A retrospective analysis of haematological side effects of olaparib in excess-weight and normal BMI patients with ovarian cancer.

Background: Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved in Europe for the treatment of platinum-sensitive patients with newly diagnosed or recurrent platinum-sensitive ovarian cancer with a confirmed BRCA mutation or homologous recombination deficiency (HRD). Epidemiological studies have shown an incompatible association between ovarian cancer and obesity, but there have also been scientific reports indicating that obesity, especially severe obesity, increases the risk of ovarian cancer. Olaparib has a wide range of side effects, especially anaemia and neutropenia, which may lead to dose reduction or therapy discontinuation. Therefore, therapeutic drug monitoring (TDM) is recommended. The aim of the study was a retrospective analysis of threshold value of the trough concentration of olaparib (Ctrough) and haematological adverse reactions after olaparib treatment (300 mg/12 h) in excess-weight and normal body mass index (BMI) patients with ovarian cancer. Materials and methods: The pilot study was conducted on 38 ovarian cancer patients who were divided into two groups: I - normal BMI patients (BMI = 18.5-24.9 kg/m2; n = 14), II - excess-weight patients, i.e. overweight and obese patients (BMI ≥ 25 kg/m2; n = 24). The severity of neutropenia and anaemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The values of the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), and red blood cell distribution width (RDW) parameters were also taken into account. HPLC-UV method (λ = 254 nm) was applied to measure olaparib plasma concentrations. Results: There were no statistically significant differences in olaparib Ctrough between the groups - 1602.86 vs. 1567.40 ng/mL (p = 0.9156). However, the overweight and obese patients had slightly higher dose/kg-adjusted olaparib Ctrough - 204.17 vs. 159.32 ng/mL/mg/kg. The incidence of grade 1 anaemia in the groups was as follows: I - 42.86%, II - 41.67%. Grade 2 and 3 anaemia was observed only in group II - 4.17% and 8.33%, respectively. The incidence of neutropenia in the groups of patients was as follows: grade 1: group I - 21.43%, group II - 20.83%; grade 2: group I - 7.14%, group II - 4.17%. Conclusions: The incidence of haematological adverse reactions to olaparib, such as neutropenia and grade 1 anaemia in the group of overweight and obese patients was the same as in the normal BMI group. The overweight and obese patients were characterised by higher severity of haematological adverse reactions to olaparib and slightly higher dose/kg-adjusted olaparib Ctrough. After one month of treatment with olaparib the overweight and obese patients had significantly lower red blood cells (RBC) and haemoglobin (Hgb) levels than the patients with normal BMI, which may indicate that anaemia develops faster in this group of patients.

Bidirectional pharmacokinetic drug interactions between olaparib and metformin.

OBJECTIVE: Olaparib is a PARP (poly-ADP-ribose polymerase) inhibitor used for maintenance therapy in BRCA-mutated cancers. Metformin is a first-choice drug used in the treatment of type 2 diabetes. Both drugs are commonly co-administered to oncologic patients with add-on type 2 diabetes mellitus. Olaparib is metabolized by the CYP3A4 enzyme, which may be inhibited by metformin through the Pregnane X Receptor. In vitro studies have shown that olaparib inhibits the following metformin transporters: OCT1, MATE1, and MATE2K. The aim of the study was to assess the influence of 'the perpetrator drug' on the pharmacokinetic (PK) parameters of 'the victim drug' after a single dose. To evaluate the effect, the AUC0→∞ (area under the curve) ratio was determined (the ratio between AUC0→∞ in the presence of the perpetrator and AUC0→∞ without the presence of the perpetrator). METHODS: Male Wistar rats were assigned to three groups (eight animals in each group), which were orally administered: metformin and olaparib (IMET+OLA), vehiculum with metformin (IIMET), and vehiculum with olaparib (IIIOLA). Blood samples were collected after 24 h. HPLC was applied to measure the concentrations of olaparib and metformin. The PK parameters were calculated in a non-compartmental model. RESULTS: Metformin did not affect the olaparib PK parameters. The AUC0→∞ IMET+OLA/IIIOLA ratio was 0.99. Olaparib significantly increased the metformin Cmax (by 177.8%), AUC0→t (by 159.8%), and AUC0→∞ (by 74.1%). The AUC0→∞ IMET+OLA/IIMET ratio was 1.74. CONCLUSIONS: A single dose of metformin did not affect the PK parameters of olaparib, nor did it inhibit the olaparib metabolism, but olaparib significantly changed the metformin pharmacokinetics, which may be of clinical importance.

Metformin in selected malignancies in women.

The results of preclinical, epidemiological and clinical studies have shown that metformin, the main drug used in the treatment of type 2 diabetes, has antitumor activity. Metformin reduces the incidence of malignant neoplasms in various locations, including gynaecological tumours. It lowers morbidity, has a positive effect on the course of the disease and reduces mortality. The mechanism of the antitumor action of metformin is pleiotropic and involves several signalling pathways, including AMPK/mTOR (mitogen activated protein kinase/mammalian target rapamycin), STAT3 (signal transducer and activator of transcription) and numerous factors: NF-KB (nuclear factor kappa), HIF-1 alpha (hypoxia inducible factor 1), IGF-1 (insulin-like growth factor-1), which affect cell proliferation and apoptosis. In addition, metformin eliminates CSCs (cancer stem cells) that are associated with cancer progression, metastasis and resistance to treatment. The effect of metformin in breast and endometrial cancer is favourable in the vast majority of studies. The results of studies on ovarian and cervical cancer promote metformin as a candidate in the combination treatment of these cancers. More results from meta-analyzes and clinical trials are awaited. It is clearly recognized that metformin as an antidiabetic in women with type 2 diabetes has an advantage over other antidiabetics due to its anticancer activity.

