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1.
J Antimicrob Chemother ; 79(7): 1547-1554, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38727613

RESUMO

INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. METHODS: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20 mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. RESULTS: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 µg/g (IQR: 21.94-60.65 µg/g) in skin and 33.29 µg/mL (IQR: 25.9-42.58 µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6 mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. CONCLUSION: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.


Assuntos
Anfotericina B , Antiprotozoários , Leishmaniose Cutânea , Leishmaniose Visceral , Fosforilcolina , Pele , Humanos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacocinética , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Antiprotozoários/farmacocinética , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Masculino , Adulto , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Feminino , Pele/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Pessoa de Meia-Idade , Adulto Jovem , Anfotericina B/farmacocinética , Anfotericina B/uso terapêutico , Anfotericina B/administração & dosagem , Adolescente , Ásia Meridional
2.
CPT Pharmacometrics Syst Pharmacol ; 13(6): 1029-1043, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38576225

RESUMO

Statins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane transporters that are present in diverse tissues, local differences in intracellular tissue concentrations cannot be ruled out. Thus, plasma concentration may not be an adequate indicator of efficacy and toxicity. To bridge this gap, we used physiologically based pharmacokinetic (PBPK) modeling to predict intracellular concentrations of statins. Quantitative data on transporter clearance were scaled from in vitro to in vivo conditions by integrating targeted proteomics and transporter kinetics data. The developed PBPK models, informed by proteomics, suggested that organic anion-transporting polypeptide 2B1 (OATP2B1) and multidrug resistance-associated protein 1 (MRP1) play a pivotal role in the distribution of statins in muscle. Using these PBPK models, we were able to predict the impact of alterations in transporter function due to genotype or drug-drug interactions on statin systemic concentrations and exposure in liver and muscle. These results underscore the potential of proteomics-guided PBPK modeling to scale transporter clearance from in vitro data to real-world implications. It is important to evaluate the role of drug transporters when predicting tissue exposure associated with on- and off-target effects.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Fígado , Modelos Biológicos , Transportadores de Ânions Orgânicos , Proteômica , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Fígado/metabolismo , Proteômica/métodos , Humanos , Transportadores de Ânions Orgânicos/metabolismo , Músculo Esquelético/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Interações Medicamentosas , Distribuição Tecidual , Masculino
3.
Drug Deliv Transl Res ; 14(4): 970-983, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37824040

RESUMO

Novel tumor-on-a-chip approaches are increasingly used to investigate tumor progression and potential treatment options. To improve the effect of any cancer treatment it is important to have an in depth understanding of drug diffusion, penetration through the tumor extracellular matrix and cellular uptake. In this study, we have developed a miniaturized chip where drug diffusion and cellular uptake in different hydrogel environments can be quantified at high resolution using live imaging. Diffusion of doxorubicin was reduced in a biomimetic hydrogel mimicking tissue properties of cirrhotic liver and early stage hepatocellular carcinoma (373 ± 108 µm2/s) as compared to an agarose gel (501 ± 77 µm2/s, p = 0.019). The diffusion was further lowered to 256 ± 30 µm2/s (p = 0.028) by preparing the biomimetic gel in cell media instead of phosphate buffered saline. The addition of liver tumor cells (Huh7 or HepG2) to the gel, at two different densities, did not significantly influence drug diffusion. Clinically relevant and quantifiable doxorubicin concentration gradients (1-20 µM) were established in the chip within one hour. Intracellular increases in doxorubicin fluorescence correlated with decreasing fluorescence of the DNA-binding stain Hoechst 33342 and based on the quantified intracellular uptake of doxorubicin an apparent cell permeability (9.00 ± 0.74 × 10-4 µm/s for HepG2) was determined. Finally, the data derived from the in vitro model were applied to a spatio-temporal tissue concentration model to evaluate the potential clinical impact of a cirrhotic extracellular matrix on doxorubicin diffusion and tumor cell uptake.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Biomimética , Doxorrubicina , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Cirrose Hepática , Hidrogéis/uso terapêutico
4.
Clin Pharmacol Ther ; 114(4): 825-835, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37376792

