Therapeutic Drug Monitoring in Oncohematological Patients: A Fast and Accurate HPLC-UV Method for the Quantification of Nilotinib in Human Plasma and Its Clinical Application.

Nilotinib, a second-generation tyrosine kinase inhibitor, has demonstrated clinical activity in chronic myeloid leukemia. As an exposure-response relationship has been observed for nilotinib, its therapeutic drug monitoring could be a valuable tool in clinical practice. Therefore, the aim of this study was to develop and validate a selective and precise high performance liquid chromatography-ultraviolet method for the measurement of nilotinib in plasma from patients with cancer. After protein precipitation extraction with acetonitrile, nilotinib and rilpivirine were separated using isocratic elution on a Tracer Excel 120 ODS C18 column using a mobile phase consisting of a mixture of potassium dihydrogen phosphate-buffered solution (pH 5.5; 0.037 M)-methanol-acetonitrile (45:45:10, v/v/v), pumped at a flow rate of 1.7 mL·min-1. A wavelength of 254 nm was selected for the quantification of the analyte and the internal standard (IS). The technique was validated following the guidelines for the validation of analytical methods of regulatory agencies (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)). Linearity was established in a concentration range between 125 and 7000 ng/mL. The detection limit was 90 ng/mL, and the lower limit of quantification was 125 ng/mL. For all concentrations in the calibration curve, the intraday and interday coefficients of variation were less than 4.1%. Median recovery of nilotinib from plasma was ≥65.1% (±21.4%). The method described is sensitive, selective, reproducible, and rapid, and can be used for the accurate determination of nilotinib in human plasma for pharmacokinetics studies and for therapeutic drug monitoring (TDM) of nilotinib in routine clinical practice.

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study.

INTRODUCTION: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. OBJECTIVE: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. MATERIALS AND METHODS: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. RESULTS: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure-efficacy analysis. CONCLUSIONS: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

Psycho-Oncological Intervention Through Counseling in Patients With Differentiated Thyroid Cancer in Treatment With Radioiodine (COUNTHY, NCT05054634): A Non-randomized Controlled Study.

Background: Diagnosis and treatment of differentiated thyroid carcinomas (DTC) cause anxiety and depression. Additionally, these patients suffer hormonal alterations that are associated with psychological symptoms (e.g., changes in mood, emotional instability, and memory loss). This study aims to evaluate the effectiveness of a psycho-oncological intervention based on counseling to reduce anxiety and depression related to the treatment in patients with DTC. Methods: A non-randomized controlled study, with two groups [experimental group (EG), n = 37, and control group (CG), n = 38] and baseline and posttreatment measures, was designed. Patients in the EG received a psycho-oncological intervention based on counseling in addition to the standard treatment. The independent variable was the assigned group and the dependent one was the evolution of anxiety and depression, which were analyzed separately, and both were evaluated using the Hospital Anxiety and Depression Scale. Other relevant covariables related to the quality of life (QoL) were also analyzed using Short Form-36 Health Survey and Psychological General Wellbeing Index scales. Results: The difference of the posttreatment-baseline variation showed a statistically significant reduction in anxiety and depression in the EG in relation to the CG (p < 0.001). The mean of the Psychological General Wellbeing Index scales score increased significantly in the EG (p < 0.001) and decreased significantly in the CG (p < 0.001). All the baseline and the posttreatment scores of the variables evaluated showed a statistically significant improvement in the EG vs. the CG. Conclusion: This study demonstrates significant benefits of psycho-oncological intervention based on counseling in anxiety, depression, QoL, and wellbeing of the patient with differentiated thyroid carcinomas.

Therapeutic Drug Monitoring of Erlotinib in Non-Small Cell Lung Carcinoma: A Case Study.

ABSTRACT: We describe a clinical case of an 84-year-old man diagnosed with non-small cell lung carcinoma and epidermal growth factor receptor mutation, who was treated with erlotinib, with doses adjusted by therapeutic drug monitoring. This case involved a clearance fluctuation leading to over-therapeutic drug concentrations of erlotinib and toxicity. The intrapatient and interpatient variability of erlotinib, in addition to other factors such as age or variations in liver clearance, create situations that are challenging in clinical practice. During treatment, erlotinib serum concentrations were measured, and the dose was accordingly adjusted. The erlotinib dose required to reduce toxicity (rash grade III) and maintain effective plasma concentrations, as well as clinical and radiological responses, was 50% of the initial dose, underscoring the relevance of therapeutic drug monitoring for tyrosine kinase inhibitors in routine clinical practice.

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin.

