Time Course Of Plasma Concentrations Research Articles

Pharmacokinetic and Pharmacodynamic Modeling Analysis of Delpazolid (LCB01-0371) in Adult Patients with Pulmonary Tuberculosis.

Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid Emax model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested.

Population pharmacokinetic–pharmacodynamic analysis of givinostat

ABSTRACT Background Givinostat (ITF2357), an oral, synthetic histone deacetylase inhibitor, significantly improved all histological muscle biopsy parameters in a Phase II study in boys with Duchenne muscular dystrophy (DMD). Research Design and Methods A population pharmacokinetic (PK) model, including seven clinical studies, was developed to explore the effect of covariates on givinostat PK. The final model was qualified to simulate pediatric dosing recommendations. A PK/pharmacodynamic (PD) model was developed to simulate the link between givinostat plasma concentration and platelet time course in 10–70-kg children following 6 months of givinostat 20–70 mg twice daily. Results A two-compartment model, with first-order input with lag and first-order elimination from the central compartment, described givinostat PK, demonstrating increasing apparent clearance with increasing body weight. The PK/PD model well-described platelet count time course. Weight-based dosing (arithmetic mean systemic exposure of 554–641 ng·h/mL) produced an average platelet count decrease from baseline of 45% with maximum decrease within 28 days. After 1 week and 6 months, ~1% and ~14–15% of patients, respectively, had a platelet count <75 × 109/L. Conclusions Based on these data, givinostat dosing will be body weight adjusted and include monitoring of platelet counts to support efficacy and safety in a Phase III DMD study.

The Novel Nano-Formulation of the HDAC Inhibitor, Romidepsin, for the Treatment of Relapsed, Refractory Peripheral T-Cell Lymphoma

Background: The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of diseases often associated with a poor outcome. Since conventional chemotherapy fails to produce cure in the majority of patients, there is a lack of accepted standard of care for most PTCL subtypes. The PTCL appear to be a group of diseases characterized by gross epigenetic dysregulation with a unique vulnerability to epigenetic modulation. Recurring mutations in IDH2, TET2 and DNMT3A, which create a hypermethylator phenotype, coupled with mutations in genes that control histone acetylation such as EP300 and CREBBP, have been identified as recurrent in several subtypes of PTCL. Despite the approval of several drugs for patients with relapsed or refractory disease, the prognosis for patients with PTCL are dismally low. The approval of histone deacetylase inhibitors (HDACi) coupled with recent evidence suggesting that combinations of epigenetically targeted drugs induce clinically meaningful results has created a drug development strategy that offers an innovative approach to these complex diseases. The HDACi exhibit a lineage selective activity against the PTCL, with 4 HDACi (Belinostat, Romidepsin, Vorinostat and Chidamide) approved for Relapsed/Refractory (R/R) TCL patients around the world. Although Romidepsin was approved by the FDA for the treatment of cutaneous TCL and R/R PTCL, its indication in R/R PTCL was recently withdrawn due to the negative result of the Phase 4 commitment study. Objectives: We aim to develop a novel nano-encapsulated formulation of Romidepsin (Romi) with a superior safety and efficacy profile with a more convenient dosing schedule. Methods: Using a combinatorial strategy of solvent screening and polymer chemistries, we developed a first-in-class nano-romidepsin (NanoRomi). We utilized Dynamic Light Scattering (DLS), Cryo-EM to characterize the size and morphology of the nanoparticles and LC-MS-defined drug loading to "lock down” a nanoparticle formulation for in vitro testing. Cell viability, flow cytometry and western blotting (WB) assays were performed to determine the NanoRomi mediated cell death, apoptosis and histone acetylation in TCL cell lines. To determine maximum tolerated dose of the NanoRomi vs free Romi, in vivo single-dose toxicity study was performed. The clinical score and weight loss of the mice were considered endpoints. For pharmacokinetics study, mice were treated at the ½ MTD and plasma was isolated from blood collected at time points following a single treatment for mass spectrometry based quantification of drug levels. Results: We developed NanoRomi by nanoprecipitation or solvent displacement method using a specific Drug/Polymer/Surfactant ratio. Cryo-EM and DLS confirmed that NanoRomi had a poly-dispersity index between 0.16 to 0.27 and a z-average of 60-70 nm, indicating uniform size and homogenous particle distribution. At 60 hours, the TCL cell lines were consistently sensitive to NanoRomi (IC50: 0.7-1.9 nM), which was comparable to Romi (Fig 1A). Flow cytometry for cleaved PARP demonstrated that treatment with NanoRomi induced apoptosis similar to Romi. WB analysis showed increased acetylation of histone H3 and H4 in a time and concentration-dependent manner. In vivo single-dose toxicity assay showed a clear correlation between dose and weight loss and/or clinical score in both free Romi and NanoRomi treated groups. Mice reached humane endpoints at 8 mg/kg treatment for intraperitoneal route of administration for both the drugs. Preliminary PK analysis indicated that the t1/2 of Romi (plasma) is comparable between free Romi and NanoRomi treatments while the Cmax and AUC for NanoRomi is 3 to 4-fold higher compared to the free Romi. The plasma-concentration time courses of Romi after the intraperitoneal administration of the free Romi and NanoRomi showed that the drug reached maximum concentration after 6 hours and 3 hours for free Romi and NanoRomi, respectively (Fig 1B). Conclusions: These studies confirm that NanoRomi effectively targets tumor cells producing the same constellation of effects seen with free Romi. In addition, the in vivo studies suggest a likely superior safety and pharmacokinetic profile. NanoRomi may represent a valuable asset with unique properties that favorably distinguish it from free Romi. Ongoing studies are focused on the in vivo therapeutic efficacy, as we translate the development of this agent to Phase 1 studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fatal cocaine poisoning in a body stuffer

