Pharmacokinetics Of Sorafenib Research Articles

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.

Drug-Eluting Embolic Loaded with Tyrosine Kinase Inhibitor Targeted Therapies for Transarterial Chemoembolization in a VX2 Model

Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.

Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031.

High allelic ratio (HAR) FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population. Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients. The maximum tolerated dose of sorafenib was 200 mg/m2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, P = .010). Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.

Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: An Overview.

Molecular therapy with sorafenib remains the mainstay for advancedstage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients obtaining long-lasting benefits due to the high chemoresistance rate. To perform, for the first time, an overview of the literature concerning the role of adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma. Three online databases (PubMed, Web of Science, and Scopus) were searched, from inception to October 2020. Study selection, analysis, and data collection were independently performed by two authors. The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance by increasing absorption and intracellular concentration. A deeper understanding of ABC transporters' mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.

OATP1B1 Plays an Important Role in the Transport and Treatment Efficacy of Sorafenib in Hepatocellular Carcinoma.

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.

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study.

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.

Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib.

Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0–12 h decreased by 27% (90% CI: −38% to −14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.

Pharmacokinetics and pharmacogenetics of sorafenib in patients with hepatocellular carcinoma: Implications for combination trials.

Sorafenib and lenvatinib are the first-line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. We assessed the pharmacokinetics of sorafenib and its N-oxide metabolite at day-0, day-7, day-30, day-60, day-90, day-120, day-150 and day-180 and nine single-nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. We prospectively included 49 patients (96% cirrhotic, 37% hepatitis-C, 82% Child-Pugh-A and 59% BCLC-C). Pharmacokinetic values peaked at day-7 and progressively declined until day-60. In the 16 patients without further dose modifications after day-60, pharmacokinetic values remained stable through day-180 (sorafenib P=.90; N-oxide P=.93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N-oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972. Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors.

P-86 Comparison of the pharmacokinetics of donafenib and sorafenib in patients with advanced hepatocellular carcinoma: An open-label, randomized, parallel-controlled, multicentre phase II/III trial

Donafenib is a deuterated derivative of sorafenib with improved efficacy and safety in patients with advanced hepatocellular carcinoma (HCC). Here we assess the pharmacokinetic profile of donafenib as compared with sorafenib to support the clinical findings.

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

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). 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). The median sorafenib concentration was 2.91μg/mL (range 0.74-8.8μg/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 ≥ 3months) was 3.45μg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40μg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45µg/mL had a tendency to be longer than those of patients administered < 1.40μg/mL and ≥ 3.45μg/mL [median 17.8months (1.40-3.45μg/mL) vs. 5.3months (< 1.40μg/mL) and 9.5months (≥ 3.45μg/mL)]. From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45μg/mL in patients with HCC.

Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies

To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies. Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated. In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; P < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (P = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (P = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (P < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent (P = 0.0015) but not with sequential (P = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (P = 0.0004) and sorafenib N-oxide (P = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR. Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.

Sorafenib in Combination with Standard Chemotherapy for Children with High Allelic Ratio FLT3/ITD+ AML Improves Event-Free Survival and Reduces Relapse Risk: A Report from the Children's Oncology Group Protocol AAML1031

