ABSTRACT
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.
Subject(s)
Adenine , Benzamides , Chemistry, Pharmaceutical , Lipids , Nitriles , Phenylthiohydantoin , Piperidines , Solubility , Temperature , Nitriles/chemistry , Nitriles/administration & dosage , Piperidines/chemistry , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Benzamides/chemistry , Benzamides/pharmacokinetics , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/administration & dosage , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/administration & dosage , Lipids/chemistry , Animals , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Male , Pyrimidines/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/administration & dosage , Drug Stability , Crystallization/methods , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/administration & dosage , Lipolysis/drug effects , RatsABSTRACT
BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.
Subject(s)
Drug Monitoring , Neoplasms , Pyridines , Humans , Drug Monitoring/methods , Prospective Studies , Neoplasms/drug therapy , Pyridines/pharmacokinetics , Pyridines/administration & dosage , Feasibility Studies , Administration, Oral , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Molecular Targeted Therapy , Imidazoles/pharmacokinetics , Imidazoles/administration & dosage , Anilides/pharmacokinetics , Anilides/administration & dosage , Male , Everolimus/pharmacokinetics , Everolimus/administration & dosage , Female , Oximes/pharmacokinetics , Oximes/administration & dosage , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/administration & dosage , Nitriles/pharmacokinetics , Nitriles/administration & dosage , Phenylurea Compounds , Pyridones , Pyrimidinones , Piperazines , BenzamidesABSTRACT
PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzamides , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Receptors, Glucocorticoid , Humans , Male , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/therapeutic use , Phenylthiohydantoin/pharmacokinetics , Benzamides/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Nitriles/administration & dosage , Aged , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Neoplasm Metastasis , Androgen Receptor Antagonists/therapeutic use , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/pharmacokinetics , Androgen Receptor Antagonists/adverse effects , Receptors, Androgen/metabolism , Treatment OutcomeABSTRACT
BACKGROUND: Preclinical studies showed that HC-1119, a deuterated version of enzalutamide, could competitively inhibit androgen binding to androgen receptor by blocking the transmission of androgen receptor signaling pathway as enzalutamide, inducing apoptosis of prostate cancer cells and reducing the proliferation of prostate cancer cells. Animal pharmacokinetic studies also show that deuterization of enzalutamide as HC-1119 could retain the basic properties of mother drug, increases the stability of compounds to metabolic enzymes and the drug exposure in vivo, prolong the half-life and reduce the production of metabolites, which may lead to a better efficacy and safety of HC-1119 compared with enzalutamide. METHODS: To evaluate the pharmacokinetics and safety of HC-1119 and the effects of food on pharmacokinetics in healthy adult Chinese men after single-dose administration of HC-1119. A total of 47 Chinese healthy adult male subjects received HC-1119 soft capsule at a single oral dose of 40, 80, or 160 mg followed on fasting or 160 mg after high-fat meal respectively. HC-1119 prototype and its metabolites M1 and M2 in plasma were collected individually in a total 23 time points. Pharmacokinetics were determined by sensitive LC/MS/MS for dose-proportionality study. RESULTS: In subjects taking HC-1119 soft capsules on fasting, Cmax of HC-1119 prototype increased dose-dependently. Either Cmax and AUC0-∞ of M1 or Cmax of M2 showed statistically significant difference. Dose-proportionality evaluation showed linear pharmacokinetic characteristics in Cmax of HC-1119 prototype, Cmax and AUC0-∞ of M2 in dose range of 40-160 mg. Cmax of HC-1119 was significantly different between the two groups as 160 mg HC-1119 on fasting or after a high-fat diet respectively, while the other parameter were not. HC-1119 and its metabolites M1 and M2 showed a linear dynamic trend. CONCLUSIONS: HC-1119 is expected to have lower clinical dose than the similar drug enzalutamide. The absorption of HC-1119 and the main pharmacokinetic parameters of HC-1119 and its metabolites M1 and M2 were not affected by high-fat diet. The clinical application of HC-1119 soft capsule in the later stage can be recommended for both fasting and postprandial. The safety and tolerance were good in this population.
