BACKGROUND: Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients. METHODS: In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. RESULTS: Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1-21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency. CONCLUSIONS: Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014-000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).
- MeSH
- Benzimidazoles * administration & dosage adverse effects pharmacokinetics MeSH
- Adult MeSH
- Protein Kinase Inhibitors administration & dosage adverse effects MeSH
- Colorectal Neoplasms * drug therapy genetics pathology MeSH
- Crizotinib * administration & dosage adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- MAP Kinase Kinase 1 antagonists & inhibitors MeSH
- MAP Kinase Kinase 2 antagonists & inhibitors MeSH
- Maximum Tolerated Dose MeSH
- Mutation MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects pharmacokinetics administration & dosage MeSH
- Proto-Oncogene Proteins c-met antagonists & inhibitors genetics MeSH
- ras Proteins genetics MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
AIMS: Despite receiving guideline-directed medical heart failure (HF) therapy, patients with pulmonary hypertension associated with left heart disease (PH-LHD) experience higher mortality and hospitalization rates than the general HF population. AZD3427 is a functionally selective, long-acting mimetic of relaxin, a hormone that has the potential to induce vasodilation and prevent fibrosis. In a phase 1b study conducted in patients with HF, AZD3427 demonstrated a favourable safety and pharmacokinetic profile. To address the unmet medical need in patients with PH-LHD in the context of HF, AZD3427 is currently under development as a potential treatment option. METHODS AND RESULTS: The Re-PHIRE study is a phase 2b, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study to evaluate the effect of AZD3427 on a broad range of PH-LHD phenotypes. In total, 220 patients will be randomized to four treatment groups to receive a subcutaneous injection of AZD3427 or placebo every 2 weeks for 24 weeks. The primary endpoint of the study is the change in pulmonary vascular resistance in patients treated with AZD3427 versus placebo after 24 weeks of treatment. Key secondary endpoints include changes in mean pulmonary arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance, 6-min walking distance, N-terminal pro B-type natriuretic peptide levels, echocardiographic parameters, and health-related quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire). CONCLUSIONS: Re-PHIRE is the first study of a relaxin mimetic in patients with PH-LHD. The insights gained from the Re-PHIRE study are expected to inform the further development of AZD3427 in the PH-LHD population, including identifying the most suitable pulmonary hypertension and HF phenotypes for treatment.
- MeSH
- Vascular Resistance drug effects MeSH
- Double-Blind Method MeSH
- Clinical Trials, Phase II as Topic MeSH
- Middle Aged MeSH
- Humans MeSH
- Multicenter Studies as Topic MeSH
- Hypertension, Pulmonary * drug therapy physiopathology etiology MeSH
- Randomized Controlled Trials as Topic MeSH
- Relaxin * analogs & derivatives MeSH
- Aged MeSH
- Heart Failure * complications physiopathology drug therapy MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial Protocol MeSH
AIM: The aim of this study was to evaluate adherence to spironolactone in a group of unselected patients with arterial hypertension by analysis of measured serum spironolactone and canrenone concentrations according to a proposed two-step decision scheme based on pharmacokinetic considerations. MATERIALS AND METHODS: Simulation of serum concentration-time profiles of spironolactone and canrenone based on population pharmacokinetic parameters described in literature and a body weight-normalized spironolactone dose / canrenone level nomogram derived from a group of adherent patients with conservatively treated primary hyperaldosteronism, were used to create a two-step decision scheme. 71 outpatients treated with spironolactone for resistant hypertension with spironolactone and canrenone serum concentrations measured between 2018 and 2021 were analyzed according to the proposed scheme. We compared our proposed methodology to the standard approach for adherence testing. RESULTS: With the most sensitive traditional approach to adherence assessment through detectable serum concentrations of spironolactone and/or canrenone, 9 (12.7%) non-adherent patients were identified. With our two-step assessment of adherence, we were able to identify 18 (25.4%) non-adherent patients. CONCLUSION: Consideration of the pharmacokinetic properties of parental drug and its metabolite led to improved sensitivity in non-adherence detection in patients with arterial hypertension. This approach enables better interpretation of measured spironolactone and canrenone serum concentrations and should be used in clinical practice.