The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N = 18) or CRS and HIO (N = 62) were used to estimate the baseline platelet count (PLT0), rate constants for platelet maturation (k tr ) and platelet random destruction (k s ), feedback on progenitor cell proliferation (γ), and the drug-specific model parameters (α, ß). Plasma oxaliplatin concentrations, C p , reduced the proliferation rate of progenitor cells (k prol) according to a power function α × C p (ß) . The surgery effect on k prol and k s was explored. The typical values (between subject variability) of the PLT0, k tr , k s , γ, α, and ß were estimated to be 237 × 10(9) cells/L (32.9%), 7.09 × 10(-3) h(-1) (47.1%), 8.86 × 10(-3) h(-1) (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k prol that was attenuated with a half-life of 8.42 days. Splenectomy decreased k s by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity.

Development and validation of an HPLC-UV method for pazopanib quantification in human plasma and application to patients with cancer in routine clinical practice.

BACKGROUND: Pazopanib, a new oral angiogenesis inhibitor, has demonstrated clinical activity against multiple solid tumors and was approved for the treatment of patients with advanced renal cell carcinoma. As an exposure-response relationship has been observed for pazopanib, its therapeutic drug monitoring could be a valuable tool in clinical practice. Therefore, the aim of this study was to develop and validate a selective and precise high performance liquid chromatography-ultraviolet method for the measurement of pazopanib in plasma from patients with cancer. METHODS: After liquid-liquid extraction with diethyl ether, pazopanib and gefitinib (internal standard) were separated using isocratic elution on an Ultrabase C18 column using a mobile phase consisting of a mixture in vol/vol proportion of 47:53 of ammonium acetate (pH, 7; 0.02 mol/L) and acetonitrile/methanol (70:30, vol/vol) pumped at a constant flow rate of 1 mL/min. Quantification was performed at 260 nm. Method validation was undertaken as per the guidelines for Bioanalytical Method Validation published by the Food and Drug Administration and European Medicines Agency. RESULTS: Calibration curves were linear over the range 0.5-100 mcg/mL. Interday and intraday coefficients of variations were less than 4.5%. The limit of detection and the lower limit of quantification were 0.2 and 0.5 mcg/mL, respectively. Recovery of pazopanib from plasma was >80%. CONCLUSIONS: This is the first high performance liquid chromatography-ultraviolet method for pazopanib quantification that has been validated within a wide range of plasma concentrations and is a suitable method for therapeutic drug monitoring of pazopanib.

Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients.

PURPOSE: To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters. METHODS: Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model (NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap. RESULTS: An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (V a) exponentially decreased due to the carrier solute absorption. The reduction in V a was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h(-1) for icodextrin 4 % and from 0.86 to 1.09 h(-1) for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution. CONCLUSIONS: Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min.

Development and validation of an HPLC-UV method for sorafenib quantification in human plasma and application to patients with cancer in routine clinical practice.

BACKGROUND: Several factors such as low therapeutic index, large interindividual variability in systemic exposure, and the relationships between exposure and toxicity for sorafenib could justify its therapeutic drug monitoring (TDM). To support TDM, a selective and precise high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method was developed and validated for the determination of sorafenib in human plasma. METHODS: After protein precipitation with acetonitrile, sorafenib and lapatinib (internal standard) were separated using isocratic elution on a Kromasil C18 column using a mobile phase of acetonitrile and 20 mmol/L ammonium acetate in a proportion 53:47 (vol/vol) pumped at a constant flow rate of 1.2 mL/min. Quantification was performed at 260 nm. Validation experiments were carried out after the guidelines for Bioanalytical Method Validation published by the Food and Drug Administration and the European Medicines Agency. RESULTS: Calibration curves were linear over the range 0.1-20 mcg/mL. Inter- and intra-day coefficients of variation were <3%. The limit of detection and the lower limit of quantification were 0.06 and 0.1 mcg/mL, respectively. Recoveries of sorafenib from plasma were >99% in all cases. CONCLUSIONS: This method was successfully applied to the determination of the drug in the plasma of 2 patients with cancer receiving sorafenib 200 and 400 mg orally twice daily, respectively, and could be useful for TDM of sorafenib in routine clinical practice.

Development and validation of a high-performance liquid chromatography ultraviolet method for lapatinib quantification in human plasma.