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats.

A combination of the tyrosine kinase inhibitor-sorafenib-and the opioid analgesic-morphine-can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug-drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC0-t, and AUC0-∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0-t of its active metabolite-sorafenib N-oxide-was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0-t, and AUC0-∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood-Brain Barrier in Rats.

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.

The oxidation and hypoglycaemic effect of sorafenib in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetes reduces the activity of CYP3A4 and may increase the exposure for the drugs metabolized by the isoenzyme. Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI), used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. The TKI undergoes CYP3A4-dependent oxidative transformation, which may be influenced by hyperglycaemia. The aim of the study was to compare the oxidation for sorafenib between healthy and streptozotocin-induced diabetic rats. Additionally, the effect of sorafenib on glucose levels was investigated. METHODS: The rats were assigned to the groups: streptozotocin-induced diabetic (DG, n = 8) or healthy (HG, n = 8). The rats received sorafenib orally as a single dose of 100 mg/kg. The plasma concentrations of sorafenib and its metabolite N-oxide were measured with the validated high-performance liquid chromatography with ultraviolet detection. RESULTS: The difference between groups in Cmax and AUC0-t values for sorafenib were significant (p = 0.0004, p = 0.0104), and similarly for the metabolite (p = 0.0008, p = 0.0011). Greater exposure for the parent drug and analysed metabolite was achieved in diabetic group. However, the Cmax, AUC0-t, and AUC0-∞ ratios between the metabolite and sorafenib were similar in both groups. The significant reduction of glycaemia was observed only in the diabetic animals. CONCLUSION: The findings of the study provide evidence that diabetes significantly influence on the exposition for sorafenib and its metabolite, but similar ratios N-oxide/sorafenib for AUC and Cmax in healthy and diabetic animals suggest that oxidation of the TKI is rather unchanged. Additionally, sorafenib-associated hypoglycaemia was confirmed in diabetic animals.

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.

In vivo assessment of the drug interaction between sorafenib and paracetamol in rats.

PURPOSE: Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. Neoplastic diseases are the cause of pain, which may occur regardless of the stage of the disease. Paracetamol is a non-opioid analgesic used alone or in combination with opioids for the treatment of cancer pain. Numerous studies have pointed out changes in the pharmacokinetic parameters of TKIs when co-administered with paracetamol. The aim of the study was to assess drug-drug interactions (DDIs) between sorafenib and paracetamol. METHODS: Rats were divided into three groups, each consisting of eight animals. The first group received sorafenib (IIS), the second group received sorafenib + paracetamol (IS+PA), whereas the third group received only paracetamol (IIIPA). A single dose of sorafenib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. The plasma concentrations of sorafenib and its metabolite-N-oxide as well as paracetamol and its glucuronide and sulphate metabolites were measured using validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. RESULTS: The co-administration of sorafenib and paracetamol increased the maximum concentration (Cmax) of paracetamol by 33% (p = 0.0372). In the IS+ PA group the Cmax of paracetamol glucuronide was reduced by 48% (p = < 0.0001), whereas the Cmax of paracetamol sulphate was higher by 153% (p = 0.0012) than in the IIIPA group. Paracetamol increased sorafenib and sorafenib N-oxide Cmax by 60% (p = 0.0068) and 83% (p = 0.0023), respectively. CONCLUSIONS: A greater knowledge of DDI between sorafenib and paracetamol may help adjust dose properly and avoid toxicity effects in individual patients.

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats.

The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib-metformin and sorafenib-atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2-hydroxy atorvastatin (p = 0.0239) and 4-hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.

Significance of BRCA1 expression in breast and ovarian cancer patients with brain metastasis - A multicentre study.

PURPOSE: Cerebral metastases develop in 10-30% of patients with breast cancer (BC) and in around 3.3 to 4% of patients with ovarian cancer (OC). The aim of the multicenter study is to investigate the correlation between the expression of estrogen alpha receptors (ERα), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), breast cancer metastasis suppressor 1 (BRMS1), astrocyte elevated gene 1 (AEG1), depending on the status of BRCA1 protein, in patients suffering from OC and BC with brain metastases. PATIENTS AND METHODS: The analysis included 51 patients: 29 with BC and 22 with OC, in whom brain metastases were disclosed. RESULTS: In most patients (65.5% of BC patients and 68.2% of patients with OC tumors) BRCA1 protein loss was found. No correlation was disclosed between the levels of ERα, PR receptors, HER2, SDF1, CXCR4, AEG1, BRMS1 and BRCA1 status, patient age, stage of disease advancement, grade of histological maturity of the cells, presence of metastases to lymph nodes. A statistically significant correlation was disclosed between the negative expression of PR receptors and a high expression of CXCR4 in patients with BC. High values of the AEG1 protein (linked to metastases) were detected alongside a high expression of BRMS1 (a suppressor of metastases). CONCLUSIONS: Patients with BC and OC and brain metastases have a frequent loss of BRCA1 expression. The role of ERα, PR, HER2, SDF1, CXCR4, AEG1, BRMS1 in metastatic process needs further studies.