ABSTRACT
Prostate cancer (PCa) with a high incidence worldwide is a serious threat to men's health. Despite the continuous development of treatment strategies for PCa in recent years, the long-term prognosis of patients is still poor. Hence, the discovery and development of novel, secure, and efficient therapeutic approaches hold significant clinical significance. Although sorafenib (SOR) displays potential as a therapeutic option for PCa, its clinical efficacy is hindered by drug resistance, limited water solubility, and rapid metabolism. Therefore, we proposed to prepare nanoparticles (named SOR@8P4 NPs) utilizing the phenylalanine-based poly(ester amide) polymer (8P4) as the drug carrier to enhance the solubility and drug stability of SOR and improve the therapeutic targeting and bioavailability. SOR@8P4 NPs had high stability and showed acid-responsive drug release at the acidic tumor microenvironment. Additionally, SOR@8P4 NPs demonstrated more remarkable anticancer, antimetastatic, and antiproliferative abilities in vitro, compared with those of free drugs. SOR@8P4 NPs showed high tumor targeting and significantly inhibited tumor growth in vivo. In summary, the drug delivery system of SOR@8P4 NPs provides new ideas for the clinical treatment of PCa.
Subject(s)
Antineoplastic Agents , Nanoparticles , Prostatic Neoplasms , Sorafenib , Male , Sorafenib/therapeutic use , Sorafenib/pharmacology , Sorafenib/chemistry , Sorafenib/pharmacokinetics , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Humans , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Polyesters/chemistry , Mice , Drug Carriers/chemistry , Amides/chemistry , Amides/therapeutic use , Amides/pharmacology , Drug Liberation , Cell Proliferation/drug effects , Mice, Nude , Mice, Inbred BALB CABSTRACT
Aim: Investigation of the pharmacokinetics of sorafenib (SRF) in rats with hepatocellular carcinoma (HCC). Methods: A reproducible ultra-HPLC-MS method for simultaneous determination of serum SRF, N-hydroxymethyl sorafenib and N-demethylation sorafenib. Results: Both the maximum serum concentrations (2.5-times) and the area under the serum concentration-time curve from 0 h to infinity (4.5-times) of SRF were observed to be significantly higher, with a greater than 3.0-fold decrease in the clearance rate in the HCC-bearing rats compared with these values in healthy animals. Further study revealed approximately 3.8- and 3.2-times increases in the apparent Michaelis constant for N-hydroxymethyl sorafenib and N-demethylation sorafenib conversions in the HCC-bearing rats. Conclusion: The low efficiency for the SRF conversions was a key contributor to the increased serum concentrations of SRF.
[Box: see text].
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Niacinamide , Phenylurea Compounds , Sorafenib , Sorafenib/pharmacokinetics , Sorafenib/blood , Sorafenib/therapeutic use , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Niacinamide/analogs & derivatives , Niacinamide/blood , Niacinamide/pharmacokinetics , Rats , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Male , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/blood , Phenylurea Compounds/therapeutic use , Chromatography, High Pressure Liquid/methods , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/blood , Rats, Sprague-Dawley , Mass SpectrometryABSTRACT
Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups I-III were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group IV received sorafenib and canagliflozin; while Group V received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and Cmax of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in Vz/F and CLz/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.
