Clinical Importance of Plasma Drug Concentration of Oral Molecular Targeted Drugs for Renal Cell Carcinoma.

PURPOSE: Therapeutic drug monitoring (TDM) is widely used in clinical practice to maximize drug efficacy and minimize toxicities. Currently, it is also practiced in the use of oral molecular targeted drugs. The objective of this study was to assess the clinical importance of measuring the systemic concentration of oral molecular targeted drugs used to treat renal cell carcinoma (RCC). METHODS: The systemic concentrations of the oral molecular targeted drugs sorafenib, sunitinib, axitinib, pazopanib, and everolimus used for RCC were useful for therapeutic interventions, and clinical outcomes were evaluated retrospectively. RESULTS: The interventional use of systemic drug concentration was confirmed in 26 of 87, and their categories are presented. The systemic concentration of sunitinib was useful in dose reduction and/or discontinuation (n = 10), dose escalation (n = 3), and adherence monitoring (n = 2). Nine of the 10 patients whose dose was reduced showed reduced adverse event. Two patients who were intervened in adherence monitor showed improved adherence. For axitinib, dose reduction and/or discontinuation (n = 1) and dose escalation (n = 6) were confirmed. For pazopanib, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, both of them were confirmed to have reduced adverse events. For everolimus, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, a patient with reduced dose recovered from adverse events. Interventions for sorafenib were not identified. CONCLUSIONS: This study demonstrated that systemic concentrations of oral molecular targeted drugs for RCC were considered to be clinically useful for dose adjustment, monitoring of treatment adherence, and the detection of drug interactions. Moreover, this information could be successfully used to guide individualized therapy to maximize the antitumor effects of these drugs.

Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities.

Deuterium substitution has been widely known that can improve the pharmacokinetic profiles due to isotope effect. Herein, a series of deuterated sorafenib derivatives have been synthesized and characterized by 1H NMR, 13C NMR and MS. Their antitumor activities were evaluated in vitro against human hepatoma cell line HepG2 and human cervical carcinoma cell line HeLa. The LogP values were detected by high-performance liquid chromatography. Subsequently, the metabolic stability and pharmacokinetics study were assessed in vitro and in vivo.

Pharmacokinetics and apparent Michaelis constant for metabolite conversion of sorafenib in healthy and hepatocellular carcinoma-bearing rats.

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.

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In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol.

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.

Sorafenib exposure and its correlation with response and safety in advanced hepatocellular carcinoma: results from an observational retrospective study.

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.

Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake.

A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 (UGT1A9-rs3832043) and nuclear receptor PXR (NR1I2-rs3814055, NR1I2-rs2472677 and NR1I2-rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting UGT1A9, genetic polymorphisms of NR1I2 have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.

Relationship Between Adverse Events and Microbiomes in Advanced Hepatocellular Carcinoma Patients Treated With Sorafenib.

BACKGROUND/AIM: Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups. RESULTS: The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups. CONCLUSION: The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups.

Pharmacokinetic interaction study of novel combination of palbociclib and sorafenib for hepatocellular carcinoma in SD rats.

Hepatocellular carcinoma (HCC) is a fatal oncogenic disorder with few therapeutic options. Novel therapeutic strategy with combination of a selective CDK4/6 inhibitor palbociclib (PAL) with a tyrosine kinase inhibitor (TKI) sorafenib (SOR) is reported to impair tumour growth and significantly increased survival in various preclinical models of HCC. In the current work a sensitive and rapid UHPLC-QTOF-MS method was established for the concurrent quantification of PAL and SOR in rat plasma using ibrutinib as internal standard (IS). Chromatographic separation was carried out on an Agilent Poroshell EC C18 (50 mm × 3 mm, 2.7 µm) using gradient mobile phase consisting of 0.1% formic acid and acetonitrile. Flow rate of 0. 45 mL/min with a run time of 5 min was used for separation. A simple sample preparation approach of protein precipitation was used in the current study. The mass spectrometric analysis of selective ions at [M + H]+m/z 448.2455 for PAL, m/z 465.0936 for SOR and m/z 441.2034 for IS was monitored with extracted ion chromatography. The LC-MS method meets the regulatory bio-analytical guidelines, exhibited good sensitivity and linearity over the range of 1.0-2000.0 ng/mL for PAL and SOR. The pharmacokinetic parameters of PAL remained unchanged when SOR was co-administered with PAL. The study pointed out that the co-intake of PAL with SOR resulted in a slight increment of Cmax (11.21%) and AUC (7.95%) levels of SOR when co-administered with PAL when compared to individual oral intake in SD rats. The current method provides a modern rapid and sensitive tool for pharmacokinetic studies of PAL and SOR in a pre-clinical set up.

A Pharmacokinetic Interaction Study of Sorafenib and Iced Teas in Rats Using UPLC-MS/MS: An Illustration of Beverage-Drug Interaction.