Subject(s)
Benzamides , Cell Proliferation/drug effects , Drug Stability , Food-Drug Interactions , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms , Receptors, Androgen/metabolism , Administration, Oral , Adult , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzamides/administration & dosage , Benzamides/adverse effects , Benzamides/pharmacokinetics , Biomarkers, Pharmacological/analysis , Capsules , China , Dose-Response Relationship, Drug , Half-Life , Healthy Volunteers , Humans , Male , Nitriles/administration & dosage , Nitriles/adverse effects , Nitriles/pharmacokinetics , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Signal Transduction/drug effectsABSTRACT
BACKGROUND: One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC. METHODS: LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide). RESULTS: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes. CONCLUSIONS: Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.
Subject(s)
Androgen Receptor Antagonists/pharmacology , Benzamides/pharmacokinetics , Cell Cycle Proteins/metabolism , Drug Therapy, Combination/methods , Nitriles/pharmacokinetics , Phenylthiohydantoin/pharmacokinetics , Prostatic Neoplasms, Castration-Resistant , Pyrazoles/pharmacology , Simvastatin/pharmacology , Thiohydantoins/pharmacology , Animals , Cell Count/methods , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Male , Mice , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Signal Transduction/drug effects , Tissue Array Analysis/methods , Xenograft Model Antitumor Assays/methodsABSTRACT
The purpose of our study was to investigate the safety, pharmacokinetics (PK), and initial antitumor efficacy of HC-1119 in patients with metastatic castration-resistant prostate cancer (mCRPC). Eligible mCRPC patients were included in our study (NCT03774056) with two parts. Part A was a dose escalation study in which patients received a dose escalation of HC-1119 (40, 80, 160 and 200 mg/day). Part B was a dose expansion study in which patients received HC-1119 at the dose of 80 and 160 mg. Safety assessment and pharmacokinetic samplings were performed for all patients at the given time points; preliminary tumor response was also assessed. Twenty-four patients were enrolled in part A and 19 patients in part B, respectively. HC-1119 was safe, well tolerated and no dose-limiting toxicity was observed. Fatigue was the most common treatment-related adverse event and no seizures were observed. At the dose levels of 40, 80 and 160 mg, the AUC and Cmax of HC-1119 in plasma increased almost dose-proportionally at the steady state in mCRPC patients. Maximum prostate-specific antigen (PSA) response rates (≥50% reduction from the baseline) in dose escalation and dose expansion cohorts were 77% and 75%, respectively; the overall disease control rate (22 patients available for imaging analysis) was 72.7%, with PR in 4 patients, SD in 12 patients and PD in 6 patients; the 2-year overall survival rate in patients from Part B was 56.8%. HC-1119 was safe, well tolerated and efficacious and HC-1119 at 80 mg/day is recommended for further studies.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms/drug therapy , Adenocarcinoma/secondary , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacokinetics , Benzamides/pharmacokinetics , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nitriles/pharmacokinetics , Phenylthiohydantoin/pharmacokinetics , Prognosis , Prostatic Neoplasms/pathology , Tissue DistributionABSTRACT
Aim: Comparison of the efficacy/safety/health-related quality of life of apalutamide, enzalutamide and darolutamide in Phase III clinical trials involving patients with nonmetastatic castration-resistant prostate cancer was performed. Materials & methods: Relevant studies were identified by searching PubMed as well as conference abstracts reporting updated overall survival. Three pivotal trials were identified, SPARTAN (apalutamide), PROSPER (enzalutamide) and ARAMIS (darolutamide), and form the basis of this analysis. Results: All three drugs significantly prolonged metastasis-free survival, prostate-specific antigen response and overall survival versus placebo, and were generally well tolerated. Conclusion: Drug selection will likely be influenced by tolerability/safety and other factors, such as the propensity for drug-drug interactions and the presence of comorbidities, that affect the risk-benefit balance in individual patients.