Subject(s)
Canagliflozin , Phenylurea Compounds , Quinolines , Sorafenib , Animals , Canagliflozin/pharmacokinetics , Carcinoma, Hepatocellular/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Interactions , Liver Neoplasms/drug therapy , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/pharmacokinetics , Rats , Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics , Sorafenib/pharmacokineticsABSTRACT
Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)1α in liver cancer cells. However, to date, no selective HIF1α inhibitor has been clinically approved. The aim of this study is to investigate a drugtargetable molecule that can regulate HIF1α under hypoxia. The present study demonstrated that hyperactivation of dualspecificity tyrosinephosphorylationregulated kinase 1A (DYRK1A)/HIF1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpressionvector transfection in liver cancer cell lines notably induced HIF1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF1α and positively regulate HIF1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the antiliver cancer effects of regorafenib and sorafenib under hypoxia. Cotreatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia/metabolism , Liver Neoplasms/drug therapy , Phenylurea Compounds/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/pharmacology , Sorafenib/pharmacokinetics , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/physiopathology , Phenylurea Compounds/metabolism , Protective Factors , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Pyridines/metabolism , Sorafenib/metabolism , Dyrk KinasesABSTRACT
BACKGROUND: Sorafenib is an anticancer drug used in the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. It is a substrate for the human OATP1B1. This study is aimed at assessing the role of OATP1B1 in transportation and uptake of sorafenib in hepatocellular carcinoma and how OATP1B1 affects the pharmacodynamics of sorafenib in vitro and in vivo. METHODS: Sorafenib transport was measured in HepG2, HepG2-OATP1B1∗1a, HepG2-OATP1B1∗1b, HepG2-OATP1B1∗15, LO2, LO2-OATP1B1∗1a, LO2-OATP1B1∗1b, and LO2-OATP1B1∗15 cells, as well as in HepG2 cells transfected with miR-148a mimics. The viability and apoptosis rate of cells treated with sorafenib were evaluated. A liver cancer rat model was established to explore the pharmacokinetics and pharmacodynamics of sorafenib after overexpression of Oatp2. RESULTS: Changes in expression and genetic mutations of OATP1B1 significantly affected the uptake of sorafenib in HepG2 and LO2 transgenic cells, and the uptake of sorafenib was higher in HepG2 than LO2. Genetic mutations of OATP1B1 significantly affected the cell viability and apoptosis rate of HepG2 cells after sorafenib treatment. Compared to control group, the uptake of sorafenib in miR-148a mimic-transfected HepG2 cells was decreased, and the cell viability was increased. PCN significantly increased the expression of Oatp2 and affected the pharmacokinetics of sorafenib. Vascular endothelial growth factor levels and microvascular density in tumor-adjacent tissues decreased significantly, suggesting that increased Oatp2 expression improves the treatment effect of sorafenib in a rat model of liver cancer. CONCLUSIONS: OATP1B1 plays an important role in the pharmacokinetics and pharmacodynamics of sorafenib in hepatocellular carcinoma.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Liver-Specific Organic Anion Transporter 1/metabolism , Mutation , Sorafenib/pharmacology , Sorafenib/pharmacokinetics , Animals , Antineoplastic Agents , Apoptosis , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Proliferation , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver-Specific Organic Anion Transporter 1/genetics , Male , Rats , Rats, Sprague-Dawley , Tissue Distribution , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: Cytochrome P450 3A5 (CYP3A5) is a highly polymorphic gene and the encoded protein variants differ in catalytic activity, leading to inter-individual variation in metabolic ability. The aim of the current study was to investigate the effects of seven allelic variants on the ability of CYP3A5 to metabolize sorafenib in vitro and further explore the impacts of CYP3A5 polymorphism on the proliferation and apoptosis of hepatocellular carcinoma cell line (HepG2) induced by sorafenib. METHODS: Wild-type and variant CYP3A5 enzymes were expressed in Spodoptera frugiperda insect cells using a baculovirus dual-expression system, and protein expression was checked by western blot. The enzymes were incubated with sorafenib at 37°C for 30 min, and formation of the major metabolite sorafenib N-oxide was assayed using ultra-performance liquid chromatography and tandem mass spectrometry. Intrinsic clearance values (Vmax/Km) were calculated for each enzyme. Additionally, recombinant HepG2 cells transfecting with CYP3A5 variants were used to investigate the effects of sorafenib on the proliferation of HepG2 cells. RESULTS: Intrinsic clearance of the six variants CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 was 26.41-71.04% of the wild-type (CYP3A5*1) value. In contrast, the clearance value of the variant CYP3A5*6 was significantly higher (174.74%). Additionally, the decreased ATP levels and cell viability and the increased cell apoptosis in HepG2 cells transfected with CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 were observed, whereas, the increased ATP levels and cell viability and the reduced cell apoptosis in HepG2 cells transfected with CYP3A5*6 were also investigated when compared to CYP3A5*1. CONCLUSION: Our results suggest that CYP3A5 polymorphism influences sorafenib metabolism and pharmacotherapeutic effect in hepatic carcinomas. These data may help explain differential response to drug therapy for hepatocellular carcinoma, and they support the need for individualized treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Cytochrome P-450 CYP3A/genetics , Liver Neoplasms/drug therapy , Polymorphism, Genetic , Sorafenib/therapeutic use , Antineoplastic Agents/pharmacokinetics , Humans , Sorafenib/pharmacokineticsABSTRACT
