ABSTRACT
The traditional design of food-effect studies has a high patient burden for toxic drugs with long half-lives (e.g., anticancer agents). Microtracers could be used to assess food-effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food-effect study during steady-state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half-life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food-effect). Power was defined as the fraction of clinical trials where a significant (p < 0.01) food-effect was identified. The proposed study design of 10 patients on steady-state treatment, 10 blood samples collected within 24 h after administration and an assumed food-effect of 40% had a power of 99.9%. The mean estimated food-effect was 39.8% (80% confidence interval: 31.0%-48.6%). The feasibility of microtracer food-effect studies was demonstrated. The design of the microtracer food-effect study allowed estimation of the food-effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half-lives.
Subject(s)
Carbazoles , Piperidines , Humans , Pharmaceutical Preparations , Half-Life , Carbazoles/adverse effects , Carbazoles/pharmacokinetics , Piperidines/adverse effects , Piperidines/pharmacokinetics , Administration, OralABSTRACT
Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-ß-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples. Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-ß-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples.
Subject(s)
Fluorouracil , Prodrugs , Humans , Capecitabine , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid , Chromatography, Liquid , Lithium , beta-AlanineABSTRACT
BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.
Subject(s)
Antineoplastic Agents , Neoplasms , Pregnancy , Child , Female , Humans , Docetaxel/therapeutic use , Epirubicin/pharmacokinetics , Epirubicin/therapeutic use , Models, Biological , Antineoplastic Agents/pharmacokinetics , Paclitaxel/pharmacokinetics , Doxorubicin , Neoplasms/drug therapyABSTRACT
INTRODUCTION: Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib. PATIENTS AND METHODS: An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration-time Curve and trametinib trough concentrations (Cmin), univariable and multivariable exposure-response analyses were performed. RESULTS: In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with Cmin ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib Cmin ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36-0.85, P = 0.007). Median PFS in patients with trametinib Cmin levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with Cmin below this threshold (P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47-1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities. CONCLUSIONS: Overall survival of metastasized melanoma patients with trametinib Cmin levels ≥ 15.6 ng/mL is ten months longer compared to patients with Cmin below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Skin Neoplasms/pathology , Proto-Oncogene Proteins B-raf/genetics , Melanoma/pathology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyridones/pharmacokinetics , Pyrimidinones/pharmacokinetics , Mitogen-Activated Protein Kinase Kinases , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , MutationABSTRACT
BACKGROUND: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems. PATIENTS AND METHODS: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments). RESULTS: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%). CONCLUSIONS: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.
Subject(s)
Drug Monitoring , Medical Oncology , Administration, Oral , Humans , Precision Medicine , Prospective StudiesABSTRACT
Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.
ABSTRACT
A highly sensitive method was developed for the quantification of vinblastine, vincristine, vinorelbine, and its active metabolite 4-O-deacetylvinorelbine in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Deuterated isotopes were used as internal standard and liquid-liquid extraction with tert-butyl methyl ether (TBME) was used for sample pre-treatment. The final extract was injected on a C18 column (50 × 2.1 mm ID, 5 µm). Gradient elution was used in combination with Reversed Phase chromatography to elute the analytes and internal standards from the column in 5 min and the API4000 triple quadrupole MS detector was operating in the positive ion mode. The calibration model, accuracy and precision, selectivity and specificity, dilution integrity, carryover, matrix factor and recovery, and stability were evaluated over a concentration range from 0.025 to 10 ng/mL for vinblastine, vinorelbine, and 4-O-deacetylvinorelbine and from 0.1 to 40 ng/mL for vincristine. The intra- and inter-assay bias and precisions were within ± 12.4% and ≤ 10.6%, respectively. This method was successfully applied to study the pharmacokinetics of vincristine in paediatrics and vinorelbine and 4-O-deacetylvinorelbine using in vivo mouse models.
