285920

RESUMO

BACKGROUND: Chemotherapeutic drugs cause severe toxicities if administered unprotected, without proper targeting, and controlled release. In this study, we developed topotecan- (TPT-) loaded solid lipid nanoparticles (SLNs) for their chemotherapeutic effect against colorectal cancer. The TPT-SLNs were further incorporated into a thermoresponsive hydrogel system (TRHS) (TPT-SLNs-TRHS) to ensure control release and reduce toxicity of the drug. Microemulsion technique and cold method were, respectively, used to develop TPT-SLNs and TPT-SLNs-TRHS. Particle size, polydispersive index (PDI), and incorporation efficiency (IE) of the TPT-SLNs were determined. Similarly, gelation time, gel strength, and bioadhesive force studies of the TPT-SLNs-TRHS were performed. Additionally, in vitro release and pharmacokinetic and antitumour evaluations of the formulation were done. RESULTS: TPT-SLNs have uniformly distributed particles with mean size in nanorange (174 nm) and IE of ~90%. TPT-SLNs-TRHS demonstrated suitable gelation properties upon administration into the rat's rectum. Moreover, drug release was exhibited in a control manner over an extended period of time for the incorporated TPT. Pharmacokinetic studies showed enhanced bioavailability of the TPT with improved plasma concentration and AUC. Further, it showed significantly enhanced antitumour effect in tumour-bearing mice as compared to the test formulations. CONCLUSION: It can be concluded that SLNs incorporated in TRHS could be a potential source of the antitumour drug delivery with better control of the drug release and no toxicity.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Hidrogéis/química , Lipídeos/química , Substâncias Macromoleculares/química , Nanopartículas/química , Temperatura , Topotecan/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos Nus , Mucosa/efeitos dos fármacos , Mucosa/patologia , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Sprague-Dawley , Reto/efeitos dos fármacos , Reto/patologia , Topotecan/sangue , Topotecan/farmacocinética , Topotecan/farmacologia
6.
Drug Deliv ; 28(1): 767-775, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33860729

RESUMO

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2-5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Topotecan/farmacologia , Administração por Inalação , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Química Farmacêutica , Genes erbB-1/genética , Meia-Vida , Humanos , Taxa de Depuração Metabólica , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Ratos Sprague-Dawley , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/farmacocinética , Topotecan/administração & dosagem , Topotecan/farmacocinética , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Curr Drug Metab ; 21(11): 902-909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32851958

RESUMO

BACKGROUND: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. OBJECTIVE: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. METHODS: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. RESULTS: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. CONCLUSION: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.


Assuntos
Ácido Fólico/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Células A549 , Administração Intravenosa , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/farmacocinética , Humanos , Lipossomos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/farmacocinética , Ratos Sprague-Dawley , Inibidores da Topoisomerase I/sangue , Inibidores da Topoisomerase I/farmacocinética , Topotecan/sangue , Topotecan/farmacocinética
8.
Drug Deliv ; 27(1): 836-847, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32508162

RESUMO

In order to enhance the targeting efficiency and reduce anti-tumor drug's side effects, topotecan (TPT) and F7 were co-loaded in thermosensitive liposomes (F7-TPT-TSL), which show enhanced permeability and retention in tumors, as well as local controlled release by heating in vitro. TPT is a water-soluble inhibitor of topoisomerase I that is converted to an inactive carboxylate structure under physiological conditions (pH 7.4). F7 is a novel drug significantly resistant to cyclin-dependent kinase but its use was restricted by its high toxicity. F7-TPT-TSL had excellent particle distribution (about 103 nm), high entrapment efficiency (>95%), obvious thermosensitive property, and good stability. Confocal microscopy demonstrated specific higher accumulation of TSL in tumor cells. MTT proved F7-TPT-TSL/H had strongest cell lethality compared with other formulations. Then therapeutic efficacy revealed synergism of TPT and F7 co-loaded in TSL, together with hyperthermia. Therefore, the F7-TPT-TSL may serve as a promising system for temperature triggered cancer treatment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lipossomos , Topotecan , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Hipertermia , Lipossomos/química , Lipossomos/farmacocinética , Camundongos , Nanoestruturas , Distribuição Tecidual/efeitos dos fármacos , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacocinética , Topotecan/química , Topotecan/farmacocinética , Temperatura de Transição , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Drug Metab Dispos ; 48(6): 491-498, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32193356