In addition to early detection, early diagnosis, and early surgery, it is of great significance to use new strategies for the treatment of hepatocellular carcinoma (HCC). Studies showed that the combination of sorafenib (SFN) and triptolide (TPL) could reduce the clinical dose of SFN and maintain good anti-HCC effect. But the solubility of SFN and TPL in water is low and both drugs have certain toxicity. Therefore, we constructed a biomimetic nanosystem based on cancer cell-platelet (PLT) hybrid membrane camouflage to co-deliver SFN and TPL taking advantage of PLT membrane with long circulation functions and tumor cell membrane with homologous targeting. The biomimetic nanosystem, SFN and TPL loaded cancer cell-PLT hybrid membrane-camouflaged liquid crystalline lipid nanoparticles ((SFN + TPL)@CPLCNPs), could simultaneously load SFN and TPL at the molar ratio of SFN to TPL close to 10:1. (SFN + TPL)@CPLCNPs achieved long circulation function and tumor targeting at the same time, promoting tumor cell apoptosis, inhibiting tumor growth, and achieving a better "synergy and attenuation effect", which provided new ideas for the treatment of HCC.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Diterpenes , Liposomes , Liver Neoplasms/metabolism , Nanoparticles , Phenanthrenes , Sorafenib , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomimetic Materials/chemistry , Blood Platelets/chemistry , Cell Line, Tumor , Cell Membrane/chemistry , Diterpenes/chemistry , Diterpenes/pharmacokinetics , Diterpenes/pharmacology , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacokinetics , Epoxy Compounds/pharmacology , Humans , Liposomes/chemistry , Liposomes/pharmacokinetics , Liposomes/toxicity , Male , Mice , Mice, Inbred BALB C , Nanomedicine , Nanoparticles/chemistry , Nanoparticles/toxicity , Phenanthrenes/chemistry , Phenanthrenes/pharmacokinetics , Phenanthrenes/pharmacology , RAW 264.7 Cells , Sorafenib/chemistry , Sorafenib/pharmacokinetics , Sorafenib/pharmacologyABSTRACT
Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes. This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.
Subject(s)
Blood Coagulation , Cytochrome P-450 CYP2C9/genetics , Drug Interactions/physiology , Hemorrhage , Sorafenib , Vitamin K Epoxide Reductases/genetics , Warfarin , Anticoagulants/metabolism , Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Blood Coagulation/physiology , Computer Simulation , Dose-Response Relationship, Drug , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Humans , International Normalized Ratio , Models, Biological , Models, Theoretical , Pharmacogenomic Testing/methods , Risk Assessment/methods , Sorafenib/metabolism , Sorafenib/pharmacokinetics , Warfarin/metabolism , Warfarin/pharmacokineticsABSTRACT
Renal cell carcinoma (RCC) is a highly vascularized tumor and prone to distant metastasis. Sorafenib is the first targeted multikinase inhibitor and first-line chemical drug approved for RCC therapy. In fact, only a small number of RCC patients benefit significantly from sorafenib treatment, while the growing prevalence of sorafenib resistance has become a major obstacle for drug therapy effectivity of sorafenib. The molecular mechanisms of sorafenib resistance in RCC are not completely understood by now. Herein, we comprehensively summarize the underlying mechanisms of sorafenib resistance and molecular biomarkers for predicting sorafenib responsiveness. Moreover, we outline strategies suitable for overcoming sorafenib resistance and prospect potential approaches for identifying biomarkers associated with sorafenib resistance in RCC, which contributes to guide individualized and precision drug therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Carcinoma, Renal Cell/drug therapy , Drug Resistance, Neoplasm , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sorafenib/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/secondary , Clinical Decision-Making , Gene Expression Regulation, Neoplastic , Genomics , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Signal Transduction , Sorafenib/adverse effects , Sorafenib/pharmacokinetics , Treatment OutcomeABSTRACT
Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC0->12 h ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2 /dose) or a pharmacokinetically guided dose targeting an AUC0->12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Sorafenib/administration & dosage , Sorafenib/pharmacokinetics , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Models, Biological , Practice Guidelines as Topic , Young AdultABSTRACT
Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.