Subject(s)
Tandem Mass Spectrometry , Vinblastine , Animals , Child , Chromatography, Liquid/methods , Drug Stability , Humans , Mice , Reproducibility of Results , Tandem Mass Spectrometry/methods , Vinblastine/chemistry , Vincristine , VinorelbineABSTRACT
Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells. It has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Studies exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rats, nonhuman primates (NHP), and humans was determined as 23.4%, 29.8%, and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, and human), albumin, and α-1-acid glycoprotein (both human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism-in 10 minutes, 80% of the compound is metabolized in human-with CYP3A4 being the isoform involved in that metabolism. Results also showed NHPs being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHPs (male only), and patients (both genders) demonstrated that the principal route of excretion of 14C-lurbinectedin-related radioactivity was through the feces (88.7% ± 10.1% in patients), with only a minor fraction recovered from the urine (5.6% ± 2.0% in patients). In plasma samples, the majority of lurbinectedin-related radioactivity was attributed to unchanged compound (95% ± 3.1% and 70.2% ± 10.9% in NHPs and humans, respectively). Plasma metabolic profiling demonstrated the major (% compared with unchanged compound) circulating metabolites were N-Desmethyl-lurbinectedin (0.4% ± 0.2% and 10.4% ± 2.2% in NHPs and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9% ± 0.7% and 14.3% ± 10.4% in NHP and patients, respectively). SIGNIFICANCE STATEMENT: Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells, and was recently approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. The present study provides a complete set of information on the pharmacokinetics, biotransformation, and elimination of 14C-lurbinectedin and its metabolites, following a single intravenous administration to nonclinical species (rats and nonhuman primates) and patients.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Animals , Carbolines/pharmacology , Carbolines/therapeutic use , Feces , Female , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Rats , Small Cell Lung Carcinoma/chemically induced , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathologyABSTRACT
BACKGROUND: Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). METHODS: Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30-60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. RESULTS: 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05-16.9 µg) labeled with 92.7 MBq (range 43.4-129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. CONCLUSIONS: To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.
ABSTRACT
Lutetium-177 [177Lu] tetra-azacyclododecanetetra-acetic acid [DOTA]-(Tyr3)-octreotate [TATE] ([177Lu]Lu-DOTA-TATE) is a radiopeptide used for peptide receptor radionuclide therapy in patients with neuroendocrine tumours (NETs). This radiopeptide is made by labelling the ligand octreotate with Lutetium-177 using the linker DOTA. After labelling, and before clinical application quality control of the radiopeptide is needed and the radiochemical purity is assessed. Acceptance limits for radiochemical purity should be within 90-110% of the label claim for radiopharmaceuticals for diagnostic use and within 95-105% of the label claim for radiopharmaceuticals for therapeutic use. Moreover, the amount of unlabelled [177Lu]LuCl3 cannot exceed 2% of the radioactive dose. Since no monograph is available for [177Lu]Lu-DOTA-TATE in the European Pharmacopeia (Ph Eur), this article describes the development and validation of a high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection and radiodetection. A Waters Acquity Arc UHPLC system equipped with a Waters 2998 photodiode array (PDA) detector was used coupled to a Berthold Lb 514 Flowstar detector equipped with a BGO-X gamma measuring cell. A reversed phase Symmetry Shield C18 column (4.6 mm × 250 mm, 5 µm) was used for chromatographic separation. A flow of 1.5 mL/min was maintained during analysis, using 0.1% TFA in water as mobile phase A and 0.1% TFA in ACN as mobile phase B. The retention time was around 1.7 min and 13.5 min for [177Lu]LuCl3 and [177Lu]Lu-HA-DOTA-TATE, respectively. Stock solutions of [177Lu]LuCl3 were made by serial dilution and were injected to test for linearity, accuracy and precision, carry over and signal-to-noise ratio. A [177Lu]Lu-HA-DOTA-TATE sample was prepared and injected to determine the carry over. The results showed that the method is linear over a range of 0.300-130 MBq/mL, which covers the range for clinical samples, provided that the clinical sample is diluted ten times before analysis. The LLOQ can be measured accurately even after dilution, with a signal-to-noise ratio of at least 5. In short, the method is accurate, precise and sensitive and can be implemented as part of the quality control of [177Lu]Lu-HA-DOTA-TATE.