RESUMO

A different drug-drug interaction (DDI) scenario may exist in patients with chronic kidney disease (CKD) compared with healthy volunteers (HVs), depending on the interplay between drug-drug and disease (drug-drug-disease interaction (DDDI)). Physiologically-based pharmacokinetic (PBPK) modeling, in lieu of a clinical trial, is a promising tool for evaluating these complex DDDIs in patients. However, the prediction confidence of PBPK modeling in the severe CKD population is still low when nonrenal pathways are involved. More mechanistic virtual disease population and robust validation cases are needed. To this end, we aimed to: (i) understand the implications of severe CKD on statins (atorvastatin, simvastatin, and rosuvastatin) pharmacokinetics (PK) and DDI; and (ii) predict untested clinical scenarios of statin-roxadustat DDI risks in patients to guide suitable dose regimens. A novel virtual severe CKD population was developed incorporating the disease effect on both renal and nonrenal pathways. Drug and disease PBPK models underwent a four-way validation. The verified PBPK models successfully predicted the altered PKs in patients for substrates and inhibitors and recovered the observed statin-rifampicin DDIs in patients and the statin-roxadustat DDIs in HVs within 1.25- and 2-fold error. Further sensitivity analysis revealed that the severe CKD effect on statins PK is mainly mediated by hepatic BCRP for rosuvastatin and OATP1B1/3 for atorvastatin. The magnitude of statin-roxadustat DDI in patients with severe CKD was predicted to be similar to that in HVs. PBPK-guided suitable dose regimens were identified to minimize the risk of side effects or therapeutic failure of statins when co-administered with roxadustat.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Insuficiência Renal Crônica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Atorvastatina , Rosuvastatina Cálcica/efeitos adversos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Proteínas de Neoplasias , Interações Medicamentosas , Modelos Biológicos , Simulação por Computador
5.
BMJ Open ; 12(11): e065839, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36343995

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Idarubicina , Neoplasias Hepáticas/tratamento farmacológico , Resultado do Tratamento
6.
CPT Pharmacometrics Syst Pharmacol ; 11(9): 1194-1209, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35722750

RESUMO

Physiologically-based pharmacokinetic (PBPK) models have an important role in drug discovery/development and decision making in regulatory submissions. This is facilitated by predefined PBPK platforms with user-friendly graphical interface, such as Simcyp and PK-Sim. However, evaluations of platform differences and the potential implications for disposition-related applications are still lacking. The aim of this study was to assess how PBPK model development, input parameters, and model output are affected by the selection of PBPK platform. This is exemplified via the establishment of simvastatin PBPK models (workflow, final models, and output) in PK-Sim and Simcyp as representatives of established whole-body PBPK platforms. The major finding was that the choice of PBPK platform influenced the model development strategy and the final model input parameters, however, the predictive performance of the simvastatin models was still comparable between the platforms. The main differences between the structure and implementation of Simcyp and PK-Sim were found in the absorption and distribution models. Both platforms predicted equally well the observed simvastatin (lactone and acid) pharmacokinetics (20-80 mg), BCRP and OATP1B1 drug-gene interactions (DGIs), and drug-drug interactions (DDIs) when co-administered with CYP3A4 and OATP1B1 inhibitors/inducers. This study illustrates that in-depth knowledge of established PBPK platforms is needed to enable an assessment of the consequences of PBPK platform selection. Specifically, this work provides insights on software differences and potential implications when bridging PBPK knowledge between Simcyp and PK-Sim users. Finally, it provides a simvastatin model implemented in both platforms for risk assessment of metabolism- and transporter-mediated DGIs and DDIs.


Assuntos
Modelos Biológicos , Sinvastatina , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Simulação por Computador , Interações Medicamentosas , Humanos , Proteínas de Neoplasias , Farmacocinética
7.
Eur J Pharm Sci ; 172: 106150, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35231602

RESUMO

Hydrogels of varying complexity are routinely used as scaffolds and 3D structures for in vitro tumor models to increase physiological relevance within pre-clinical cancer research. Relatively simple hydrogels such as agarose are well characterised, meanwhile biomimetic gels containing collagen and fibrin(ogen) have been studied to a much lesser extent. In this study, hydrogels mimicking the biophysical characteristics of liver cancer progression were investigated in terms of their UV-properties and influence on diffusion coefficients of different substances. UV-imaging technology was used to both visualize and quantify the diffusion process in a simple and rapid way. In general, agarose gel diffusion agreed well with predictions using the Stokes-Einstein equation meanwhile the biomimetic gels reduced diffusion coefficients by up to 70%. For doxorubicin, spatio-temporal tissue concentration modelling was used to translate in vitro diffusion to the more clinical context of tumor penetration in a solid liver tumor supplied by arterial blood.


