Oral lorazepam can be substituted for intravenous midazolam when weaning paediatric intensive care patients off sedation

Aim: Intravenous sedatives used in the paediatric intensive care unit (PICU) need to be tapered after prolonged use to prevent ia

Bioanalytical LC-MS/MS validation of therapeutic drug monitoring assays in oncology

Therapeutic drug monitoring (TDM) has shown to benefit patients treated with drugs of many drug classes, among which is oncology. With an increasing demand for drug monitoring, new assays have to be developed and validated. Guidelines for bioanalytical validation issued by the European Medicines Agency and US Food and Drug Administration are applicable for clinical trials and toxicokinetic studies and demand fully validated bioanalytical methods to yield reliable results. However, for TDM assays a limited validation approach is suggested based on the intended use of these methods. This review presents an overview of publications that describe method validation of assays specifically designed for TDM. In addition to evaluating current practice, we provide recommendations that could serve as a guide for future validations of TDM assays

Efficacy, Tolerance, and Plasma Levels of Abiraterone and Its Main Metabolites in a Patient With Metastatic Castration-resistant Prostate Cancer With a Hepatic Transplant

Clinical Practice Points • Abiraterone acetate, which is metabolized in the liver, is a well-established treatment option for patients with metastatic castration-resistant prostate cancer. The impact of hepatic impairment on exposure to abiraterone was well-studied during registration studies, and abiraterone acetate is contraindicated for patients with severe hepatic impairment. Patients with a liver transplant are prone to impaired liver functions and use medication that may affect drug metabolism. However, no efficacy, tolerance, and pharmacokinetic data have been published on abiraterone treatment in patients who have undergone liver transplants. • In this case report, we established plasma concentrations of abiraterone and its major metabolites, Δ(4)-abiraterone, abiraterone N-oxide sulfate, and abiraterone sulfate, in a patient with metastatic castration-resistant prostate cancer with a hepatic transplant who was treated with abiraterone in a reduced dose of 500 mg daily. • Treatment was effective and well-tolerated, and plasma concentrations were above the suggested trough concentration threshold of 8.4 ng/mL. Moreover, the exposure to immunosuppressive drugs was within expected therapeutic ranges. • From this case, we conclude that abiraterone actetate seems to be a feasible and safe treatment strategy for patients with a hepatic transplant. However, further clinical studies should be performed in order to confirm these findings

LC-MS/MS assay for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in plasma from castrated prostate cancer patients treated with abiraterone acetate or enzalutamide

Prostate cancer is the most common malignancy among men in the Western world. Treatment of this patient population, e.g. by (chemical) castration, is primarily focused on depletion of tumor-stimulating androgens, with testosterone being the major androgenic hormone. After initial therapy, prostate cancer may progress to metastatic castration-resistant prostate cancer. Anti-hormonal drugs abiraterone acetate and enzalutamide are commonly used to treat patients with this disease as both drugs reduce tumor growth and increase time to tumor progression. To evaluate the pharmacodynamic effects of anti-hormonal drugs in this patient population, we developed an LC-MS/MS method for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in human plasma. The validated assay ranges from 10-10,000 pg/mL for testosterone and androstenedione, 100-10,000 pg/mL for dihydrotestosterone, 50-5000 pg/mL for cortisol and 500-50,000 pg/mL for prednisone. Intra-assay and inter-assay variabilities were within ±15% of the nominal concentrations for quality control (QC) samples at low, medium and high concentrations and within ±20% at the lower limit of quantification (LLOQ), respectively. The applicability of the method was demonstrated in plasma from patients with metastatic castrated-resistant prostate cancer using either abiraterone acetate or enzalutamide

LC-MS/MS assay for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in plasma from castrated prostate cancer patients treated with abiraterone acetate or enzalutamide