Subject(s)
Chromatography, High Pressure Liquid/methods , Octreotide/analogs & derivatives , Organometallic Compounds , Radiopharmaceuticals , Dosage Forms , Linear Models , Octreotide/analysis , Octreotide/chemistry , Organometallic Compounds/analysis , Organometallic Compounds/chemistry , Radiopharmaceuticals/analysis , Radiopharmaceuticals/chemistry , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
PURPOSE: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib. METHODS: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored. RESULTS: In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation. CONCLUSION: This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Erlotinib Hydrochloride/pharmacology , Female , Gefitinib/administration & dosage , Gefitinib/pharmacology , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Progression-Free Survival , Protein Kinase Inhibitors/pharmacology , Treatment OutcomeABSTRACT
Protein kinases inhibitors or, more generally, signal transduction inhibitors (STIs) can be used to treat diseases in which deregulation of the protein kinase activity plays a role, such as in cancer. A wide variety of drugs has been developed and/or is under investigation to act as protein kinase inhibitors, especially in tyrosine kinase inhibition. The bioanalysis of STIs has received considerable attention in the past 20 years. Liquid chromatography-tandem mass spectrometry (LC-MS-MS) in selected-reaction monitoring (SRM) mode is the method-of-choice in such studies. In several of these studies from us and others, structures are proposed for the product ions applied in SRM. A critical review of these proposed structures is presented using accurate-m/z data, which we have now generated with a linear-ion-trap-Orbitrap hybrid mass spectrometer. This led to adaptation and new structural proposals of 18 product ions for 13 STIs. Our investigation endorses the power of accurate-m/z analysis in structure elucidation of product ions in bioanalytical LC-MS-MS studies and for which the SRM mode in tandem-quadrupole instruments is apparently less suitable.
Subject(s)
Signal Transduction , Tandem Mass Spectrometry , Chromatography, Liquid , Ions , Spectrometry, Mass, Electrospray IonizationABSTRACT
PURPOSE: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). METHODS: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). RESULTS: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) µmol/L before/off treatment to 82 (IQR: 20) µmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C-derived eGFR (p = 0.918). CONCLUSIONS: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C-derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.
Subject(s)
Glomerular Filtration Rate/drug effects , Neoplasms/drug therapy , Phthalazines/adverse effects , Piperazines/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Biomarkers/metabolism , Creatinine/blood , Creatinine/metabolism , Cystatin C/blood , Cystatin C/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Monitoring/methods , Female , Glomerular Filtration Rate/physiology , Humans , Kidney Glomerulus/drug effects , Kidney Glomerulus/physiology , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/physiology , Male , Middle Aged , Neoplasms/blood , Netherlands , Phthalazines/administration & dosage , Piperazines/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Renal Elimination/drug effects , Renal Elimination/physiology , Retrospective StudiesABSTRACT
The aim of this study was to develop and to validate a UPLC-MS/MS method for the quantification of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in mouse plasma and tissue homogenates to support preclinical pharmacokinetic studies. The sample preparation consisted of protein precipitation with cold (2-8 °C) methanol:acetonitrile (1:1, v/v), evaporation of the supernatant to dryness, and reconstitution of the dry-extracts in 4 mM ammonium formate pH 3.5. Separation was achieved on a Waters UPLC HSS T3 column (150 × 2.1 mm, 1.8 µm) maintained at 50 °C and using gradient elution with a total runtime of 6.7 min. Mobile phase A consisted of 4 mM ammonium formate pH 3.5 and mobile phase B of 0.1% formic acid in methanol:acetonitrile (1:1, v/v). Detection was carried out by tandem mass spectrometry with electrospray ionization in the positive ion mode. The method was validated within a linear range of 1-2,000 ng/mL, 10-20,000 ng/mL, and 0.5-200 ng/mL for morphine, morphine-3-glucuronide, and morphine-6-glucuronide, respectively. In human plasma, the intra- and inter-run precision of all analytes, including the lower limit of quantification levels, were ≤ 15.8%, and the accuracies were between 88.1 and 111.9%. It has been shown that calibration standards prepared in control human plasma can be used for the quantification of the analytes in mouse plasma and tissue homogenates. The applicability of the method was successfully demonstrated in a preclinical pharmacokinetic study in mice.