Assuntos
Hidrogéis , Neoplasias , Biomimética , Colágeno/química , Difusão , Humanos , Hidrogéis/química , Sefarose/química
8.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359887

RESUMO

Cytostatic effects of doxorubicin in clinically applied doses are often inadequate and limited by systemic toxicity. The main objective of this in vitro study was to determine the anti-tumoral effect (IC50) and intracellular accumulation of free and liposomal doxorubicin (DOX) in four human cancer cell lines (HepG2, Huh7, SNU449 and MCF7). The results of this study showed a correlation between longer DOX exposure time and lower IC50 values, which can be attributed to an increased cellular uptake and intracellular exposure of DOX, ultimately leading to cell death. We found that the total intracellular concentrations of DOX were a median value of 230 times higher than the exposure concentrations after exposure to free DOX. The intracellular uptake of DOX from solution was at least 10 times higher than from liposomal formulation. A physiologically based pharmacokinetic model was developed to translate these novel quantitative findings to a clinical context and to simulate clinically relevant drug concentration-time curves. This showed that a liver tumor resembling the liver cancer cell line SNU449, the most resistant cell line in this study, would not reach therapeutic exposure at a standard clinical parenteral dose of doxorubicin (50 mg/m2), which is serious limitation for this drug. This study emphasizes the importance of in-vitro to in-vivo translations in the assessment of clinical consequence of experimental findings.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Lipossomos/química , Antibióticos Antineoplásicos/farmacologia , Disponibilidade Biológica , Transporte Biológico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Portadores de Fármacos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Células MCF-7 , Modelos Biológicos , Modelos Estatísticos , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia
9.
Cancers (Basel) ; 11(7)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330834

RESUMO

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 µM doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

10.
AAPS J ; 20(6): 96, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30167825

RESUMO

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.


Assuntos
Carcinoma Hepatocelular/terapia , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Neoplasias Hepáticas/terapia , Animais , Quimioembolização Terapêutica/métodos , Simulação por Computador , Doxorrubicina/administração & dosagem , Emulsões , Óleo Etiodado/química , Humanos , Fígado/irrigação sanguínea , Fígado/patologia , Neoplasias Hepáticas/patologia , Microesferas , Modelos Biológicos , Suínos
12.
Mol Pharm ; 14(3): 686-698, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28182434

RESUMO

Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (Kp,t), could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional Kp,t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration-time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.


Assuntos
Doxorrubicina/farmacocinética , Animais , Bile/metabolismo , Sítios de Ligação , Doxorrubicina/análogos & derivados , Doxorrubicina/metabolismo , Fígado/metabolismo , Modelos Biológicos , Suínos , Distribuição Tecidual/fisiologia
13.
J Pharm Pharmacol ; 69(2): 135-142, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27882559

RESUMO

OBJECTIVES: In liver cancer treatment, lipiodol is used as a pharmaceutical excipient to improve delivery of the cytostatic drug doxorubicin (DOX). As DOX and its metabolite doxorubicinol (DOXol) cause serious off-target adverse effects, we investigated the effects of drug-free lipiodol or ciclosporin (CsA) on the tissue distribution (Kp ) of DOX and DOXol in relevant pig tissues. METHODS: Four treatment groups (TI-TIV) all received an intravenous DOX solution at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), lipiodol (TII), CsA (TIII) or lipiodol and CsA (TIV). After 6 h, the pigs were euthanised, and liver, kidney, heart and intestine samples were collected and analysed. KEY FINDINGS: The tissue DOX concentrations were highest in the kidney (TI-TIV). All the investigated tissues showed extensive DOX Kp . Lipiodol had no effect on the Kp of DOX to any of the tissues. However, the tissue concentrations of DOX were increased by CsA (in liver, kidney and intestine, P < 0.05). CONCLUSION: Lipiodol injected into the portal vein does not affect the tissue distribution of DOX and DOXol.