INTRODUCTION Sorafenib, a multi-kinase tyrosine kinase inhibitor (TKI) targets FLT3 internal tandem duplication (FLT3/ITD) mutations and has efficacy in adult FLT3/ITD+ AML. High allelic ratio (HAR) FLT3/ITD mutations (allelic ratio of &amp;gt; 0.4, referred to as FLT3/ITD+) confer poor prognosis in de novo pediatric AML. COG AAML1031 Arm C studied the feasibility and efficacy of adding sorafenib to standard chemotherapy and as a single agent maintenance therapy in pediatric HAR FLT3/ITD+ patients. METHODS The AAML1031 primary randomization (Arm A vs. B) has been previously reported (Aplenc et al. Blood 2016;128:899). Patients with FLT3/ITD+ AML were offered secondary enrollment on Arm C and toxicities were monitored on respective treatment arms. An initial safety phase (Cohort 1, C1; N=12) defined the maximum tolerated dose (MTD) of sorafenib when added to induction II chemotherapy and subsequent courses. Following completion, the study was amended (Cohort 2; C2) to start sorafenib on day 11 of induction I and concomitantly with chemotherapy in subsequent cycles. A year of sorafenib maintenance was also added. Due to concerns for cardiac toxicity on interim analyses, the study was amended (Cohort 3; C3) to initiate sorafenib after chemotherapy completion in all courses. Sorafenib pharmacokinetics (PK) and plasma inhibitory activity (PIA) were measured in a subset of patients. Clinical outcome analysis was limited to cohorts 2/3 given lack of induction I sorafenib exposure in C1. Arm C results were compared to N=34 HAR FLT3/ITD+ AML patients on the control arm of COG AAML0531 (Arm A), a group that received comparable chemotherapy without sorafenib. Complete remission (CR), event-free survival (EFS), overall survival (OS) and relapse risk (RR) of patients with HAR FLT3/ITD AML enrolled on the 2 trials were compared to assess the impact of sorafenib use. Cox proportional hazards were used for multivariable analyses. RESULTS In the dose finding phase (C1), 12 patient were enrolled and the MTD of sorafenib defined as 200 mg/m2; dose limiting toxicities included rash (N=2; 1 grade III, 1 grade II), grade II hand foot syndrome and grade III fever. For the evaluation of efficacy, 80 C2/C3 (C2: N=33, C3: N=47) patients were enrolled. 30/80 (37.5%) received at least 1 maintenance cycle; 20/80 (25%) completed all courses. As outcomes were compared to N=34 HAR FLT3/ITD+ AML patients enrolled on the preceding trial AAML0531 Arm A as a historical comparison, clinical characteristics were described for the 2 groups (Table 1). For AAML1031 C2/C3, rates of induction I CR were 73% vs. 56% for AAML0531 Arm A (p=0.078). Following induction II, CR rates were 91% and 70% respectively (p=0.007). 3 year EFS from study entry was 57.5% for Arm C vs. 34.3% for AAML0531 Arm A; (p=0.007) whereas 3 year OS from study entry was not significantly different (63.9% vs. 54.1%, p=0.375, Figure 1A). RR from CR was reduced with sorafenib treatment (Arm C 18.2% vs. historical 52.5%, p=0.006, Figure 1B). The improvement in EFS and RR observed with sorafenib was retained in those with wild-type nucleophosmin (NPM-) FLT3/ITD+ AML but lacked statistical significance compared to historical in NPM+ FLT3/ITD+ disease (Figure 2A/2B). As 21/34 (62%) patients in the historical control did not undergo HSCT there was concern that the improved outcome observed for Arm C reflected increased use of HSCT in AAML1031. Multivariable analysis that adjusted for HSCT resulted in significantly lower EFS and higher RR for FLT3/ITD+ patients on AAML0531, suggesting that increased use of HSCT on Arm C did not explain the improved outcomes observed (EFS: HR 2.04, CI 1.18 - 3.53; p=0.01, RR: HR 3.09, CI 1.28 - 7.49; p=0.012). While dose modifications were more frequent for FLT3/ITD+ patients on Arm C versus arms A/B of AAML1031, targeted toxicity rates were otherwise no higher (Table 2). PIA assays demonstrated median trough FLT3 inhibition of 92% (n=29, 95% CI 79-94%), 91% (n=84, 95% CI 87-94%) and 81% (n=70, 95% CI 76-90%) for induction I, induction II and intensification I, respectively. CONCLUSION Addition of sorafenib to Arm C of AAML1031 was safe and resulted in potent FLT3 inhibition, particularly early in therapy. Sorafenib improved rates of induction II CR as well as 3 year EFS and reduced RR from CR compared to historical controls. These data support use of sorafenib in pediatric patients with HAR FLT3/ITD+ AML. Disclosures Fisher: Pfizer: Research Funding; Astellas: Other: Data Safety Monitoring Board Chair for an antifungal study; Merck: Research Funding. Levine:Viracor: Patents &amp; Royalties: biomarker patent; Biogen: Other: non-financial support; Ironwood: Consultancy; Bluebird Bio: Consultancy; National Cancer Institute: Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Kamada: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. OffLabel Disclosure: sorafenib for high allelic ratio FLT3/ITD+ AML

Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study.