A selective and precise high-performance liquid chromatography ultraviolet method was developed and validated for the determination of lapatinib in human plasma. After protein precipitation with acetonitrile, lapatinib and sorafenib were separated using isocratic elution (on a C18 Ultrabase column using a mobile phase of acetonitrile/20 mM ammonium acetate in a proportion 53:47 (v/v) pumped at a constant flow rate of 1.2 mL/min). Quantification was performed at 260 nm. Calibration curves were linear over the range 0.2-10 µg/mL. Inter- and intraday coefficients of variation were less than 7%. The limit of detection and the lower limit of quantification were 0.1 and 0.2 µg/mL, respectively. Recoveries of lapatinib from plasma were higher than 86.7% in all cases. The assay was applied to the determination of the drug in the plasma of 2 cancer patients receiving lapatinib, 1000 and 1250 mg orally, and could be useful for therapeutic drug monitoring of lapatinib in routine clinical practice.

Neutrophil dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery and hyperthermic intraperitoneal oxaliplatin.

BACKGROUND AND OBJECTIVE: Peritoneal carcinomatosis is an abdominal metastatic manifestation of a life-threatening tumour progression requiring standard palliative surgery and/or chemotherapy treatment. The aim of this study was to characterize the immediate neutrophilia response induced by cytoreductive surgery (CRS) and the myelosuppression effect of hyperthermic intraperitoneal oxaliplatin (HIO) in peritoneal carcinomatosis patients. METHODS: Absolute neutrophil counts (ANCs) from 45 patients treated with CRS and HIO diluted in isotonic 4 % icodextrin (cohort A), 21 patients undergoing CRS followed by HIO diluted in isotonic 5 % dextrose (cohort B) and 18 patients treated with CRS without HIO (cohort C) were used to estimate the system-related parameters [baseline ANC (Circ0), mean transit time (MTT) and feedback on proliferation (γ)] and drug-specific (α) parameters of a modified Friberg's model that accounts for the surgical stress-induced neutrophilia. The plasma oxaliplatin concentrations, C(p), were assumed to reduce the proliferation rate of the progenitor cells according to the function α × C(p). Model evaluation and simulations were undertaken to evaluate the effect of the dose, treatment duration and carrier solution on the incidence of severe neutropenia. RESULTS: The typical values [between-subject variability, expressed in coefficient of variation values (%)] of the Circ0, MTT, γ and α were estimated to be 3.58 × 109 cells/L (41.2 %), 144 h (70.9 %), 0.155 and 0.066 L/mg (134.9 %), respectively. Surgical stress induced a maximal 3.37-fold increase in the proliferation rate that was attenuated with a half-life of 10 days, and a maximal 68 % reduction in the MTT that was attenuated with a half-life of 28 days. Age, body surface area, sex, total proteins and carrier solution did not impact the model parameters. The model evaluation evidenced an accurate prediction of the incidence of neutropenia grade ≥2 and/or ≥3. Simulations indicated that (i) the neutropenia was reversible and short-lasting; and (ii) the HIO dose and treatment duration were the main determinants of the severity and duration of neutropenia. CONCLUSION: The time course of neutropenia was well characterized by the model that was developed, which simultaneously accounts for the acute-immediate neutrophilia response induced by CRS and the HIO myelosuppressive effect produced in the bone marrow. This model suggests that higher doses than those evaluated to date could be used in peritoneal carcinomatosis patients without substantially increasing the risk of severe neutropenia.

Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery.

PURPOSE: To characterize the hyperthermic intraperitoneal oxaliplatin (HIO) pharmacokinetics in peritoneum and plasma in patients with peritoneal carcinomatosis (PC) after cytoreductive surgery (CRS). METHODS: Data from 36 patients receiving HIO diluted in isotonic 4% icodextrin were combined with data from 13 patients receiving HIO diluted in isotonic 5% dextrose. Total oxaliplatin in peritoneal and plasma fluids were used to characterize an open two-compartment disposition model with linear distribution and elimination and first-order absorption from peritoneum to plasma using NONMEM software. The effect of patient- and treatment-related covariates on oxaliplatin pharmacokinetic parameters was explored. RESULTS: The typical value (interindividual variability, %) in k(a), CL, and V(ss) were 0.57 h(-1) (43%), 1.71 L h(-1) (39%), and 77 L (65%), respectively. No significant effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic parameters was found. A 12-15% reduction in peritoneal volume of distribution was observed in patients receiving HIO diluted in 5% dextrose relative to those patients receiving HIO diluted in 4% icodextrin. CONCLUSIONS: The integration of peritoneal and plasma data demonstrated oxaliplatin linear absorption from peritoneum to plasma, non-specific distribution to a peripheral compartment, and linear elimination from the central compartment when HIO was administered with isotonic carrier solutions to PC patients who underwent CRS. Only the effect of the carrier solution had an impact in the peritoneal volume of distribution, but its clinical relevance seems to be limited, especially for short HIO infusions (<60 min).

Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatin-induced neutropenia in subjects with peritoneal carcinomatosis.

The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m(2) of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.