RESUMO

Breast cancer resistance protein (BCRP) is expressed on the apical membrane of small intestinal epithelial cells and functions as an efflux pump with broad substrate recognition. Therefore, quantitative evaluation of the contribution of BCRP to the intestinal permeability of new chemical entities is very important in drug research and development. In this study, we assessed the BCRP-mediated efflux of several model drugs in Caco-2 cells using WK-X-34 as a dual inhibitor of P-glycoprotein (P-gp) and BCRP and LY335979 as a selective inhibitor of P-gp. The permeability of daidzein was high with an apparent permeability coefficient for apical-to-basal transport (P AB) of 20.3 × 10-6 cm/s. In addition, its efflux ratio (ER) was 1.55, indicating that the contribution of BCRP to its transport is minimal. Estrone-3-sulfate and ciprofloxacin showed relatively higher ER values (>2.0), whereas their BCRP-related absorptive quotient (AQ BCRP) was 0.21 and 0.3, respectively. These results indicate that BCRP does not play a major role in regulating the permeability of estrone-3-sulfate and ciprofloxacin in Caco-2 cells. Nitrofurantoin showed a P AB of 1.8 × 10-6 cm/s, and its ER was 7.6. However, the AQ BCRP was 0.37, suggesting minimal contribution of BCRP to nitrofurantoin transport in Caco-2 cells. In contrast, topotecan, SN-38, and sulfasalazine had low P AB values (0.81, 1.13, and 0.19 × 10-6 cm/s, respectively), and each AQ BCRP was above 0.6, indicating that BCRP significantly contributes to the transport of these compounds in Caco-2 cells. In conclusion, Caco-2 cells are useful to accurately estimate the contribution of BCRP to intestinal drug absorption. SIGNIFICANCE STATEMENT: We performed an in vitro assessment of the contribution of breast cancer resistance protein (BCRP) to the transport of BCRP and/or P-glycoprotein (P-gp) substrates across Caco-2 cell monolayers using absorptive quotient, which has been proposed to represent the contribution of drug efflux transporters to the net efflux. The present study demonstrates that the combined use of a BCRP/P-gp dual inhibitor and a P-gp selective inhibitor is useful to estimate the impact of BCRP and P-gp on the permeability of tested compounds in Caco-2 cells.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de Neoplasias/metabolismo , Células CACO-2 , Ciprofloxacina/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Estrona/análogos & derivados , Estrona/farmacocinética , Estudos de Viabilidade , Humanos , Irinotecano/farmacocinética , Nitrofurantoína/farmacocinética , Permeabilidade , Sulfassalazina/farmacocinética , Topotecan/farmacocinética
10.
J Pharm Sci ; 108(3): 1315-1325, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30389568

RESUMO

Breast cancer resistance protein transporter (ABCG2/BCRP) is highly expressed on the intestinal epithelial membrane and has a significant impact on the oral absorption of topotecan. In this study, we examined 6 pharmaceutical excipients including BL-9EX, Brij97, Cremophor EL, Labrasol, Pluronic F68, and Tween 20 for their BCRP inhibitory effects. A bidirectional transport study using Caco-2 cells demonstrated that Tween 20 and Cremophor EL significantly increased the absorptive transport of topotecan, while simultaneously decreasing secretory transport. Interestingly, Labrasol selectively increased absorptive transport, whereas Pluronic F68 selectively decreased the secretory transport, of topotecan. Further investigation using an in situ closed loop experiment showed that 0.05% (w/v) Tween 20 and Cremophor EL significantly increased the intestinal absorption of topotecan in rats. An LDH assay demonstrated that 0.05% (w/v) Tween 20 and Cremophor EL did not cause significant damage to intestinal epithelial membranes. Furthermore, we examined the absorption-enhancing mechanisms of these excipients and found that Cremophor EL, Tween 20, and Labrasol increased the membrane fluidity of the inner lipid bilayers of the intestine. Therefore, this might be one of the most important mechanisms for inhibition of BCRP function by these excipients in the intestine.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Excipientes/farmacologia , Absorção Intestinal/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Topotecan/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Excipientes/química , Glicerídeos/química , Glicerídeos/farmacologia , Glicerol/análogos & derivados , Glicerol/química , Glicerol/farmacologia , Humanos , Bicamadas Lipídicas/metabolismo , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Poloxâmero/química , Poloxâmero/farmacologia , Polissorbatos/química , Polissorbatos/farmacologia , Ratos , Topotecan/química
11.
Pediatr Blood Cancer ; 66(4): e27578, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30548417