Lessons Learned Recruitment of patients with advanced hepatocellular carcinoma and Child‐Pugh B for sorafenib treatment and additional pharmacokinetic studies is challenging.Patients with Child‐Pugh B liver cirrhosis have high rates of cirrhosis‐related adverse events. BackgroundFew data are available on the pharmacokinetics (PK) of sorafenib in patients with advanced hepatocellular carcinoma (HCC) and Child‐Pugh B liver cirrhosis. This study aimed to explore the sorafenib PK and its relationship with efficacy and toxicity in these patients.MethodsPatients with advanced HCC and Child‐Pugh B7‐8 liver function were prospectively recruited at a tertiary center. Adverse events (AEs), progression‐free survival (PFS), and overall survival (OS) were recorded. Patients received a starting dose of 200 b.i.d. with toxicity‐adjusted dose escalation to a target dose of 400 mg b.i.d. with PK sampling at fixed time points.ResultsBetween May 2014 and March 2017, 12 patients were screened, of whom 7 progressed to a terminal stage during the screening (n = 6) or shortly after recruitment (n = 1). The five included patients had median PFS of 3.8 months (range, 1.7–10.8) and OS of 7.4 months (range, 1.7–25.8). Three patients had severe AEs and one patient had a partial response with an OS of 25.8 months. In 2017, the trial was aborted for lack of accrual.ConclusionBecause of low accrual, no conclusion can be drawn on the sorafenib PK in patients with advanced HCC and Child‐Pugh B liver cirrhosis. The poor survival and frequent cirrhosis‐related AEs suggest limited benefit for most of these patients.

Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1.

Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small-molecule multikinase inhibitor sorafenib is associated with large interindividual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter (OCT1; gene SLC22A1) has been proposed as a clinical biomarker of HCC response. Because proof is lacking that OCT1 transports sorafenib, we used a combinatorial approach to define how OCT1 contributes to sorafenib transport. Overexpression of functional OCT1 protein in Xenopus laevis oocytes and mammalian cell lines did not facilitate sorafenib transport. Otherwise, sorafenib considerably accumulated in liver cancer cell lines despite negligible OCT1 mRNA and protein levels. Sorafenib pharmacokinetics was independent of OCT1 genotype in mice. Finally, SLC22A1 mRNA expression was significantly reduced by DNA methylation in The Cancer Genome Atlas HCC cohort. These results clearly demonstrate OCT1-independent cellular sorafenib uptake indicating that OCT1 is apparently not a valid biomarker of sorafenib response in HCC.

Final results of a phase 1 trial of sorafenib, pemetrexed, and cisplatin in patients with advanced solid tumors.

e14582Background: To investigate the tolerability, safety, and pharmacokinetics of sorafenib administered in combination with pemetrexed and cisplatin in advanced solid tumors patients. Methods: Pa...

Fabrication of poly (butadiene-block-ethylene oxide) based amphiphilic polymersomes: An approach for improved oral pharmacokinetics of Sorafenib

Sorafenib (SFN), a hydrophobic anticancer drug, has several limitations predominantly poor aqueous solubility and hepatic first-pass effect, limiting its oral delivery that results into several other complications. Present study aims to develop Sorafenib loaded polymersomes using poly butadiene block poly ethylene oxide (PB-b-PEO), an amphiphilic co-block polymer. Prior to drug loading, critical aggregate concentration (CAC) of polymer was calculated for stable formulation synthesis. The developed SFN loaded PB-b-PEO polymersomes (SFN-PB-b-PEO, test formulation) characterized by DLS and cryo-TEM showed particle size 282 nm, polydispersity (PDI) of less than 0.29 and membrane thickness of about 20 nm. SFN-PB-b-PEO polymersomes demonstrated encapsulation efficiency of 71% and showed sustained drug release up to 144 h. Formulation remained stable for 3 months in suspension form. In vitro cytotoxicity against HepG2 cells showed 1.7 folds improved toxicity compared to SFN suspension. In addition, oral administration of SFN-PB-b-PEO polymersomes in BALB/c mice showed increased Cmax and AUC0–96 by 1.7 and 2.77-fold respectively (p < 0.05) compared to those of SFN suspension (reference formulation). Findings suggest that the SFN-PB-b-PEO polymersomes can be a potential candidate for oral delivery of SFN.