Subject(s)
Benzamides/administration & dosage , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyrazoles/administration & dosage , Thiohydantoins/administration & dosage , Benzamides/adverse effects , Benzamides/pharmacokinetics , Clinical Trials, Phase III as Topic , Disease-Free Survival , Drug Interactions , Humans , Kallikreins/blood , Kaplan-Meier Estimate , Male , Nitriles/adverse effects , Nitriles/pharmacokinetics , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/mortality , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Quality of Life , Thiohydantoins/adverse effects , Thiohydantoins/pharmacokinetics , Time FactorsABSTRACT
PURPOSE: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. METHODS: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Camptothecin/pharmacokinetics , Cyclodextrins/pharmacokinetics , Models, Biological , Neoplasms/drug therapy , Topoisomerase I Inhibitors/pharmacokinetics , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzamides/administration & dosage , Benzamides/pharmacokinetics , Camptothecin/administration & dosage , Cyclodextrins/administration & dosage , Drug Liberation , Female , Half-Life , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms/blood , Neoplasms/diagnosis , Neoplasms/pathology , Nitriles/administration & dosage , Nitriles/pharmacokinetics , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/pharmacokinetics , Phthalazines/administration & dosage , Phthalazines/pharmacokinetics , Piperazines/administration & dosage , Piperazines/pharmacokinetics , Topoisomerase I Inhibitors/administration & dosageABSTRACT
BACKGROUND: Several treatment options were recently added for metastatic castration-resistant prostate cancer (mCRPC). However, response to therapy is variable, and biomarkers that can guide treatment selection and response evaluation are lacking. Circulating RNAs are a promising source of biomarkers. We explored messenger RNAs (mRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs) as potential biomarkers in liquid biopsies of patients with mCRPC treated with enzalutamide. METHODS: Forty patients were included in this prospective multicenter observational study. Whole blood was drawn at baseline and 1, 3, and 6 months after start of therapy. Four mRNAs, 6 miRNAs, and 5 lncRNAs were analyzed by quantitative PCR. RNA levels in 30 healthy individuals were used as controls. RNA expression data were analyzed by Kaplan-Meier and Cox regression analyses, and the primary end point was progression-free survival. Clinical factors were included in the multivariable Cox regression analysis. RESULTS: Levels of 2 miRNAs, miR-375 and miR-3687, and 1 lncRNA, N-acetylated alpha-linked acidic dipeptidase like 2 antisense RNA 2 (NAALADL2-AS2), were more than 2-fold higher in patients with mCRPC compared with healthy volunteers. Patients with higher levels of miR-375 or miR-3687 showed a shorter time to progression. Patients with higher levels of NAALADL2-AS2 showed a longer time to progression. In the multivariable Cox regression analysis, higher miR-375, miR-3687 and serum prostate-specific antigen concentrations were shown to be independent predictors for shorter time to progression. CONCLUSIONS: We identified miR-3687 as a novel prognostic marker for response in patients with CRPC treated with enzalutamide, and we confirmed the prognostic value of miR-375.