Subject(s)
Drug Carriers/chemistry , High-Throughput Screening Assays/methods , Nanoparticles/chemistry , Sorafenib/pharmacology , Terbinafine/pharmacology , Animals , Candida albicans/drug effects , Computer Simulation , Drug Carriers/chemical synthesis , Drug Design , Drug Evaluation, Preclinical/methods , Dynamic Light Scattering , Excipients/chemistry , Female , Glycyrrhizic Acid/chemistry , Humans , Machine Learning , Mice, Inbred Strains , Skin Absorption , Sorafenib/chemistry , Sorafenib/pharmacokinetics , Taurocholic Acid/chemistry , Terbinafine/chemistry , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Sorafenib tosylate (SFN) belongs to the BCS class II drug with low solubility and undergoes first-pass metabolism, which leads to reduced bioavailability of 38%. OBJECTIVE: The present study aimed at developing SFN SNEDDS to improve their solubility and bioavailability. METHODS: Preliminary solubility studies were performed to identify oil, surfactant, and co-surfactant ratios. Pseudo tertiary phase diagram was constructed to select the areas of nanoemulsion based on the monophasic region. A total of 15 formulations of SFN SNEDDS were prepared and screened for phase separation and temperature variation using thermodynamic stability studies. These SNEDDS further characterized for % transmission, content of the drug, and in vitro dissolution analysis. The optimized formulation was analyzed for particle size, Z average, entrapment efficiency, and SEM analysis. RESULTS: Based on the pseudo tertiary phase diagram, acrysol EL 135, kolliphor, and transcutol-P as oil, surfactant, and co-surfactant were selected, respectively. All the formulations were stable with no phase separation and maximum % transmittance of 98.92%. The formulation F15 was selected as an optimized one, based on maximum drug content of 99.89%, with 98.94% drug release within 1 hour and it will be stable for 6 months. From in vivo bioavailability studies, the Cmax of optimized SNEDDS (94.12±2.12ng/ml) is higher than pure SFN suspension (15.32±1.46 ng/ml) and the AUC0-∞ of optimized SNEDDS is also increased by 5 times (512.1±8.54 ng.h/ml) than pure drug (98.75±6.45ng.h/ml), which indicates improved bioavailability of the formulation. CONCLUSION: SFN loaded SNEDDS could potentially be exploited as a delivery system for improving oral bioavailability by minimizing first-pass metabolism and increased solubility. Lay Summary: Renal cell carcinoma accounts for 2% of global cancer diagnoses and deaths, it has more than doubled in incidence in the developed world over the past half-century, and today is the ninth most common neoplasm in the United States. Sorafenib is a protein kinase inhibitor indicated as a treatment for advanced renal cell carcinoma. The present study aimed at developing Sorafenib SNEDDS to improve their solubility and bioavailability. A total of 15 formulations of Sorafenib SNEDDS were prepared and screened for phase separation and temperature variation using thermodynamic stability studies. Sorafenib loaded SNEDDS could potentially be exploited as a delivery system for increased oral bioavailability by 5 times when comparing with pure drug by minimizing first-pass metabolism and increased solubility.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Drug Delivery Systems/methods , Protein Kinase Inhibitors/pharmacokinetics , Sorafenib/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Carcinoma, Renal Cell/diagnosis , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Drug Liberation/physiology , Emulsions/chemistry , Kidney Neoplasms/pathology , Models, Animal , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Oils/chemistry , Particle Size , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Wistar , Solubility , Sorafenib/administration & dosage , Sorafenib/therapeutic use , Surface-Active Agents/chemistry , ThermodynamicsABSTRACT