- MeSH
- Medication Adherence * MeSH
- Mineralocorticoid Receptor Antagonists pharmacokinetics MeSH
- Adult MeSH
- Hyperaldosteronism drug therapy blood MeSH
- Hypertension * drug therapy MeSH
- Canrenone * pharmacokinetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Pilot Projects MeSH
- Aged MeSH
- Spironolactone * pharmacokinetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
A simple, sensitive and quick HPLC method was developed for the determination of ketoprofen in cell culture media (EMEM, DMEM, RPMI). Separation was performed using a gradient on the C18 column with a mobile phase of acetonitrile and miliQ water acidified by 0.1 % (v/v) formic acid. The method was validated for parameters including linearity, accuracy, precision, limit of quantitation and limit of detection, as well as robustness. The response was found linear over the range of 3-100 μg/mL as demonstrated by the acquired value of correlation coefficient R2=0.9997. The described method is applicable for determination of various pharmacokinetic aspects of ketoprofen in vitro.
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.
- MeSH
- Administration, Oral MeSH
- Pain drug therapy MeSH
- Emulsions MeSH
- Cannabidiol * pharmacology chemistry MeSH
- Cross-Over Studies MeSH
- Rats MeSH
- Quality of Life MeSH
- Arthritis, Rheumatoid * drug therapy MeSH
- Water MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
V důsledku obezity dochází ke změnám farmakokinetických parametrů a hladin podávaných léků v krvi, což může významně komplikovat farmakoterapii obézních pacientů. Zpravidla dochází ke zvětšování distribučního objemu, tyto změny však nejsou vždy přímo úměrné nárůstu celkové tělesné hmotnosti, uplatňuje se relativní zvýšení množství tukové hmoty oproti hydrofilnímu kompartmentu. Vlivem obezity mohou být ovlivněny i eliminační orgány, což vede ke změnám clearance léčiv. Prosté navýšení dávek podle celkové tělesné hmotnosti by u mnohých pacientů mohlo vést k předávkování, naopak fixní dávky mohou být spojeny s nedostatečným efektem. Změny tělesného složení a eliminace se však u různých léčiv neprojeví stejným způsobem. Nelze tedy jednoznačně určit univerzální postup úpravy dávek pro všechna léčiva. Specifickou problematikou je dávkování léčiv po bariatrických operacích, kdy je nutné zohlednit jak změny biodostupnosti a jejich postupnou úpravu v čase od výkonu, tak dramatickou redukci hmotnosti vyžadující pravidelné přehodnocování farmakoterapie. Přestože je obezita celosvětově narůstajícím problémem, stále se potýkáme s nedostatečným množstvím spolehlivých dat a klinických studií zabývajících se problematikou dávkování léčiv u obézních pacientů. Předložený článek uvádí na základě dostupných informací základní principy dávkování u obézních pacientů.
Obesity is related to changes in pharmacokinetic parameters and blood levels of administered drugs, which can significantly complicate the pharmacotherapy of obese patients. An increase in the volume of distribution is generally expected, but due to a relative increase in the amount of fat mass compared to the hydrophilic compartment, this change is not always directly proportional to the increase in total body weight. The elimination organs may also be affected by obesity, leading to changes in drug clearance. Simply increasing doses according to total body weight could lead to overdose in many patients, whereas fixed doses may be associated with insufficient therapeutic effect. However, changes in body composition and elimination are not consistent for different drugs. Therefore, an unambiguous recommendation for dose adjustment of all drugs cannot be made. Drug dosing after bariatric surgery presents a unique challenge, when it is necessary to assess changes in bioavailability and their gradual adjustment over time from the procedure, as well as dramatic weight reduction requiring regular reassessment of pharmacotherapy. Although obesity is a growing problem worldwide, we still face an insufficient amount of reliable data and clinical studies dealing with drug dosing in obese patients. Based on the available information, this article describes the basic principles of dosing in obesity.