To describe a fatal cocaine poisoning in a body stuffer resulting from extremely high plasma concentrations. Body stuffing refers to the swallowing of small amounts of poorly wrapped drug aiming to conceal it. Usually, complications are due to the direct drug toxicity (Roberts et al., Am J Emerg Med 1986:24–27). We report a 34-year-old male who developed seizures after swallowing small drug packs in a parking. Rapidly, he presented a cardiac arrest when the prehospital medical team arrived (no flow, 1 min). During tracheal intubation, a plastic pack containing a white powder was extracted from the patient's mouth. Due to refractory cardiac arrest, venoarterial ECMO was implemented on intensive care unit (ICU) admission. Despite optimal supportive care, multiple organ failure developed, and the patient died 24 h after ICU admission. Four blood and one urine samples were collected between ICU admission and death onset. The small pack containing a white powder was sent to the laboratory. Extensive toxicological screening was performed using immunological and enzymatic methods, LC-DAD/MS, LC-HR/MS and GC-MS. Plasma concentrations of cocaine and its two major metabolites benzoylecgonine and ecgonine methyl ester (EME) were determined using a specific LC-MS/MS assay. Toxicological analysis of the powder was performed using a specific GC-MS method. Cocaine and tetrahydrocannabinol screening was positive in urine. Plasma concentrations of cocaine, benzoylecgonine and EME were 8600, 13,420 and 9540 ng/mL, respectively in the earliest sample collected 2.8 hours post-cardiac arrest onset. In the last sample collected at 21.3 hours post-cardiac arrest, plasma cocaine concentration declined to 1240 ng/mL whereas benzoylecgonine and EME concentrations increased to 32,720 and 12,700 ng/mL, respectively. Cocaine elimination half-life was estimated at 6 h. During the first 4 hours, metabolic ratios were 1.5 (benzoylecgonine/cocaine) and 1 (EME/cocaine) before a marked increase in benzoylecgonine/cocaine and EME/cocaine ratios up to 11–26 and 6–10, respectively. Positive tetrahydrocannabinol was confirmed in LC-HR/MS. No usual adulterant as levamisole or phenacetin compounds was detected in blood and urine. Quantitative analysis GC-MS analysis reported a pure cocaine powder. The acute toxicity including sudden cardiac arrest in this body stuffer appeared in relation to extremely high plasma cocaine concentrations. Such elevated concentrations were rarely observed in body stuffers/packers (Soichot et al., ToxAC 2018;30:229–238) with metabolic ratios of ∼1 in the first hour post-ingestion. Here we described the time-course of plasma concentrations of cocaine and its metabolites during a 21h-period before the patient's death. There was a marked increase in cocaine metabolite concentrations and metabolic ratios, particularly the benzoylecgonine/cocaine ratio. Prolongation to 6 h of cocaine elimination half-life was consistent with the previously reported value of 7.6 h in a body packer (De Prost et al., Hum Exp Toxicol 2010;29:49–53). However, our report presents limitations related to the lack of information regarding cocaine consumption by the patient and the small sample number not allowing performing a toxicokinetic study. By contrast, to body packers, body stuffers mostly carry small cocaine amounts. However, cocaine concentration can be extremely high following the low-quality pack rupture in the stuffer's mouth like in our case. Drug purity found in our analysis supported a street deal with the attempt to conceal the sales product. Nevertheless, body stuffers are often drug users, which could be questioned in our patient, as suggested by the positive tetrahydrocannabinol screening. Our body stuffer developed a fatal cardiac arrest in relation to elevated plasma concentrations of cocaine and its metabolites resulting from a cocaine pack rupture. Toxicokinetic data are still expected to better understand the physiopathology of cocaine toxicity in such cases.