RESUMO

BACKGROUND: Topotecan is a chemotherapeutic agent that is active against many pediatric tumors. Although its effect is related to systemic exposure, the interpatient variability in systemic clearance makes it challenging to achieve desired topotecan targets. This study aims to evaluate the success of the pharmacokinetically (PK) guided dosing process, which was used to achieve a target topotecan area under the concentration-time curve (AUC). METHODS: Patients received an empiric topotecan dosage on the first day; the topotecan lactone AUC was determined, and based upon these values the topotecan dosage was adjusted. The success rates of both the empiric and PK-guided strategies were calculated. Patient-specific covariates were collected to explain variability observed in the empiric and PK-guided results. A simulation study was performed to assess the differences in cumulative topotecan dosage and systemic exposure between a PK-guided and standard dosing approach. RESULTS: Data were collected from nine clinical trials open from 1996 to 2016 (n = 232 patients). The empiric dosing success rate was 35.5%, while the PK-guided rate was 64.4%. A difference in mean serum creatinine was observed between successful empiric studies and those above the AUC target. Compared to a standard dosing approach, the PK-guided group had a higher average cumulative dosage and systemic exposure. CONCLUSION: The low empiric dosing success rate indicates that additional studies are needed to refine the initial topotecan dosage. The role of renal function, measured as serum creatinine, remains to be elucidated. However, the PK-guided targeting success rate highlighted the need to account for variable topotecan systemic clearance.


Assuntos
Antineoplásicos , Neoplasias , Topotecan , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Área Sob a Curva , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estudos Retrospectivos , Topotecan/administração & dosagem , Topotecan/farmacocinética
12.
Cancer Chemother Pharmacol ; 82(4): 723-732, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30128950

RESUMO

PURPOSE: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. METHODS: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120-360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. RESULTS: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy. CONCLUSIONS: The combination of topotecan and oral tivantinib was not tolerable in this patient population.


Assuntos
Neoplasias/tratamento farmacológico , Neutropenia , Pirrolidinonas , Quinolinas , Trombocitopenia , Topotecan , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/classificação , Neoplasias/metabolismo , Neoplasias/patologia , Neutropenia/induzido quimicamente , Neutropenia/diagnóstico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirrolidinonas/administração & dosagem , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinética , Falha de Tratamento , Resultado do Tratamento
13.
J Control Release ; 280: 87-98, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29723616

RESUMO

Image guided drug delivery using imageable thermosensitive liposomes (iTSLs) and high intensity focused ultrasound (FUS or HIFU) has attracted interest as a novel and non-invasive route to targeted delivery of anti-cancer therapeutics. FUS-induced hyperthermia is used as an externally applied "trigger" for the release of a drug cargo from within thermosensitive drug carriers. It is suggested that sub-ablative hyperthermia significantly modifies the permeability of tumour vasculature and enhances nanoparticle uptake. Here we describe the preparation and use of magnetic resonance imaging (MRI) and near infrared fluorescence (NIRF) labelled thermosensitive liposomes for imaging and tracking of biodistribution and drug release in a murine cancer model. We prepared iTSLs to encapsulate topotecan (Hycamtin®), a chemotherapeutic agent which when released in tumours can be monitored by an increase in its intrinsic drug fluorescence. FUS was applied using feedback via subcutaneously placed fine-wire thermocouples to maintain and monitor hyperthermic temperatures. iTSL accumulation was detected within tumours using NIRF imaging immediately after liposome administration. Mild FUS-induced hyperthermia (3 min at 42 °C, 30 min post i.v. administration) greatly enhanced iTSLs uptake. A co-localised enhancement of topotecan fluorescence emission was also observed immediately after application of FUS indicating rapid triggered drug release. The phenomena of increased iTSL accumulation and concomitant topotecan release appeared to be amplified by a second mild hyperthermia treatment applied one hour after the first. MRI in vivo also confirmed enhanced iTSLs uptake due to the FUS treatments. Our imaging results indicate the effects of hyperthermia on the uptake of carriers and drug. FUS-induced hyperthermia combined with real time imaging could be used as a tool for tumour targeted drug delivery.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Febre/induzido quimicamente , Lipídeos/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Topotecan/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/uso terapêutico , Liberação Controlada de Fármacos , Gadolínio/química , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Humanos , Hipertermia Induzida/métodos , Indicadores e Reagentes/química , Lipossomos/química , Imageamento por Ressonância Magnética/métodos , Camundongos Endogâmicos BALB C , Imagem Óptica/métodos , Temperatura , Distribuição Tecidual/efeitos dos fármacos , Topotecan/farmacocinética , Topotecan/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
14.
J Photochem Photobiol B ; 183: 222-232, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29729631