INTRODUCTION: In silico tools capable of predicting the functional consequences of genomic differences between individuals, many of which are AI-driven, have been the most effective over the past two decades for non-synonymous single nucleotide variants (nsSNVs). When appropriately selected for the purpose of the study, a high predictive performance can be expected. In this feasibility study, we investigate the distribution of nsSNVs with an allele frequency below 5%. To classify the putative functional consequence, a tier-based filtration led by AI-driven predictors and scoring system was implemented to the overall decision-making process, resulting in a list of prioritised genes. METHODS: The study has been conducted on breast cancer patients of homogeneous ethnicity. Germline rare variants have been sequenced in genes that influence pharmacokinetic parameters of anticancer drugs or molecular signalling pathways in cancer. After AI-driven functional pathogenicity classification and data mining in pharmacogenomic (PGx) databases, variants were collapsed to the gene level and ranked according to their putative deleterious role. RESULTS: In breast cancer patients, seven of the twelve genes prioritised based on the predictions were found to be associated with response to oncotherapy, histological grade, and tumour subtype. Most importantly, we showed that the group of patients with at least one rare nsSNVs in cystic fibrosis transmembrane conductance regulator (CFTR) had significantly reduced disease-free (log rank, p = 0.002) and overall survival (log rank, p = 0.006). CONCLUSION: AI-driven in silico analysis with PGx data mining provided an effective approach navigating for functional consequences across germline genetic background, which can be easily integrated into the overall decision-making process for future studies. The study revealed a statistically significant association with numerous clinicopathological parameters, including treatment response. Our study indicates that CFTR may be involved in the processes influencing the effectiveness of oncotherapy or in the malignant progression of the disease itself.
- MeSH
- Adult MeSH
- Gene Frequency MeSH
- Polymorphism, Single Nucleotide MeSH
- Middle Aged MeSH
- Humans MeSH
- Breast Neoplasms * genetics drug therapy pathology MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator * genetics MeSH
- Aged MeSH
- Feasibility Studies * MeSH
- Artificial Intelligence * MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
- MeSH
- Models, Biological MeSH
- Child MeSH
- Adult MeSH
- Inotuzumab Ozogamicin * pharmacokinetics administration & dosage MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Precursor B-Cell Lymphoblastic Leukemia-Lymphoma * drug therapy blood MeSH
- Child, Preschool MeSH
- Antineoplastic Agents, Immunological * pharmacokinetics administration & dosage therapeutic use MeSH
- Recurrence MeSH
- Aged MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.
- MeSH
- Antipsychotic Agents * pharmacokinetics therapeutic use MeSH
- Humans MeSH
- Drug Monitoring * methods MeSH
- Schizophrenia drug therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
This study aimed to investigate the concentration of pregabalin in the plasma of chicks to determine its pharmacokinetic parameters. Pregabalin (300 mg/kg) was administered orally to 42 clinically healthy Ross chicks as part of a randomized controlled study. Blood samples were collected from the jugular vein at 0.5, 1, 2, 4, 8, and 24 h after drug administration from six chicks per each time. The concentrations of pregabalin in the plasma samples were determined using a quantitative HPLC assay, and pharmacokinetic parameters were calculated using the PKSolver program. Pharmacokinetic parameters were determined using a noncom-partmental model. The concentrations of pregabalin were 133.80 ± 2.35, 183.20 ± 3.91, 295.60 ± 2.82, 248.40 ± 7.60, 219.00 ± 2.72 and 154.00 ± 5.50 μg/ml at the times 0.5, 1, 2, 4, 8, and 24 h respectively. The pharmacokinetics parameters were t1/2β 29 h, Tmax 2 h, Cmax 295 μg, Kel 0.023 h-1, MRT 43h, Vd 1.127 L/h/kg, Cl 0.026 L/h/kg and AUC0-∞ 11420.31 μg.h/ml. This study concluded that pregabalin has a long elimination half-life and poor clearance from the animal body, which is reflected in the prolonged impact of its action.