Nitrofurantoin plasma- and urine exposure in eight healthy beagle dogs following standard nitrofurantoin dosing regimen

Bacterial cystitis is common in dogs and is usually treated with antibiotics. Nitrofurantoin is used for treatment of bacterial cystitis in humans and might provide a feasible treatment option in dogs. The aim of this study was to investigate the nitrofurantoin plasma concentration-time course and potential adverse effects in dogs. Nitrofurantoin (4.4–5.0 mg/kg) was administered orally to eight healthy beagles every 8 h for five days before repeated plasma and urine samples were collected. An additional four beagles served as untreated controls. The nitrofurantoin plasma and urine concentrations were measured using ultra high precision liquid chromatography coupled to tandem mass-spectrometry and further analysed using a non-compartmental pharmacokinetic model. In plasma, the median Cmax was 2.1 μg/mL, tmax was 2 h, the terminal rate constant was 0.9 per h and the terminal half-life was 0.8 h. In urine, median Cmax was 56 μg/mL, tmax was 1 h and the terminal half-life was 4.3 h. No adverse effects were observed clinically or in haematology or biochemistry. The data presented in this study combined with in vitro sensitivity data from common urine pathogens and the lack of observed adverse effects suggest that nitrofurantoin in a standard dosing regimen could be effective in sporadic bacterial cystitis treatment in dogs. Further clinical studies are highly warranted to verify the effectiveness in clinical cases.

Pharmacokinetic/Pharmacodynamic Modeling and Application in Antibacterial and Antifungal Pharmacotherapy: A Narrative Review.

Pharmacokinetics and pharmacodynamics are areas in pharmacology related to different themes in the pharmaceutical sciences, including therapeutic drug monitoring and different stages of drug development. Although the knowledge of these disciplines is essential, they have historically been treated separately. While pharmacokinetics was limited to describing the time course of plasma concentrations after administering a drug-dose, pharmacodynamics describes the intensity of the response to these concentrations. In the last decades, the concept of pharmacokinetic/pharmacodynamic modeling (PK/PD) emerged, which seeks to establish mathematical models to describe the complete time course of the dose-response relationship. The integration of these two fields has had applications in optimizing dose regimens in treating antibacterial and antifungals. The anti-infective PK/PD models predict the relationship between different dosing regimens and their pharmacological activity. The reviewed studies show that PK/PD modeling is an essential and efficient tool for a better understanding of the pharmacological activity of antibacterial and antifungal agents.

Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling of Diazepam: Unbound Interstitial Brain Concentrations Correspond to Clinical End Points.

Benzodiazepines induce a series of clinical effects by modulating subtypes of γ-aminobutyric acid type A receptors in the central nervous system. The brain concentration-time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4-benzodiazepines diazepam and nordiazepam was developed from plasma concentration-time courses with PK-Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration-time profiles correlated with diazepam pharmacodynamic end points. With a 30-mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant γ-aminobutyric acid type A receptors composed of α1β2γ2s, α2β2γ2s, and α5β2γ2s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10-mg peroral administrations of diazepam delivered every 24 hours, steady-state peak and trough unbound interstitial brain diazepam concentrations are 22.3 ± 7.5 and 9.3 ± 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13- to 30-Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.