Subject(s)
Biomarkers, Tumor/blood , Circulating MicroRNA/blood , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/diagnosis , Aged , Benzamides , Humans , Liquid Biopsy , Male , MicroRNAs/blood , Nitriles , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/therapeutic use , Prognosis , Prospective Studies , Prostatic Neoplasms, Castration-Resistant/drug therapyABSTRACT
PURPOSE: The aim of the study is to investigate the influence of patient characteristics, age and body mass index (BMI), on pharmacokinetics of enzalutamide, and to study the relationships between drug exposure and enzalutamide efficacy and toxicity, in mCRPC patients. METHODS: Data were collected in a longitudinal cohort study (ANDROPS) and a prospective observational study (ILUMINATE), both in mCRPC patients treated with enzalutamide. To investigate the influence of age and BMI on exposure, enzalutamide and N-desmethylenzalutamide levels were compared by ANOVA. To investigate the relation of exposure versus time to progression (TTP), the sum plasma levels were divided into quartiles and compared by Kaplan-Meier analysis. To assess the relation of exposure with fatigue, plasma levels in patients experiencing fatigue vs. no fatigue were compared by and independent t test. RESULTS: Data of 68 mCRPC patients were included for analysis. Plasma levels were not different for age or BMI. No difference in TTP between both studies was observed (383 days (95% CI 287-859), and 567 days (95% CI 351-NR), p = 0.36). Kaplan-Meier analysis of quartiles of sum levels showed no difference for TTP. Fatigue was reported by 22 patients, no difference in sum plasma levels was observed between patients with and without fatigue. CONCLUSIONS: We observed that age and BMI did not influence systemic exposure in patients treated with enzalutamide. No relation of exposure with efficacy or fatigue was observed. Further research using enzalutamide at a lower dose is needed to understand the relation of enzalutamide exposure and fatigue.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/epidemiology , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Benzamides , Drug-Related Side Effects and Adverse Reactions/etiology , Follow-Up Studies , Humans , Longitudinal Studies , Male , Netherlands/epidemiology , Nitriles , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/pharmacology , Prognosis , Prospective Studies , Prostatic Neoplasms, Castration-Resistant/pathology , Survival Rate , Tissue DistributionABSTRACT
Camptothecin (CPT), a potent inhibitor of topoisomerase I and HIF-1α, failed to demonstrate utility as an anti-cancer agent in early clinical trial investigations, primarily due to limited clinical activity and significant toxicity attributable to unfavorable physicochemical properties (e.g. low plasma solubility, pH-labile lactone ring). NLG207 (formerly CRLX101), a nanoparticle-drug conjugate (NDC) of CPT designed to optimize plasma pharmacokinetics and facilitate drug delivery to tumors, is included as part of combination treatment in two Phase II clinical trials ongoing at the National Cancer Institute (NCT02769962 and NCT03531827). To better understand the potential for drug-drug interactions and to correlate drug exposure to clinical outcomes and pharmacodynamic biomarkers, a robust analytical method was developed to measure CPT in human plasma. Two sample processing methods were developed to quantify both NDC-bound CPT and free CPT, primarily via alteration of pH conditions. A solid-phase extraction recovered >79 % of CPT prior to quantitative analysis by ultra HPLC-MS/MS. Dynamic calibration ranges of 10 to 10,000â¯ng/mL and 1 to 1000â¯ng/mL for total and free CPT, respectively were utilized to capture clinical ranges. NLG207 NDCs demonstrated significant rates of CPT release in human plasma at room temperature after 2â¯h but were shown to be stable at 4⯰C for 24â¯h and through 4 freeze/thaw cycles. This assay was used to quantitate CPT plasma concentrations in clinical samples to confirm clinical utility following NLG207 treatment in subjects with advanced prostate cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Camptothecin/blood , Cyclodextrins/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides , Camptothecin/isolation & purification , Camptothecin/pharmacokinetics , Camptothecin/therapeutic use , Cyclodextrins/isolation & purification , Cyclodextrins/pharmacokinetics , Cyclodextrins/therapeutic use , Drug Interactions , Drug Stability , Humans , Male , Middle Aged , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/bloodABSTRACT