Subject(s)
Chromatography, High Pressure Liquid/methods , Morphine Derivatives/blood , Tandem Mass Spectrometry/methods , Animals , Linear Models , Mice , Morphine Derivatives/analysis , Morphine Derivatives/chemistry , Morphine Derivatives/pharmacokinetics , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
In the original publication of the article, the second author name has been misspelled.
ABSTRACT
Here we describe the development and validation of an LC-MS/MS method for the quantification of imatinib and imatinib-d8 in plasma for the support of a clinical absolute bioavailability microdosing trial. The focus lies on the technical aspects to analyse high concentrations of imatinib and low concentrations of imatinib-d8 that are present simultaneously in study samples, using a single sample processing and analytical method. With the validated assay, imatinib and imatinib-d8 can be quantified simultaneously in ranges from 25.0 - 5,000 ng/mL and 0.01 - 2.0 ng/mL, respectively. The method was successfully applied in an imatinib-d8 absolute bioavailability microdosing trial, where a 100 µg imatinib-d8 microdose was intravenously administered to a patient on oral imatinib treatment 400 mg once daily.
Subject(s)
Imatinib Mesylate/blood , Imatinib Mesylate/pharmacokinetics , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Biological Availability , Chromatography, High Pressure Liquid , Humans , Imatinib Mesylate/administration & dosage , Limit of Detection , Mass Spectrometry , Protein Kinase Inhibitors/administration & dosage , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
An liquid chromatography-mass spectrometry (LC-MS/MS) assay was developed for the combined analysis of the five poly (ADP-ribose) polymerase (PARP) inhibitors niraparib, olaparib, rucaparib talazoparib and veliparib. A simple and fast sample pre-treatment method was used by protein precipitating of plasma samples with acetonitrile and dilution of the supernatant with formic acid (0.1% v/v in water). This was followed by chromatographic separation on a reversed-phase UPLC BEH C18 column and detection with a triple quadrupole mass spectrometer operating in the positive mode. A simplified validation procedure specifically designed for bioanalytical methods for clinical therapeutic drug monitoring (TDM) purposes, was applied. This included assessment of the calibration model, accuracy and precision, lower limit of quantification (LLOQ), specificity and selectivity, carry-over and stability. The validated range was 30-3000 ng/mL for niraparib, 100-10,000 ng/mL for olaparib, 50-5000 ng/mL for rucaparib, 0.5-50 ng/mL for talazoparib and 50-5000 for veliparib. All results were within the criteria of the US Food and Drug Administration (FDA) guidance and European Medicines Agency (EMA) guidelines on method validation. The assay has been successfully implemented in our laboratory.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drug Monitoring/methods , Poly(ADP-ribose) Polymerase Inhibitors/blood , Tandem Mass Spectrometry/methods , Benzimidazoles/blood , Chromatography, Reverse-Phase/methods , Heterocyclic Compounds, 1-Ring/blood , Humans , Indoles/blood , Limit of Detection , Linear Models , Reproducibility of ResultsABSTRACT
Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the pharmacokinetics of gemcitabine at a therapeutic dose could be predicted from the pharmacokinetics of a microdose. In this prospective, open-label microdosing study, a gemcitabine microdose (100 µg) was given intravenously to participants on day 1, followed by a therapeutic dose (1250 mg/m2 ) on day 2. Gemcitabine and its metabolite 2',2'-difluorodeoxyuracil (dFdU) were quantified in plasma and intracellularly by using liquid chromatography-mass spectrometry). Noncompartmental pharmacokinetic analysis was performed. Ten patients participated in this study. The mean area under the plasma concentration-time curve (AUC0-8 ) of gemcitabine after microdosing was 0.00074 h·mg/L and after therapeutic dosing was 16 h·mg/L. The mean AUC0-8 of dFdU following the microdose and therapeutic dose were 0.022 h·mg/L and 169 h·mg/L, respectively. Exposure to gemcitabine after the therapeutic dose was within 2-fold of the exposure following a microdose, when linearly extrapolated to 1250 mg/m2 . However, the shape of the concentration-time curve was different, as reflected by poor scalability in volume of distribution (939 L versus 222 L). Furthermore, intracellularly phosphorylated gemcitabine and phosphorylated dFdU levels could not be predicted from the microdose. The AUC0-8 of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg/m2 . Volume of distribution, elimination rate constant, and intracellular pharmacokinetics of the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case.
Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Chromatography, Liquid/methods , Deoxycytidine/analogs & derivatives , Dose-Response Relationship, Drug , Mass Spectrometry/instrumentation , Administration, Intravenous , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/therapeutic use , Area Under Curve , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/administration & dosage , Deoxycytidine/blood , Deoxycytidine/pharmacokinetics , Deoxycytidine/therapeutic use , Female , Humans , Male , Mesothelioma/drug therapy , Middle Aged , Pilot Projects , Predictive Value of Tests , Prospective Studies , Thymoma/drug therapy , GemcitabineABSTRACT
INTRODUCTION: The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia. METHODS: Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m2 twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model. RESULTS: The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664-0.728) after administration. CONCLUSION: The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib.
Subject(s)
Bortezomib/pharmacokinetics , Erythrocytes/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Proteasome Inhibitors/pharmacokinetics , Administration, Intravenous , Adolescent , Bortezomib/administration & dosage , Bortezomib/blood , Bortezomib/therapeutic use , Child , Child, Preschool , Dose-Response Relationship, Drug , Erythrocytes/metabolism , Feasibility Studies , Female , Humans , Infant , Male , Models, Biological , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/blood , Proteasome Inhibitors/therapeutic use , RecurrenceABSTRACT
BACKGROUND: Abiraterone acetate is an oral 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCPRC) patients. Previously, a prospective observational trial demonstrated a relationship between abiraterone trough concentrations (Cmin) in plasma and treatment efficacy. The aim of our study was to investigate the exposure-response relationship of abiraterone and its metabolites, and to study if the proposed target for abiraterone of 8.4 ng/mL is feasible in a "real-world" patient cohort. PATIENTS AND METHODS: mCRPC patients who had at least one abiraterone plasma concentration at steady-state were included in this study. Plasma abiraterone and its metabolites levels were analyzed using a validated liquid chromatography-mass spectrometry method. Using calculated Cmin values of abiraterone and its active metabolite Δ(4)-abiraterone (D4A), univariate, and multivariable Cox regression analyses were performed. RESULTS: Sixty-two patients were included in this retrospective analysis, of which 42% were underexposed (mean abiraterone Cmin ≤ 8.4 ng/mL). In multivariable analysis, Cmin ≥ 8.4 ng/mL was associated with longer prostate-specific antigen (PSA) independent progression-free survival (16.9 vs 6.1 months; p = 0.033), which resulted in a hazard ratio of 0.44 (95% confidence interval: 0.23-0.82, p = 0.01). D4A Cmin did not show a relationship with treatment efficacy. CONCLUSION: Our study shows that mCRPC patients with an abiraterone Cmin ≥ 8.4 ng/mL have a better prognosis compared with patients with low Cmin. Monitoring Cmin of abiraterone can help to identify those patients at risk of suboptimal treatment for whom treatment optimization may be appropriate.