Tailoring therapeutic effect for chronotherapy of variant angina based on pharmacodynamic/deconvolution integrated model method

The onset of variant angina (VA) shows circadian rhythmicity that its attacks occur most often from midnight to early morning. Thus, chronotherapeutic treatments should be tailored accordingly to its occurrence frequency. Tanshinol (TS), the bioactive component of Salvia miltiorrhiza was used as the model drug. The pharmacokinetics, pharmacodynamics and PK-PD relationship of TS was investigated in angina model rabbits. The therapeutic effect of TS was evaluated from different aspects including cardiac injury, oxidative stress and vascular endothelium by measuring the serum levels of cTn-I, CK-MB, SOD and NO. In addition, the change of cTn-I levels from baseline as the pharmacodynamic endpoint was used for establishing the pharmacodynamic model. To synchronize the therapeutic effect profile of TS to the occurrence frequency of VA, ideal time courses of therapeutic effect, plasma concentration and drug release were simulated and calculated based on pharmacodynamic/deconvolution integrated model method. Then, sustained release pellets of TS (TS-SRPs) were developed according to the above calculated results and evaluated in vitro-in vivo. The established pharmacodynamic model of TS could precisely quantify the relationship between its effect and concentration. Then, ideal time courses of therapeutic effect, plasma concentration and release of TS were simulated and calculated successfully. After formulation optimization, the prepared TS-SRPs exhibited similar in vitro and in vivo behaviors to the corresponding ideal ones. Meanwhile, the effect curves of TS were synchronous with the occurrence frequency of VA, implying that appropriate therapeutic effect could be provided according to the needs of patients. In conclusion, the tailor of therapeutic effect based on integrated model method is efficient, feasible and reliable.

A Pharmacokinetic and Metabolism Study of the TRPC6 Inhibitor SH045 in Mice by LC-MS/MS.

TRPC6, the sixth member of the family of canonical transient receptor potential (TRP) channels, contributes to a variety of physiological processes and human pathologies. This study extends the knowledge on the newly developed TRPC6 blocker SH045 with respect to its main target organs beyond the description of plasma kinetics. According to the plasma concentration-time course in mice, SH045 is measurable up to 24 h after administration of 20 mg/kg BW (i.v.) and up to 6 h orally. The short plasma half-life and rather low oral bioavailability are contrasted by its reported high potency. Dosage limits were not worked out, but absence of safety concerns for 20 mg/kg BW supports further dose exploration. The disposition of SH045 is described. In particular, a high extravascular distribution, most prominent in lung, and a considerable renal elimination of SH045 were observed. SH045 is a substrate of CYP3A4 and CYP2A6. Hydroxylated and glucuronidated metabolites were identified under optimized LC-MS/MS conditions. The results guide a reasonable selection of dose and application route of SH045 for target-directed preclinical studies in vivo with one of the rare high potent and subtype-selective TRPC6 inhibitors available.

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib.

Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364μg/L) and rats (0.782-2.565μg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6mg. The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.

Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats.

As antimicrobial resistance has been increasing, new antimicrobial agents are desperately needed. Azalomycin F, a natural polyhydroxy macrolide, presents remarkable antimicrobial activities. To investigate its pharmacokinetic characteristics in rats, the concentrations of azalomycin F contained in biological samples, in vitro, were determined using a validated high-performance liquid chromatography–ultraviolet (HPLC-UV) method, and, in vivo, samples were assayed by an ultra-high performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method. Based on these methods, the pharmacokinetics of azalomycin F were first investigated. Its plasma concentration-time courses and pharmacokinetic parameters in rats were obtained by a non-compartment model for oral (26.4 mg/kg) and intravenous (2.2 mg/kg) administrations. The results indicate that the oral absolute bioavailability of azalomycin F is very low (2.39 ± 1.28%). From combinational analyses of these pharmacokinetic parameters, and of the results of the in-vitro absorption and metabolism experiments, we conclude that azalomycin F is absorbed relatively slowly and with difficulty by the intestinal tract, and subsequently can be rapidly distributed into the tissues and/or intracellular f of rats. Azalomycin F is stable in plasma, whole blood, and the liver, and presents plasma protein binding ratios of more than 90%. Moreover, one of the major elimination routes of azalomycin F is its excretion through bile and feces. Together, the above indicate that azalomycin F is suitable for administration by intravenous injection when used for systemic diseases, while, by oral administration, it can be used in the treatment of diseases of the gastrointestinal tract.

Prediction of Human Pharmacokinetic Profiles of the Antituberculosis Drug Delamanid from Nonclinical Data: Potential Therapeutic Value against Extrapulmonary Tuberculosis.

Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that, in rats, delamanid was broadly distributed to various tissues in addition to the lungs. In this study, we simulated human plasma concentration-time courses (pharmacokinetic profile) of delamanid, which has a unique property of metabolism by albumin, using two different approaches (steady-state concentration of plasma-mean residence time [Css-MRT] and physiologically based pharmacokinetic [PBPK] modeling). In Css-MRT, allometric scaling predicted the distribution volume at steady state based on data from mice, rats, and dogs. Total clearance was predicted by in vitro-in vivo extrapolation using a scaled albumin amount. A simulated human pharmacokinetic profile using a combination of human-predicted Css and MRT was almost identical to the observed profile after single oral administration, which suggests that the pharmacokinetic profile of delamanid could be predicted by allometric scaling from these animals and metabolic capacity in vitro. The PBPK model was constructed on the assumption that delamanid was metabolized by albumin in circulating plasma and tissues, to which the simulated pharmacokinetic profile was consistent. Moreover, the PBPK modeling approach demonstrated that the simulated concentrations of delamanid at steady state in the lung, brain, liver, and heart were higher than the in vivo effective concentration for Mycobacterium tuberculosis. These results indicate that delamanid may achieve similar concentrations in various organs to that of the lung and may have the potential to treat extrapulmonary tuberculosis.

Pharmacokinetics/Pharmacodynamic Analysis to Link Pharmacokinetics to Efficacy and Drug Interaction of Alzheimer's Disease Drugs

In recent years, the number of patients with Alzheimer's type dementia continues to increase year by year. As a first-line drug, cholinesterase inhibitor is used. There is a close relationship between the time course of the drug plasma concentration (pharmacokinetics; PK) and the time course of its effects and side effects (pharmacodynamics; PD). However, the relationship between PK and PD is not simply that plasma concentrations are proportional to the effects. The effect is expressed through the characteristics of various pharmacokinetic processes. Therefore, it is important to investigate the transition of effects accompanying its pharmacokinetics. We conducted a fundamental PK/PD analysis using donepezil. Time course of acetylcholine in the hippocampus was investigated with relation to its PK after donepezil administration using rats. The PK and PD characteristics of the drug, including its active metabolite, were investigated. Additionally, Alzheimer's type dementia drugs are often given in combination with antiplatelet drugs such as cilostazol. It is reported that donepezil and cilostazol interact clinically, partly due to inhibition in the efflux transporters in certain tissues. There are various transporters in the body, and interactions through them may cause unexpected changes in the effects. So, it is important to calculate the correlation between the donepezil level in plasma and tissues after their combined administration. From the PK/PD point of view, the results of this study will provide insight into the time course of effects and the characteristics of drug-drug interaction in clinical practice.

Validation of an LC-MS/MS Method to Quantify the New TRPC6 Inhibitor SH045 (Larixyl N-methylcarbamate) and Its Application in an Exploratory Pharmacokinetic Study in Mice.

TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from Larix decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2–1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC50 values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies.

Extent and rate of oral drug absorption in minipigs: Comparison with mice, rats and humans

In this study, in order to evaluate the usability of minipigs as an experimental animal in the oral drug development process, extent and rate of oral absorption of 17 commercially drugs were investigated in minipigs and compared with those in mice rats and humans. Extent of oral bioavailability (BA) of tested drugs tended to be lower in minipigs as well as in mice and rats than in humans. From a pharmacokinetic (PK) analysis, it was revealed that the higher activity of intestinal first-pass metabolism, thus the lower intestinal availability, is a major factor causing the lower extent of BA in minipigs, rats and mice than in humans. Whereas the similar value of hepatic availability was observed between minipigs and humans, suggesting the advantage of minipigs to use in oral absorption study for high hepatic clearance drugs. On the other hand, from the plasma concentration-time profiles of orally administered drugs, gastric emptying and intestinal transit rates in minipigs were indicated to be slower than other animals and humans. These slow processes of gastrointestinal transit in minipigs might cause the difficulty in simulating the time-course of plasma concentrations of orally administered drugs in humans, especially as sustained release or controlled release products.

Changing the Drug Delivery System: Does It Add to Non-Compliance Ramifications Control? A Simulation Study on the Pharmacokinetics and Pharmacodynamics of Atypical Antipsychotic Drug.