Recently published studies have proposed that amorphous drug nanoparticles in gastrointestinal fluids may be beneficial for the absorption of poorly soluble compounds. Nanosized drug particles are known to provide rapid dissolution rates and, in some instances, a slight increase in solubility. However, in recent studies, the differences observed in vivo could not be explained solely by these attributes. Given the high dose and very low aqueous solubility of the study compounds, rapid equilibration to the drug-saturated solubility in gastrointestinal fluid would occur independent of the presence of nanoparticles. Alternatively, it has been proposed that drug nanoparticles (ca. ≤ 200 to 300 nm) may provide a "shuttle" for drug across the unstirred water layer (UWL) adjacent to the intestinal epithelium, particularly for low solubility/lipophilic compounds where absorption may be largely UWL-limited. This transport mechanism would result in a higher unbound drug concentration at the surface of the epithelium for absorption. This study evaluates this mechanism using a simple modification of the effective permeability to account for the effect of drug nanoparticles diffusing across the UWL. The modification can be made using inputs for solubility and nanoparticle size. The permeability modification was evaluated using three published case studies for amorphous formulations of itraconazole, anacetrapib, and enzalutamide, where the formation of amorphous drug nanoparticles upon dissolution resulted in improved drug absorption. Absorption modeling was performed using GastroPlus to assess the impact of the nanomodified permeability method on the accuracy of model prediction compared to in vivo data. Simulation results were compared to those for baseline simulations using an unmodified effective permeability. The results show good agreement using the nanomodified permeability, which described the data better than the standard baseline predictions. The nanomodified permeability method can be a suitable, fit-for-purpose in silico approach for evaluating or predicting oral absorption of poorly soluble, UWL-limited drugs from formulations that produce a significant number of amorphous drug nanoparticles.
Subject(s)
Itraconazole/pharmacokinetics , Oxazolidinones/pharmacokinetics , Phenylthiohydantoin/analogs & derivatives , Administration, Oral , Animals , Benzamides , Chemistry, Pharmaceutical , Colloids/pharmacology , Diffusion , Excipients/pharmacology , Humans , Intestinal Absorption , Itraconazole/administration & dosage , Itraconazole/blood , Itraconazole/chemistry , Models, Biological , Nanoparticles , Nitriles , Oxazolidinones/administration & dosage , Oxazolidinones/blood , Permeability , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/blood , Phenylthiohydantoin/pharmacokinetics , SolubilityABSTRACT
INTRODUCTION: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting. PATIENTS AND METHODS: Trough plasma concentration (Ctrough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann-Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma Ctrough (ENZA, NDE, and composite). RESULTS: Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma Ctrough of ENZA and NDE were 12.4 ± 3.0 µg/mL and 8.8 ± 2.1 µg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma Ctrough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma Ctrough was observed compared with 18 remaining patients (16.1 ± 2.4 µg/mL vs. 11.6 ± 2.6 µg/mL, respectively; P = .027). CONCLUSION: The low interindividual variability in ENZA and NDE Ctrough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.
Subject(s)
Androgen Receptor Antagonists/administration & dosage , Asthenia/diagnosis , Drug Monitoring/statistics & numerical data , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Administration, Oral , Aged , Androgen Receptor Antagonists/adverse effects , Androgen Receptor Antagonists/pharmacokinetics , Asthenia/chemically induced , Benzamides , Biological Variation, Population , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , Kallikreins/blood , Kaplan-Meier Estimate , Male , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Progression-Free Survival , Prospective Studies , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Severity of Illness IndexABSTRACT
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Kallikreins/blood , Phenylthiohydantoin/analogs & derivatives , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzamides , Chromatography, Liquid , Cohort Studies , Disease Progression , Humans , Male , Middle Aged , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Progression-Free Survival , Retrospective Studies , Tandem Mass Spectrometry , Treatment OutcomeABSTRACT
PURPOSE: This open-label, single-dose study evaluated the pharmacokinetic profiles of enzalutamide and its major metabolites and the safety of enzalutamide in healthy, Chinese male volunteers. METHODS: Fourteen volunteers (median age, 28.5 years) received a single oral dose of enzalutamide (160 mg) under fasting conditions on day 1 and were followed for 50 days. Pharmacokinetic profiles were obtained for enzalutamide and its major metabolites, carboxylic acid metabolite (M1; inactive metabolite) and N-desmethyl enzalutamide (M2; active metabolite), on day 1 up to 1176 hours (49 days). Safety data were also collected. FINDINGS: Enzalutamide plasma concentration rapidly increased (median Tmax, 1.5 hours) followed by a slow decrease (mean t½, 90.7 hours). M1 and M2 plasma concentrations increased gradually with a median Tmax of 72.0 and 121 hours, respectively. M1 and M2 mean metabolite-to-parent ratios were 0.2 and 1.3, respectively. Mean AUC0-∞ of enzalutamide plus M2 was 828 µg h/mL versus 368 µg h/mL for enzalutamide alone. Mean t½, maximum concentration, and Tmax of enzalutamide plus M2 were comparable with those of enzalutamide. Drug-related treatment-emergent adverse events were reported in 4 men (28.6%): 1 each of upper respiratory tract infection, chest discomfort, increased blood bilirubin, and decreased white blood cell count. No deaths or serious treatment-emergent adverse events were observed. IMPLICATIONS: The pharmacokinetic profiles of enzalutamide, M1, M2, and enzalutamide plus M2 in healthy Chinese men were generally consistent with those in white men. No new safety concerns were found. Chinese Clinical Trial Registration identifier: CTR20150635.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Phenylthiohydantoin/analogs & derivatives , Administration, Oral , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Area Under Curve , Asian People , Benzamides , Fasting/metabolism , Healthy Volunteers , Humans , Male , Nitriles , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/blood , Phenylthiohydantoin/pharmacokinetics , Young AdultSubject(s)
Kidney Failure, Chronic/therapy , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Benzamides , Comorbidity , Humans , Male , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Prostatic Neoplasms, Castration-Resistant/blood , Renal Dialysis , Treatment OutcomeABSTRACT
Enzalutamide is a fast crystallizing, hydrophobic compound that has solubility limited absorption in vivo. Given the low aqueous solubility of this compound, it was of interest to evaluate amorphous formulations in vitro and in vivo. Amorphous solid dispersions (ASD) of enzalutamide were prepared with the hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone (PVPVA). A side-by-side diffusion cell was developed as an in vitro characterization tool to discriminate enzalutamide ASDs based upon the solute thermodynamic activity achieved during dissolution and its impact on the subsequent membrane transport rates, phase behavior, and drug speciation. The same formulations were then tested in vivo in rats using oral dosing of ASD suspensions. Different levels of plasma exposure were observed between the ASDs, which could be correlated to the phase behaviors of the ASDs following dissolution. Unsurprisingly, ASDs that underwent crystallization show lower plasma exposures. However, differences were also observed between ASDs that dissolved to form nanosized amorphous drug aggregates versus those that dissolved to yield only supersaturated solutions, with the former outperforming the latter in terms of the plasma exposure. These observations highlight the importance of thoroughly understanding the phase behavior of an amorphous formulation following dissolution and the need to discriminate between different types of precipitation, specifically crystallization versus glass liquid phase separation to form nanosized amorphous aggregates.