RESUMO

The study focuses on widening up the therapeutic perspective of anti-cancer therapy by entrapping a hydrophilic anticancer drug, topotecan hydrochloride (TOPO) in biodegradable poly (lactide-co-glycolide) (PLGA) matrix to form topotecan nanoparticles (TOPO NPs) by a double emulsion solvent evaporation technique. Statistical optimization using Box-Behnken design showed that sonication time of primary emulsion for 120 s, drug: polymer ratio of 1:12.65, organic phase: external aqueous phase ratio of 1:2.82 and 0.5% w/v of polyvinyl alcohol in the drug containing phase produced TOPO NPs with a size of 243.2 ±â€¯4 nm and an entrapment efficiency of 60.9 ±â€¯2.2%. TOPO NPs illustrated sustained release of TOPO for a week in phosphate buffer saline (PBS) at simulating physiological (pH 7.4) and acidic tumor microenvironmental (pH 6.5) conditions. A dramatic increase in cellular uptake with a corresponding enhanced cytotoxic potency was also displayed by TOPO NPs against human ovarian cancer cells (SKOV3) over time as compared to native drug, TOPO. These findings were further supported by the enhancement of bioavailability (13.05 fold) conferred by TOPO NPs from the in vivo pharmacokinetic study. The study represents a logistic approach for formulating TOPO NPs which can be used as an effective drug delivery system for the treatment of ovarian cancer.


Assuntos
Antineoplásicos/química , Nanopartículas/química , Topotecan/química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Área Sob a Curva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/química , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Curva ROC , Topotecan/farmacocinética , Topotecan/toxicidade
15.
Clin Cancer Res ; 24(4): 744-752, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29138343

RESUMO

Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome.Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10, and 15-17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST.Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10, and 15-17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1-26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles).Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation. Clin Cancer Res; 24(4); 744-52. ©2017 AACR.


Assuntos
Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Mutação em Linhagem Germinativa , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinética
16.
Drug Deliv ; 24(1): 1565-1573, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29029577

RESUMO

The oral administration of water-soluble chemotherapeutical agents is limited by their serious gastrointestinal side effects, instability at intestinal pH, and poor absorption. Aiming to solve these problems, we chose topotecan (TPT) as a model drug and developed a novel lipid formulation containing core-shell lipid nanoparticle (CLN) that makes the water-soluble drug to 'dissolve' in oil. TPT molecules can be encapsulated into nanoparticles surrounded by oil barrier while avoiding the direct contact with intestinal environment, thus easing the intestinal hydrolytic degradation and gastrointestinal (GI) irritation. Microstructure and mean particle size of TPT-CLN were characterized by Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS), respectively. The average size of nanoparticles was approximately 60 nm with a homogeneous distribution in shapes of spheres or ellipsoid. According to in vitro stability studies, more initial form of TPT was observed in presence of lipid nanoparticle compared with free topotecan solution in artificial intestinal juice (pH 6.5). After oral administration of TPT-CLN in rats, AUC and Cmax of TPT were all increased compared with free TPT, indicating significant enhancement of oral absorption. Intestinal lymphatic transport was confirmed as the major way for CLN to enhance oral absorption of TPT by the treatment of blocking chylomicron flow. Lower GI irritation of TPT-CLN was observed in the gastrointestinal damage studies. The in vivo antitumor activity of TPT-CLN showed an improved antitumor efficacy by oral treatment of TPT-CLN compared to free TPT. From the obtained data, the systems appear an attractive progress in oral administration of topotecan.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Portadores de Fármacos/química , Nanopartículas/química , Topotecan/administração & dosagem , Topotecan/farmacocinética , Administração Oral , Animais , Antineoplásicos/efeitos adversos , Área Sob a Curva , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Lipossomos/química , Masculino , Taxa de Depuração Metabólica , Tamanho da Partícula , Ratos , Ratos Wistar , Topotecan/efeitos adversos
17.
J Control Release ; 264: 34-44, 2017 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-28830790

RESUMO

Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma. CHEMICAL COMPOUNDS INCLUDED IN THIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Barreira Hematorretiniana/efeitos dos fármacos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematorretiniana/metabolismo , Humanos , Camundongos Nus , Pantoprazol , Coelhos , Neoplasias da Retina/genética , Neoplasias da Retina/metabolismo , Retinoblastoma/genética , Retinoblastoma/metabolismo , Inibidores da Topoisomerase I/farmacocinética , Topotecan/farmacocinética , Corpo Vítreo/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cancer Med ; 6(6): 1240-1254, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28544814

RESUMO

The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy.