BACKGROUND AND OBJECTIVE: Sorafenib is an oral, multikinase inhibitor with established single-agent activity in several tumor types. Sorafenib was moderately transported by P-glycoprotein (P-gp) and more efficiently by breast cancer resistance protein. The constitutive androstane receptor (CAR) is a ligand-activated transcription factor involved in P-gp regulation in the brain microvasculature. Paracetamol is a CAR activator. The purpose of this study was to investigate the effect of paracetamol on the brain uptake of sorafenib and sorafenib N-oxide. METHODS: The rats were assigned to two groups-rats receiving oral paracetamol 100 mg/kg and sorafenib 100 mg/kg (n = 42, ISR+PA) and rats receiving oral vehicle and sorafenib 100 mg/kg (n = 42, IISR). The sorafenib and sorafenib N-oxide concentrations in blood plasma and brain tissue were determined by a high-performance liquid chromatography method with ultraviolet detection. Brain-to-plasma partition coefficient (Kp) was calculated as a ratio of the area under the curve from zero to 24 h (AUC) in the brain and plasma. A drug targeting index (DTI) was estimated as the group ISR+PA Kp to group IISR Kp ratio. RESULTS: Pharmacokinetic analysis revealed increased brain exposure to sorafenib and sorafenib N-oxide after co-administration of paracetamol. The brain maximum concentration (Cmax) and the AUC of the parent drug in the ISR+PA group compared with the IISR group were greater by 49.5 and 77.8%, respectively, and the same parameters for the metabolite were higher by 51.4 and 50.9%. However, the Kp values of sorafenib and sorafenib N-oxide did not differ significantly between the two animal groups and the DTI values were close to 1. CONCLUSION: Paracetamol increases exposure to sorafenib and sorafenib N-oxide in the brain, likely due to increased exposure in plasma.
Subject(s)
Acetaminophen/pharmacology , Analgesics, Non-Narcotic/pharmacology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Sorafenib/pharmacokinetics , Animals , Area Under Curve , Brain/metabolism , Male , Pharmaceutical Vehicles , Rats , Rats, WistarABSTRACT
Sorafenib (SR) is one of the most potent UGT (1A1, 1A9) inhibitors (in in vitro tests). The inhibition of UGT1A1 may cause hyperbilirubinaemia, whereas the inhibition of UGT1A9 and 1A1 may result in drug-drug interactions (DDIs). Tapentadol (TAP) is a synthetic µ-opioid agonist and is used to treat moderate to severe acute pain. Tapentadol is highly glucuronidated by the UGT1A9 and UGT2B7 isoenzymes. The aim of the study was to assess the DDI between SR and TAP. Wistar rats were divided into three groups, with eight animals in each. The rats were orally treated with SR (100 mg/kg) or TAP (4.64 mg/kg) or in combination with 100 mg/kg SOR and 4.64 TAP mg/kg. The concentrations of SR and sorafenib N-oxide, TAP and tapentadol glucuronide were respectively measured by means of high-performance liquid chromatography (HPLC) with ultraviolet detection and by means of ultra-performance liquid chromatography-tandem mass spectrometry. The co-administration of TAP with SR caused TAP maximum plasma concentration (Cmax) to increase 5.3-fold whereas its area under the plasma concentration-time curve (AUC0-∞) increased 1.5-fold. The tapentadol glucuronide Cmax increased 5.3-fold and whereas its AUC0-∞ increased 2.0-fold. The tapentadol glucuronide/TAP AUC0-∞ ratio increased 1.4-fold (p = 0.0118). TAP also increased SR Cmax 1.9-fold, whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide Cmax increased 1.9-fold whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide/SR AUC0-t ratio increased 1.4-fold (p = 0.0127). The results show that the co-administration of sorafenib and tapentadol increases the exposure to both drugs and changes their metabolism. In consequence, the pharmacological effect may be intensified, but the toxicity may increases, too.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Antineoplastic Agents/pharmacokinetics , Glucuronosyltransferase/antagonists & inhibitors , Sorafenib/pharmacokinetics , Tapentadol/pharmacology , Animals , Antineoplastic Agents/blood , Area Under Curve , Chromatography, High Pressure Liquid , Drug Interactions , Glucuronides/metabolism , Male , Rats , Rats, Wistar , Reproducibility of Results , Sorafenib/blood , Spectrophotometry, Ultraviolet , Tandem Mass SpectrometryABSTRACT
Aim: To predict the impact of the different CYP2C9 and VKORC1 genotypes on warfarin-sorafenib interactions in whites and Asians. Materials & methods: The influences of the CYP2C9*1/*3 and VKORC1 -1639 A/A genotypes on increases in anticoagulation responses (international normalized ratio [INR]) in the presence of sorafenib were predicted using the population pharmacokinetic/pharmacodynamic (PK/PD) model in whites and Asians. Results: INRs were predicted to be 2.0-2.1- versus 1.8-1.9-times higher in the presence of sorafenib in the CYP2C9 (*1/*1 vs *1/*3) groups than those for warfarin alone in both whites and Asians. INRs were also predicted to be 2.1-2.2- versus 1.9-2.1-times higher in the VKORC1 (GG or GA vs AA) groups. Conclusion: Warfarin-sorafenib interactions might be similar irrespective of CYP2C9 and VKORC1 genotypes or ethnicity.