Iced teas (ITs), also known as ready-to-drink teas, have gained much popularity among many nations. The modulatory effect of tea beverages on CYP3A4 increases the possibility of their potential interactions with many coadministered medications. Being a substrate of CYP3A4, sorafenib (SOR), the first-line therapy for the treatment of hepatocellular carcinoma, shows a great probability to exhibit pharmacokinetic (PK) interaction with ITs. For this purpose, different groups of Wistar rats were given oral doses of SOR (40 mg/kg), along with different types of ITs. The concentration of SOR in rat plasma was determined using UPLC-MS/MS. Chromatographic analysis was performed on a C18 analytical column, Acquity UPLC BEH™ (100 × 1.0 mm, i.d., 1.7 µm particle size), using erlotinib (ERL) as an internal standard. Isocratic elution was performed with a mobile phase consisting of two solvents: solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid), in a ratio of 30 : 70, v/v, respectively. Quantitation was performed using MRM of the transitions from protonated precursor ions [M+H]+ to product ions at m/z 465.12 > 252.02 (SOR) and m/z 394.29 > 278.19 (ERL). The method was fully validated as per the FDA guidance for bioanalytical method validation in the concentration range of 2.5-500 ng/mL. Different PK parameters were calculated for SOR in all rat groups and groups administered with ITs and SOR, compared with groups with simply water and SOR. Experimental data revealed that ITs caused a general reduction in SOR bioavailability; an approximate reduction of 30% was recorded for all types of tested ITs. These data indicate that ITs could affect the PK profile of SOR in rats.

Design And Characterisation Of Novel Sorafenib-Loaded Carbon Nanotubes With Distinct Tumour-Suppressive Activity In Hepatocellular Carcinoma.

PURPOSE: Over the past 30 years, no consistent survival benefits have been recorded for anticancer agents of advanced hepatocellular carcinoma (HCC), except for the multikinase inhibitor sorafenib (Nexavar®), which clinically achieves only ~3 months overall survival benefit. This modest benefit is attributed to limited aqueous solubility, slow dissolution rate and, consequently, limited absorption from the gastrointestinal tract. Thus, novel formulation modalities are in demand to improve the bioavailability of the drug to attack HCC in a more efficient manner. In the current study, we aimed to design a novel sorafenib-loaded carbon nanotubes (CNTs) formula that is able to improve the therapeutic efficacy of carried cargo against HCC and subsequently investigate the antitumour activity of this formula. MATERIALS AND METHODS: Sorafenib was loaded on functionalized CNTs through physical adsorption, and an alginate-based method was subsequently applied to microcapsulate the drug-loaded CNTs (CNTs-SFN). The therapeutic efficacy of the new formula was estimated and compared to that of conventional sorafenib, both in vitro (against HepG2 cells) and in vivo (in a DENA-induced HCC rat model). RESULTS: The in vitro MTT anti-proliferative assay revealed that the drug-loaded CNTs formula was at least two-fold more cytotoxic towards HepG2 cells than was sorafenib itself. Moreover, the in vivo animal experiments proved that our innovative formula was superior to conventional sorafenib at all assessed end points. Circulating AFP-L3% was significantly decreased in the CNTs-SFN-MCs-treated group (14.0%) in comparison to that of the DENA (40.3%) and sorafenib (38.8%) groups. This superiority was further confirmed by Western blot analysis and immunofluorescence assessment of some HCC-relevant biomarkers. CONCLUSION: Our results firmly suggest the distinctive cancer-suppressive nature of CNTs-SFN-MCs, both against HepG2 cells in vitro and in a DENA-induced HCC rat model in vivo, with a preferential superiority over conventional sorafenib.

Development of sorafenib loaded nanoparticles to improve oral bioavailability using a quality by design approach.

Sorafenib, a potent anticancer drug, has low absorption in the gastrointestinal tract due to its poor aqueous solubility. The main purpose of this investigation was to design sorafenib nanoparticle using a newly developed technique, nanoparticulation using fat and supercritical fluid (NUFS™) to improve the absorption of sorafenib. The quality by design (QbD) tool was adopted to define the optimal formulation variables: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone K30 (PVP), and poloxamer. The studied response variables were particle size of nanoparticle, dissolution (5, 60, and 180 min), drug concentration time profile of nanoparticle formulations, and maximum drug concentration. The result of particle size revealed that an increase in concentration of poloxamer and HPMC decreased the particle size of nanoparticles (p < 0.05). Likewise, the concentration of drug release at different time point (5, 60, and 180 min) showed HPMC and poloxamer had positive effects on drug dissolution while PVP had negative effects on it. The design space was built in accordance with the particle size of nanoparticle (target < 500 nm) and dissolution of sorafenib (target > 7 µm/mL), following failure probability analysis using Monte Carlo simulations. In vivo pharmacokinetics studies in beagle dogs demonstrated that optimized formulation of sorafenib (F3 and F4 tablets) exhibited higher blood drug profiles indicating better absorption compared to the reference tablet (Nexavar®). In conclusion, this study showed the importance of systematic formulation design for understanding the effect of formulation variables on the characteristics of nanoparticles of the poorly soluble drug.