Assuntos
Neuroblastoma/tratamento farmacológico , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Animais , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Lipossomos , Masculino , Camundongos , Neuroblastoma/metabolismo , Distribuição Tecidual , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/química , Topotecan/farmacocinética , Topotecan/uso terapêutico
19.
Br J Clin Pharmacol ; 83(8): 1688-1700, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28156017

RESUMO

AIMS: Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukaemia, and compare veliparib concentration in various biological matrices. METHODS: A population pharmacokinetic model was developed and effect of age, body size indices, sex, creatinine clearance (CrCL) and co-administration of T + C on the pharmacokinetics of veliparib were evaluated. The final model was qualified using bootstrap and quantitative predictive check. Linear regression was conducted to correlate concentrations of veliparib in various biological matrices. RESULTS: A two compartment model with first-order absorption with Tlag described veliparib pharmacokinetics. The apparent clearance (CL/F) and volume (Vc /F) were 16.5 l h-1 and 122.7 l, respectively. The concomitant administration of T + C was not found to affect veliparib CL/F. CrCL and lean body mass (LBM) were significant covariates on CL/F and Vc/F, respectively. While a strong positive relationship was observed between veliparib concentrations in plasma and bone marrow supernatant, no correlation was observed between plasma and peripheral blood or bone marrow blasts. CONCLUSIONS: Consistent with veliparib's physiochemical properties and its elimination mechanism, LBM and CrCL were found to affect pharmacokinetics of veliparib while concomitant administration of T + C did not affect veliparib's CL/F. Plasma concentrations were found to be a reasonable surrogate for veliparib concentrations in peripheral blood and bone marrow supernatant but not blasts. The current model will be utilized to conduct exposure-response analysis to support dosing recommendations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/farmacocinética , Leucemia/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/análise , Benzimidazóis/uso terapêutico , Carboplatina/farmacocinética , Carboplatina/uso terapêutico , Cálculos da Dosagem de Medicamento , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Biológicos , Inibidores de Poli(ADP-Ribose) Polimerases/análise , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Topotecan/farmacocinética , Topotecan/uso terapêutico , Adulto Jovem
20.
Curr Med Chem ; 24(2): 193-214, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27686655

RESUMO

Cancer is the uncontrolled growth of cells in the body and is considered as one of the major causes of death globally. There are several cytotoxic chemotherapeutic agents used to treat cancer including methotrexate, 5-fluorouracil, cisplatin, tamoxifen, doxorubicin and others. Although billions of dollars have been spent on cancer research to develop these chemotherapies, it still remains a major illness for mankind partly due to the shortcomings of these therapies. These shortcomings include low targeting specificity, severe side effects (due to high doses) and poor pharmacokinetics. To avoid these drawbacks, anti-cancer drug delivery systems have been developed recently using nanocarriers including liposomes, micelles, polyelectrolyte capsules and others. One of the recent class of nanoparticles investigated for chemotherapeutic use are metal organic frameworks (MOFs) which are hybrid polymers that consist of metal ions or clusters and organic ligands. MOFs are used in many applications including gas/vapor separation, gas storage, catalysis, luminescent materials, and biomedical imaging. These structures have additional features that promote their use as drug carriers in the biomedical field. First, they are nontoxic, biodegradable and have the ability to carry high loadings of the anti-neoplastic agent due to their porous nature. Also, they have well-defined crystalline structures that can be characterized by different analytical techniques and their sizes are suitable to control their in vivo drug release. This paper reviews the methods used to synthesize MOFs and their recent use as antineoplastic drug delivery carriers.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Organometálicos/síntese química , Antineoplásicos/farmacocinética , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Nanopartículas , Compostos Organometálicos/química , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/farmacologia , Polímeros/síntese química , Polímeros/química , Porosidade , Succinatos/farmacocinética , Succinatos/farmacologia , Topotecan/administração & dosagem , Topotecan/farmacocinética
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