Subject(s)
Asian People/genetics , Cytochrome P-450 CYP2C9/genetics , Sorafenib/pharmacokinetics , Vitamin K Epoxide Reductases/genetics , Warfarin/pharmacokinetics , White People/genetics , Aged , Aged, 80 and over , Anticoagulants/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Drug Interactions/genetics , Female , Forecasting , Genotype , Humans , International Normalized Ratio/methods , Male , Middle AgedABSTRACT
PURPOSE: Lipid-based formulations (LBF) have shown oral bioavailability enhancement of lipophilic drugs, but not necessarily in the case of hydrophobic drugs. This study explored the potential of lipid vehicles to improve the bioavailability of the hydrophobic drug nilotinib comparing a chase dosing approach and lipid suspensions. METHODS: Nilotinib in vivo bioavailability in rats was determined after administering an aqueous suspension chase dosed with blank olive oil, Captex 1000, Peceol or Capmul MCM, respectively. Absolute bioavailability was determined (relative to an intravenous formulation). Pharmacokinetic parameters were compared to lipid suspensions. RESULTS: Compared to the lipid suspensions, the chase dosed lipids showed a 2- to 7-fold higher bioavailability. Both long chain chase dosed excipients also significantly increased the bioavailability up to 2-fold compared to the aqueous suspension. Deconvolution of the pharmacokinetic data indicated that chase dosing of nilotinib resulted in prolonged absorption compared to the aqueous suspension. CONCLUSION: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for 'brick dust' molecules such as nilotinib. Graphical Abstract The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.
Subject(s)
Lipids/chemistry , Liposomes/chemistry , Pyrimidines/chemistry , Animals , Biological Availability , Chemistry, Pharmaceutical , Diglycerides/chemistry , Dose-Response Relationship, Drug , Excipients/chemistry , Hydrophobic and Hydrophilic Interactions , Male , Monoglycerides/chemistry , Oleic Acids/chemistry , Olive Oil/chemistry , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Solubility , Sorafenib/chemistry , Sorafenib/pharmacokinetics , Suspensions/chemistry , WaterABSTRACT
PURPOSE: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS). RESULTS: The median sorafenib concentration was 2.91 µg/mL (range 0.74-8.8 µg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 µg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 µg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 µg/mL and ≥ 3.45 µg/mL [median 17.8 months (1.40-3.45 µg/mL) vs. 5.3 months (< 1.40 µg/mL) and 9.5 months (≥ 3.45 µg/mL)]. CONCLUSIONS: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 µg/mL in patients with HCC.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Sorafenib/therapeutic use , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Carcinoma, Hepatocellular/mortality , Female , Humans , Liver Neoplasms/mortality , Male , Middle Aged , Retrospective Studies , Sorafenib/adverse effects , Sorafenib/blood , Sorafenib/pharmacokinetics , Treatment OutcomeABSTRACT
To evaluate the effect and mechanism of radiotherapy (RT)-sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent RT2Gy and RT9Gy groups and the sequential RT9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential RT2Gy group (p = 0.036). Sequential RT2Gy and RT9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Portal Vein/radiation effects , Protein Kinase Inhibitors/pharmacokinetics , Radiosurgery/methods , Sorafenib/pharmacokinetics , Venous Thrombosis/radiotherapy , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B/radiation effects , Animals , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/complications , Cell Line, Tumor , Combined Modality Therapy , Cyclosporine/pharmacology , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Dose-Response Relationship, Radiation , Enzyme Induction/radiation effects , Humans , Liver Neoplasms/complications , Male , NF-kappa B/metabolism , NF-kappa B/radiation effects , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Sprague-Dawley , Retrospective Studies , Sorafenib/therapeutic use , Specific Pathogen-Free Organisms , Tissue Distribution , Venous Thrombosis/etiologyABSTRACT