Effect of conventional liver irradiation on the pharmacokinetics of sorafenib through p-glycoprotein: Results of concurrent and sequential strategy.

338 Background: Sorafenib is a multi-kinase inhibitor that demonstrated a significant improved survival of patients with hepatocellular carcinoma (HCC). The efficacy of radiotherapy (RT) concurrent or sequential with sorafenib in unresectable HCC patients has better effects than single agent. However, the mechanism for local RT on sorafenib in the plasma system remains unclear. Here, we evaluate the mechanism of liver irradiation on the pharmacokinetics (PK) of sorafenib using rats as an experimental model. Methods: Free-moving rat model was used in the current study. Image-guided RT with 2 Gy was delivered to the whole liver of Sprague-Dawley rats. The experimental animals were randomized to (A) the sorafenib-only (40 mg/kg, p.o.) group and (B) pre-treated with cyclosporin A [CsA, p-glycoprotein (p-gp) inhibitor, 20mg/kg, i.p. 30 min before RT] group. In each group, the experimental animals were randomized to sham RT (0 Gy with sorafnib), concurrent (after RT 1 hour) and sequential group (after RT 24 hour), respectively. The PK of sorafenib in the plasma system was calculated. Each group’s data was collected from six rats Results: For sorafenib-only group, compared to the sham-irradiated controls, the area under the concentration versus time curve (AUC) of sorafenib was increased by 132% in concurrent group [719 versus (vs.) 1669 min*ug/mL, p = 0.046]. On the contrary, the AUC of sorafenib was decreased by 59% in sequential group (719 vs. 297 min*ug/mL, p = 0.036). Compared to the sorafenib-only group, the AUC of sorafenib in the concurrent group pre-treated with CsA was decreased by 83% (1669 vs. 278 min*ug/mL, p = 0.011). Interestingly, the AUC of sorafenib in the sequential group pre-treated with CsA was increased by 275% (297 vs. 1113 min*ug/mL, p = 0.023). Conclusions: P-pg plays an important role for the PK of sorafenib that was modulated by whole liver irradiation in rodent model. The strategy for modulating the RT-PK phenomenon of sorafenib through p-gp is worth to investigate in the future.

PO-0684: Opposite pharmacokinetics of sorafenib modulates by liver irradiation - concurrent versus sequential

PO-0684: Opposite pharmacokinetics of sorafenib modulates by liver irradiation - concurrent versus sequential

Enterohepatic Circulation Effect in Physiologically Based Pharmacokinetic Models: The Sorafenib Case

Sorafenib was recently approved by both the FDA and EMA for the treatment of unresectable hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and thyroid cancer (DTC). This paper proposes a physiologically based model to describe its pharmacokinetic properties. Special attention is devoted to the enterohepatic circulation, which causes the characteristic double-peak in the drug’s concentration–time curves. This physiologically based pharmacokinetic (PBPK) model has a structure suitable for different mammals. The paper focuses on the anatomy and physiology of mice aiming to develop a physiologically consistent model to produce accurate simulation of sorafenib pharmacokinetics, in agreement with literature data. The in silico description of sorafenib pharmacokinetics allows understanding further its properties, by complementing the experimental data with numerical simulations based on a mechanistic approach. Modeling and simulation is a rapidly growing branch of quantitative systems pharmacology and...

The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism

Context: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb–drug interaction remains unknown.Objective: This study investigates the herb–drug interaction between triptolide and sorafenib.Materials and methods: The effects of triptolide (10 mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100 mg/kg) in rats, and blood samples were collected within 48 h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems.Results: The results showed that the Cmax (low dose: 72.38 ± 8.76 versus 49.15 ± 5.46 ng/mL; medium dose: 178.65 ± 21.05 versus 109.31 ± 14.17 ng/mL; high dose: 332.81 ± 29.38 versus 230.86 ± 9.68 ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t1/2 of sorafenib increased significant (p < 0.05) from 9.02 ± 1.16 to 12.17 ± 2.95 h at low dose with the pretreatment of triptolide. Triptolide has little effect on the absorption of sorafenib in Caco-2 cell transwell model. However, triptolide could significantly decrease the intrinsic clearance rate of sorafenib from 51.7 ± 6.37 to 32.4 ± 4.43 μL/min/mg protein in rat liver microsomes.Discussion and conclusions: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.