Assuntos
Doxorrubicina/farmacocinética , Óleo Etiodado/farmacologia , Animais , Ciclosporina/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Óleo Etiodado/administração & dosagem , Excipientes/administração & dosagem , Excipientes/farmacologia , Infusões Intravenosas , Mucosa Intestinal/metabolismo , Rim/metabolismo , Fígado/metabolismo , Miocárdio/metabolismo , Suínos
14.
Mol Pharm ; 14(2): 448-458, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-27997198

RESUMO

Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol and their short-term safety and antitumor effects were also evaluated. In this open, prospective, nonrandomized multicenter study, LIPDOX (n = 13) or DEBDOX (n = 12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p < 0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Emulsões/uso terapêutico , Óleo Etiodado/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
15.
J Pharm Sci ; 105(11): 3387-3398, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27663384

RESUMO

The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.


Assuntos
Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Microesferas , Modelos Químicos , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/química
16.
Mol Pharm ; 11(9): 3097-111, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25055161

RESUMO

The local distribution of 2-hydroxyflutamide (2-HOF) in prostate tissue after a single intraprostatic injection of a novel parenteral modified-release (MR) formulation in patients with localized prostate cancer was estimated using a semiphysiologically based biopharmaceutical model. Plasma concentration-time profiles for 2-HOF were acquired from a phase II study in 24 patients and the dissolution of the MR formulation was investigated in vitro. Human physiological values and the specific physicochemical properties of 2-HOF were obtained from the literature or calculated via established algorithms. A compartmental modeling approach was adopted for tissue and blood in the prostate gland, where the compartments were modeled as a series of concentric spherical shells contouring the centrally positioned depot formulation. Discrete fluid connections between the blood compartments were described by the representative flow of blood, whereas the mass transport of drug from tissue to tissue and tissue to blood was described by a one-dimensional diffusion approximation. An empirical dissolution approach was adopted for the release of 2-HOF from the formulation. The model adequately described the plasma concentration-time profiles of 2-HOF. Predictive simulations indicated that the local tissue concentration of 2-HOF within a distance of 5 mm from the depot formulation was approximately 40 times higher than that of unbound 2-HOF in plasma. The simulations also indicated that spreading the formulation throughout the prostate gland would expose more of the gland and increase the overall release rate of 2-HOF from the given dose. The increased release rate would initially increase the tissue and plasma concentrations but would also reduce the terminal half-life of 2-HOF in plasma. Finally, an in vitro-in vivo correlation of the release of 2-HOF from the parenteral MR formulation was established. This study shows that intraprostatic 2-HOF concentrations are significantly higher than systemic plasma concentrations and that increased distribution of 2-HOF throughout the gland, using strategic imaging-guided administration, is possible. This novel parenteral MR formulation, thus, facilitates good pharmacological effect while minimizing the risk of side effects.


Assuntos
Preparações de Ação Retardada/farmacocinética , Flutamida/análogos & derivados , Próstata/efeitos dos fármacos , Área Sob a Curva , Química Farmacêutica/métodos , Preparações de Ação Retardada/uso terapêutico , Flutamida/sangue , Flutamida/farmacocinética , Flutamida/uso terapêutico , Meia-Vida , Humanos , Masculino , Modelos Biológicos , Neoplasias da Próstata/tratamento farmacológico
17.
Ther Deliv ; 5(4): 447-66, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24856170

RESUMO

The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Óleo Etiodado/química , Neoplasias Hepáticas/tratamento farmacológico , Álcool de Polivinil/química , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Disponibilidade Biológica , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Estabilidade de Medicamentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias , Solubilidade , Distribuição Tecidual
18.
Mol Pharm ; 11(4): 1301-13, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24558959

RESUMO

Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX and its active metabolite doxorubicinol (DOXol). The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and DOXol were analyzed using UPLC-MS/MS. The developed multicompartment model described the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol were observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not directly interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Bile/metabolismo , Ciclosporina/farmacologia , Doxorrubicina/farmacocinética , Óleo Etiodado/farmacologia , Fígado/metabolismo , Animais , Masculino , Suínos
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