Background: Sorafenib for advanced hepatocellular carcinoma (HCC) is dose adjusted by toxicity. Preliminary studies have suggested an association between plasma concentrations of sorafenib and its main metabolite (M2) and clinical outcomes. This study aimed to validate these findings and establish target values for sorafenib trough concentrations.Methods: Patients with advanced HCC were prospectively recruited within a multicenter phase II study (SORAMIC). Patients with blood samples available at trough level were included for this pharmacokinetic (PK) substudy. Trough plasma concentrations of sorafenib and its main metabolite (M2) were associated with sorafenib-related toxicity and overall survival (OS).Results: Seventy-four patients were included with a median OS of 19.7 months (95% CI 16.1-23.3). Patients received sorafenib for a median of 51 weeks (IQR 27-62) and blood samples were drawn after a median of 25 weeks (IQR 10-42). Patients had a median trough concentration of 3217 ng/ml (IQR 2166-4526) and 360 ng/ml (IQR 190-593) with coefficients of variation of 65% and 146% for sorafenib and M2, respectively. Patients who experienced severe sorafenib-related toxicity received a lower average daily dose (551 vs 730 mg/day, p = .003), but showed no significant differences in sorafenib (3298 vs 2915 ng/ml, p = .442) or M2 trough levels (428 vs 283 ng/ml, p = .159). Trough levels of sorafenib or M2 showed no significant association with OS.Conclusions: In patients with advanced HCC treated with sorafenib, the administered dose, trough levels of sorafenib or M2, and clinical outcomes were poorly correlated. Toxicity-adjusted dosing remains the standard for sorafenib treatment.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Carcinoma, Hepatocellular/drug therapy , Drug-Related Side Effects and Adverse Reactions/epidemiology , Liver Neoplasms/drug therapy , Sorafenib/pharmacokinetics , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/mortality , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/blood , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Incidence , Kaplan-Meier Estimate , Liver Neoplasms/blood , Liver Neoplasms/diagnosis , Liver Neoplasms/mortality , Male , Middle Aged , Neoplasm Staging , Prospective Studies , Reference Values , Severity of Illness Index , Sorafenib/administration & dosage , Sorafenib/toxicityABSTRACT
Sorafenib (SF) is the first drug demonstrated to improve the survival of patients diagnosed with advanced-stage hepatocellular carcinoma (HCC). However, its clinical application is limited by the poor oral bioavailability and severe side effects. In this study, a multifunctional micellar nanodrug was developed for simultaneous HCC-targeted delivery of SF and tumor detection with magnetic resonance imaging (MRI). The micellar nanodrug incorporating SF and superparamagnetic iron oxide nanoparticles (SPIONs) was prepared from a diblock copolymer of monomethoxyl poly(ethylene glycol) and poly(N-(2-aminoethanethiol-co-2-aminoethyldiisopropylamine) aspartamide) and then decorated with anti-glypican-3 antibody (AbGPC3). Owing to the small size, weak positive charge and AbGPC3-mediated active targeting to HCC cells, the nanodrug exhibited an easy cellular uptake and enhanced tumor accumulation. The prominent reduction and pH dual-sensitivity allowed the nanodrug to rapidly release SF inside cancer cells via responding to the cytoplasmic glutathione and lysosomal acidity. The nanodrug not only significantly improved the anticancer effects of SF in hepatoma treatment but also facilitated a noninvasive tumor detection and monitoring of in vivo drug delivery by MRI, which revealed its great potential as a promising theranostic system.