Prostate cancer is the most common malignancy among men in the Western world. Treatment of this patient population, e.g. by (chemical) castration, is primarily focused on depletion of tumor-stimulating androgens, with testosterone being the major androgenic hormone. After initial therapy, prostate cancer may progress to metastatic castration-resistant prostate cancer. Anti-hormonal drugs abiraterone acetate and enzalutamide are commonly used to treat patients with this disease as both drugs reduce tumor growth and increase time to tumor progression. To evaluate the pharmacodynamic effects of anti-hormonal drugs in this patient population, we developed an LC-MS/MS method for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in human plasma. The validated assay ranges from 10-10,000 pg/mL for testosterone and androstenedione, 100-10,000 pg/mL for dihydrotestosterone, 50-5000 pg/mL for cortisol and 500-50,000 pg/mL for prednisone. Intra-assay and inter-assay variabilities were within ±15% of the nominal concentrations for quality control (QC) samples at low, medium and high concentrations and within ±20% at the lower limit of quantification (LLOQ), respectively. The applicability of the method was demonstrated in plasma from patients with metastatic castrated-resistant prostate cancer using either abiraterone acetate or enzalutamide

Development and Validation of an LC-MS/MS Method for the Simultaneous Quantification of Abiraterone, Enzalutamide, and Their Major Metabolites in Human Plasma

BACKGROUND: Abiraterone acetate and enzalutamide are 2 novel drugs for the treatment of metastatic castration-resistant prostate cancer. The metabolism of these drugs is extensive. Major metabolites are N-desmethyl enzalutamide, enzalutamide carboxylic acid, abiraterone N-oxide sulfate, and abiraterone sulfate; of which N-desmethyl enzalutamide is reported to possess antiandrogen capacities. A liquid chromatography-tandem mass spectrometry method for simultaneous quantification of abiraterone, enzalutamide, and the main metabolites has been developed and validated to support therapeutic drug monitoring. METHODS: Human plasma samples of patients treated with abiraterone or enzalutamide were harvested at the clinic and stored at -20°C. Proteins were precipitated by acetonitrile, and the final extract was injected on a Kinetex C18 column and separated with gradient elution. Analytes were detected by liquid chromatography-mass spectrometry (Triple Quad 6500). RESULTS: The method was validated over various linear ranges: 1-100 ng/mL for abiraterone, 5-500 ng/mL for enzalutamide and enzalutamide carboxylic acid, 10-1000 ng/mL for N-desmethyl enzalutamide, 30-3000 ng/mL for abiraterone N-oxide sulfate, and 100-10,000 ng/mL for abiraterone sulfate. Intra-assay and interassay variabilities were within ±15% of the nominal concentrations for quality control samples at medium and high concentrations and within ±20% at the lower limit of quantification, respectively. CONCLUSIONS: The described method for simultaneous determination of abiraterone and enzalutamide was validated successfully and provides a useful tool for therapeutic drug monitoring in patients treated with these agents

An LC-MS/MS method for quantification of the active abiraterone metabolite Δ(4)-abiraterone (D4A) in human plasma

Δ(4)-Abiraterone (D4A) is a recently discovered active metabolite of the oral anti-androgen drug abiraterone acetate. For quantification of this metabolite in human plasma, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. Human plasma samples of patients treated with abiraterone acetate were prepared by protein precipitation with acetonitrile. The method was validated over a linear range of 0.2-20ng/mL. Intra-assay and inter-assay variabilities were within ±15% of the nominal concentrations for quality control (QC) samples at medium and high concentrations and within ±20% at the lower limit of quantification (LLOQ), respectively. The described method for quantification of D4A was validated successfully and implemented to support therapeutic drug monitoring in patients treated with abiraterone acetate

Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer

STUDY OBJECTIVE: Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC. DESIGN: Retrospective, observational, pharmacokinetic study. SETTING: Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. PATIENTS: Sixty-five patients with mCRPC who were treated with enzalutamide 160 mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥ 50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean ± SD plasma concentrations in the 65 patients were as follows: enzalutamide 11.2 ± 2.8 μg/ml, N-desmethyl enzalutamide 9.9 ± 2.9 μg/ml, and carboxylic acid enzalutamide 6.1 ± 4.3 μg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6 μg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6 μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 μg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity. CONCLUSION: This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice

Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer

STUDY OBJECTIVE: Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC. DESIGN: Retrospective, observational, pharmacokinetic study. SETTING: Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. PATIENTS: Sixty-five patients with mCRPC who were treated with enzalutamide 160 mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥ 50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean ± SD plasma concentrations in the 65 patients were as follows: enzalutamide 11.2 ± 2.8 μg/ml, N-desmethyl enzalutamide 9.9 ± 2.9 μg/ml, and carboxylic acid enzalutamide 6.1 ± 4.3 μg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6 μg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6 μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 μg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity. CONCLUSION: This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice