Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

Preparation and Evaluation of a Novel 99mTc-Labeled Niraparib Isonitrile Complex as a Potential PARP-1 Imaging Agent.

Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become an attractive target for cancer therapy in recent years. Given that niraparib has good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled niraparib derivatives for tumor imaging to detect PARP expression and improve the accuracy of stratified patient therapy. The niraparib isonitrile derivative (CNPN) was designed, synthesized, and radiolabeled to obtain the [99mTc]Tc-CNPN complex with high radiochemical purity (>95%). It was lipophilic and stable in vitro. In HeLa cell experiments, the uptake of [99mTc]Tc-CNPN was effectively inhibited by the ligand CNPN, indicating the binding affinity for PARP. According to the biodistribution studies of HeLa tumor-bearing mice, [99mTc]Tc-CNPN has moderate tumor uptake and can be effectively inhibited, demonstrating its specificity for targeting PARP. The SPECT imaging results showed that [99mTc]Tc-CNPN had tumor uptake at 2 h postinjection. All of the results of this study indicated that [99mTc]Tc-CNPN is a promising tumor imaging agent that targets PARP.

Effects of CYP3A5*3 genetic polymorphisms on the pharmacokinetics of perampanel in Chinese pediatric patients with epilepsy.

PURPOSE: This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup. RESULTS: The plasma concentration showed a linear correlation with the daily dose taken ( r  = 0.17; P  < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ±â€…297.1 vs. 633.8 ±â€…305.5 µg/ml; P  = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ±â€…1.7 vs. 3.8 ±â€…2.0; P  = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ±â€…293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ±â€…165.6 ng/ml and 260.0 ±â€…36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ±â€…285.6 vs. 433.0 ±â€…227.2 ng/ml; P  = 0.042). CONCLUSION: The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy.

Population pharmacokinetics and dosing optimization of perampanel in children with epilepsy: A real-world study.

OBJECTIVE: The purposes of this study were to explore the pharmacokinetics of perampanel (PER) in children with epilepsy, identify factors that contribute to pharmacokinetic variations among subjects, evaluate the connection between PER exposure and clinical outcome, and establish an evidence-based approach for tailoring individualized antiepileptic treatment in this specific population. METHODS: In this prospective study, PER plasma concentrations and genetic information on metabolic enzymes were obtained from 194 patients younger than 18 years. The disposition kinetics of PER in pediatric patients following oral dosing were characterized using nonlinear mixed effect models. The effective range for the plasma concentration of PER was determined by assessing the efficacy and safety of PER treatment and analyzing the relationship between drug exposure and clinical response. Monte Carlo simulations were then performed to evaluate and optimize the current dosing regimens. RESULTS: The pharmacokinetic profile of PER was adequately described by a one-compartment model with first-order absorption and elimination. Body weight, total bilirubin level, and concomitant oxcarbazepine were found to have significant influences on PER pharmacokinetics. Model estimates of apparent clearance and volume of distribution were .016 ± .009 L/h/kg and 1.47 ± .78 L/kg, respectively. The effective range predicted from plasma concentration data in responders was 215-862 µg/L. Dosing scenarios stratified according to essential covariates were proposed through simulation analysis. SIGNIFICANCE: In this study, we captured the pharmacokinetic/pharmacodynamic characteristics of PER in pediatric epilepsy patients through analysis of real-world data and adopted a pharmacometric approach to support an individualized dosing strategy for PER in this specific population.

Quantification of the aromatase inhibitor letrozole and its carbinol metabolite in mouse plasma by UHPLC-MS/MS.

A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 µL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r2 > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug.

Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling.

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.

BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ±â€Š1.68 mg/L (mean ±â€ŠSD) and 106 ±â€Š32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ±â€Š0.03, 0.94 ±â€Š0.46 and 27.1 ±â€Š17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ±â€Š32.1, 1.68 ±â€Š0.72, 22.6 ±â€Š11.0 and 650 ±â€Š426 mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.

Changes in Perampanel Pharmacokinetics and Cytochrome P450 3A4 Activity Before, During, and After Pregnancy.

ABSTRACT: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4ß-hydroxycholesterol (4ß-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL). Similarly, serum 4ß-OHC levels did not change during pregnancy (before pregnancy, 78.2 ng/mL; during pregnancy, 62.2-83.2 ng/mL). To compare these measurements with those in nonpregnant women, we enrolled 27 nonpregnant women with epilepsy (age range, 16-40 years). In the control patients, we found a strong negative correlation between the concentration-to-dose ratio of perampanel and the 4ß-OHC level ( r = -0.78, P < 0.001). As there was no significant change in CYP3A4 activity, we concluded that the serum perampanel concentration did not change significantly before, during, or after pregnancy. More patients need to be studied to confirm these early results.

High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints.

Isavuconazole exposure-response relationships have been studied with a focus on total rather than unbound exposure, assuming a constant unbound fraction of 1%. We observed a median (range) unbound fraction of 1.59% (0.42-5.30%) in patients. This highly variable protein binding asks for re-evaluation of current pharmacokinetic and pharmacodynamic targets for isavuconazole.

A Single- and Multiple-Dose Pharmacokinetic Study of Oral Perampanel in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Perampanel is a once-daily oral anti-seizure medication indicated for focal-onset seizures and generalized tonic-clonic seizures. This study investigated the single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults. METHODS: Study 052 (NCT03424564) was a phase I, single-center, open-label, parallel-group study. In the single-dose part of the study, subjects received a single oral dose of perampanel 2, 4, or 8 mg. In the multiple-dose part, subjects received once-daily oral perampanel 2 mg on Days 1-7 and 4 mg on Days 8-21. Pharmacokinetic parameters were determined from perampanel plasma concentrations using non-compartmental analysis. Dose proportionality after single doses of perampanel was assessed. Safety and tolerability were evaluated. RESULTS: In the single-dose part (N = 30), median time to reach maximum concentration (tmax) was 0.75-1.0 h, mean terminal elimination phase half-life (t½) was 85.6-122 h, mean maximum observed concentration (Cmax) was 77.9-276 ng/mL, and mean area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) was 4070-15100 ng·h/mL. Single-dose pharmacokinetics were linear for perampanel 2-8 mg. In the multiple-dose part (N = 12), Day 21 steady-state (4 mg/day) parameters were median time at which the highest drug concentration occurs at steady state (tss,max), 1.25 h; mean t½, 109 h; mean maximum observed concentration at steady state (Css,max), 453 ng/mL; and mean area under the concentration-time curve over the dosing interval on multiple dosing (AUC(0- τ)), 7540 ng·h/mL. For single- and multiple-dose perampanel, the most common treatment-emergent adverse events were dizziness and somnolence. CONCLUSIONS: Single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults revealed rapid perampanel absorption, slow elimination, and a linear relationship with single perampanel doses of 2-8 mg. Findings were consistent with previous studies of perampanel pharmacokinetics in other ethnic/racial populations of healthy subjects. Single and multiple doses of perampanel were generally safe and well tolerated. CLINICAL TRIAL REGISTRATION: NCT03424564; registered February 2018.

New Perspectives on Antimicrobial Agents: Isavuconazole.

Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi. Its current FDA-approved indications include the management of invasive aspergillosis as well as mucormycosis, though the latter indication is supported by limited clinical data. Isavuconazole did not achieve noninferiority to caspofungin for the treatment of invasive candidiasis and therefore lacks an FDA-approved indication for this invasive disease. Significant advantages of isavuconazole, primarily over voriconazole but in some circumstances posaconazole as well, make it an appealing option for the management of complex patients with invasive fungal infections. These potential advantages include lack of QTc interval prolongation, more predictable pharmacokinetics, a less complicated drug interaction profile, and improved tolerability, particularly when compared to voriconazole. This review discusses these topics in addition to addressing the in vitro activity of the compound against a variety of fungi and provides insight into other distinguishing factors among isavuconazole, voriconazole, and posaconazole. The review concludes with an opinion section in which the authors provide the reader with a framework for the current role of isavuconazole in the antifungal armamentarium and where further data are required.

Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration.

BACKGROUND: Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats. OBJECTIVES: To determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose. ANIMALS: Eight healthy, adult research cats. METHODS: Four cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra-high performance liquid chromatography-tandem mass spectrometry. Data were analyzed using a 2-compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y2 weighting for IV administration. Predicted 24 and 48-hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed. RESULTS: Both PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half-life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%. CONCLUSIONS AND CLINICAL IMPORTANCE: Isavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long-term isavuconazole use are needed.

Physiologically-Based Pharmacokinetic-Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor With Nirmatrelvir-Ritonavir for the Treatment of COVID-19.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.

The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern.

There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.

Design, Synthesis, and Biological Evaluation of 2-((4-Bisarylmethyl-piperazin-1-yl)methyl)benzonitrile Derivatives as HCV Entry Inhibitors.

Viral entry inhibitors are absent in hepatitis C virus (HCV) treatment regimens although a dozen direct-acting antiviral (DAA) drugs are available now. Based on a previously identified HCV entry inhibitor L0909, chemical space exploration and structure-activity relationship (SAR) studies led to the discovery of a new derived scaffold 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile. Several new scaffold derivatives exhibited higher in vitro anti-HCV activity at low nanomolar concentrations compared to L0909. A biological study indicated that the high potency of active derivatives 3d, 3h, and 3i was primarily driven by the inhibitory effect on the virus entry stage. Moreover, an SPR experiment confirmed that this class of derivatives might target the HCV E1 protein. Pharmacokinetic studies indicated that compounds 3d and 3i are orally available and long-lasting in rat plasma after oral administration to rats by a single dose of 15 mg/kg. In conclusion, this work provided a novel 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile chemotype deserving further investigation into its antiviral therapeutic potential.

Combination therapy with novel androgen receptor antagonists and statin for castration-resistant prostate cancer.

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.

Phase I clinical trial of HC-1119 soft capsule in Chinese healthy adult male subjects: Pharmacokinetics and safety of single-dose proportionality and effects of food.

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.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial.

PURPOSE: Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. METHODS: 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. RESULTS: Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). CONCLUSION: Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.