Subject(s)
Antineoplastic Agents/chemistry , Phenylthiohydantoin/analogs & derivatives , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Benzamides , Biological Transport , Crystallization , Drug Liberation , Intestinal Absorption , Male , Membranes, Artificial , Nitriles , Phenylthiohydantoin/blood , Phenylthiohydantoin/chemistry , Phenylthiohydantoin/pharmacokinetics , Rats, Sprague-Dawley , SolubilityABSTRACT
BACKGROUND: Niclosamide, an FDA-approved anti-helminthic drug, has activity in preclinical models of castration-resistant prostate cancer (CRPC). Potential mechanisms of action include degrading constitutively active androgen receptor splice variants (AR-Vs) or inhibiting other drug-resistance pathways (e.g., Wnt-signaling). Published pharmacokinetics data suggests that niclosamide has poor oral bioavailability, potentially limiting its use as a cancer drug. Therefore, we launched a Phase I study testing oral niclosamide in combination with enzalutamide, for longer and at higher doses than those used to treat helminthic infections. METHODS: We conducted a Phase I dose-escalation study testing oral niclosamide plus standard-dose enzalutamide in men with metastatic CRPC previously treated with abiraterone. Niclosamide was given three-times-daily (TID) at the following dose-levels: 500, 1000 or 1500mg. The primary objective was to assess safety. Secondary objectives, included measuring AR-V expression from circulating tumor cells (CTCs) using the AdnaTest assay, evaluating PSA changes and determining niclosamide's pharmacokinetic profile. RESULTS: 20 patients screened and 5 enrolled after passing all screening procedures. 13(65%) patients had detectable CTCs, but only one was AR-V+. There were no dose-limiting toxicities (DLTs) in 3 patients on the 500mg TID cohort; however, both (N = 2) subjects on the 1000mg TID cohort experienced DLTs (prolonged grade 3 nausea, vomiting, diarrhea; and colitis). The maximum plasma concentration ranged from 35.7 to 182 ng/mL and was not consistently above the minimum effective concentration in preclinical studies. There were no PSA declines in any enrolled subject. Because plasma concentrations at the maximum tolerated dose (500mg TID) were not consistently above the expected therapeutic threshold, the Data Safety Monitoring Board closed the study for futility. CONCLUSIONS: Oral niclosamide could not be escalated above 500mg TID, and plasma concentrations were not consistently above the threshold shown to inhibit growth in CRPC models. Oral niclosamide is not a viable compound for repurposing as a CRPC treatment. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov: NCT02532114.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Niclosamide/administration & dosage , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzamides , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Niclosamide/adverse effects , Niclosamide/pharmacokinetics , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathologyABSTRACT
INTRODUCTION: Enzalutamide is the first approved second-generation androgen receptor (AR) antagonist in the treatment of metastatic castration-resistant prostate cancer (mCRPC) with or without docetaxel-based chemotherapy. Over the past 5 years, a number of attempts were made to determine the efficacy of enzalutamide in the different clinical settings. Areas covered: A literature search was performed at the PubMed, Embase, and Web of Science database to collect the most relevant and impactful studies, including basic science investigations, clinical trials, and reviews. This article focuses on the pharmacology, efficacy, tolerability, and future perspective of enzalutamide. Expert opinion: The treatment paradigm of CRPC has been dramatically challenged of late. Enzalutamide are in wide use because of its favorable efficacy and safety, but primary or acquired resistance to the drug will eventually develop. Further studies are thus necessary to identify appropriate patients who can achieve apparent benefits from enzalutamide alone or in combination with other drugs.
Subject(s)
Androgen Receptor Antagonists/administration & dosage , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Androgen Receptor Antagonists/pharmacokinetics , Androgen Receptor Antagonists/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzamides , Docetaxel , Drug Resistance, Neoplasm , Humans , Male , Neoplasm Metastasis , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms, Castration-Resistant/pathology , Taxoids/administration & dosageABSTRACT
Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, the mechanisms of induction are poorly investigated and the effects of the active metabolite N-desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2 and ABCG2 mRNA. Induction of CYP3A4 and ABCB1 was confirmed by Western blot analysis and is likely mediated by activation of the nuclear receptor pregnane x receptor, elucidated by a luciferase-based reporter gene assay. Enzalutamide's main active metabolite N-desmethyl enzalutamide exhibited only weak induction properties. mRNA expression of UGT2B7 was suppressed by enzalutamide and its metabolite. Both compounds are apparently not transported by P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). N-desmethyl enzalutamide more potently inhibited important drug transporters (P-gp, BCRP, OATPs) than enzalutamide. Taken together, the pharmacokinetics of concurrently administered drugs is likely altered during enzalutamide therapy. Levels of metabolically (mainly CYP3A4) eliminated drugs are expected to be decreased, whereas the abundance of compounds with solely transporter-determined pharmacokinetics (P-gp, OATPs) is likely enhanced.