This study investigates the pharmacokinetic (PK) and pharmacodynamic (PD) consequences of shifting from Quetiapine fumarate immediate-release (IR) to extended-release (XR) formulation in non-adherent schizophrenia patients. Monte-Carlo simulations using population PK and PD models were implemented to predict the time course of plasma concentration and Brief Psychiatric Rating Scale (BPRS) scores following the oral administration of 200 mg Seroquel® every 12 h and 400 mg Seroquel XR® every 24 h in patients experiencing dose delay, omission or doubling. Parameters were computed and their distributions were compared using the Kolmogorov–Smirnov test. Dose irregularities with both formulations had different effects on plasma concentration and %reduction in BPRS scores from baseline. However, the odds ratio of getting a %reduction in BPRS below 14%, or plasma concentration exceeding 500 µg/L, were comparable for adherent and non-adherent patients. Plasma therapeutic concentration after treatment cessation was maintained for <24 h in 48% and 29.6% of patients, and a steady state recovery time of <48 h was achieved in 51% and 13.4% of patients on the IR and XR formulations, respectively. Monte-Carlo simulations predict that the risks associated with the IR dose irregularities are not worsened when the XR formulation is used instead. Non-adherence events involving a single dose of either formulation do not require rescue doses.

Toxicokinetics of bisphenol-S and its glucuronide in plasma and urine following oral and dermal exposure in volunteers for the interpretation of biomonitoring data

The measurement of bisphenol-S (BPS) and its glucurono-conjugate (BPSG) in urine may be used for the biomonitoring of exposure in populations. However, this requires a thorough knowledge of their toxicokinetics. The time courses of BPS and BPSG were assessed in accessible biological matrices of orally and dermally exposed volunteers. Under the approval of the Research Ethics Committee of the University of Montreal, six volunteers were orally exposed to a BPS-d8 deuterated dose of 0.1 mg/kg body weight (bw). One month later, 1 mg/kg bw of BPS-d8 were applied on 40 cm2 of the forearm and then washed 6 h after application. Blood samples were taken prior to dosing and at fixed time periods over 48 h after treatment; complete urine voids were collected pre-exposure and at pre-established intervals over 72 h postdosing. Following oral exposure, the plasma concentration–time courses of BPS-d8 and BPSG-d8 over 48 h evolved in parallel, and showed a rapid appearance and elimination. Average peak values (±SD) were reached at 0.7 ± 0.1 and 1.1 ± 0.4 h postdosing and mean (±SD) apparent elimination half-lives (t½) of 7.9 ± 1.1 and 9.3 ± 7.0 h were calculated from the terminal phase of BPS-d8 and BPSG-d8 in plasma, respectively. The fraction of BPS-d8 reaching the systemic circulation unchanged (i.e. bioavailability) was further estimated at 62 ± 5% on average (±SD) and the systemic plasma clearance at 0.57 ± 0.07 L/kg bw/h. Plasma concentration–time courses and urinary excretion rate profiles roughly evolved in parallel for both substances, as expected. The average percent (±SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 over the 0–72 h period postdosing was 1.72 ± 1.3 and 54 ± 10%. Following dermal application, plasma levels were under the lower limit of quantification (LLOQ) at most time points. However, peak values were reached between 5 and 8 h depending on individuals, suggesting a slower absorption rate compared to oral exposure. Similarly, limited amounts of BPS-d8 and its conjugate were recovered in urine and peak excretion rates were reached between 5 and 11 h postdosing. The average percent (±SD) of the administered dose recovered in urine as BPS-d8 and BPSG-d8 was about 0.004 ± 0.003 and 0.09 ± 0.07%, respectively. This study provided greater precision on the kinetics of this contaminant in humans and, in particular, evidenced major differences between BPA and BPS kinetics with much higher systemic levels of active BPS than BPA, an observation explained by a higher oral bioavailability of BPS than BPA. These data should also be useful in developing a toxicokinetic model for a better interpretation of biomonitoring data.

Effects of mild and moderate renal dysfunction on pharmacokinetics, pharmacodynamics, and safety of dotinurad: a novel selective urate reabsorption inhibitor

BackgroundDotinurad, a novel selective urate reabsorption inhibitor, exerts a serum uric acid-lowering effect by selectively inhibiting urate transporter 1 (URAT1) in patients with hyperuricemia. It is generally known that the progression of renal dysfunction is associated with a reduction in the serum uric acid-lowering effects of uricosuric drugs. We, therefore, investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with renal dysfunction.MethodsThis was a parallel-group, open-label, single-dose clinical pharmacology study. Dotinurad (1 mg) was administered once, orally to subjects with mild (estimated glomerular filtration rate [eGFR], ≥ 60 to < 90 mL/min/1.73 m2) or moderate (eGFR, ≥ 30 to < 60 mL/min/1.73 m2) renal dysfunction or normal (eGFR, ≥ 90 mL/min/1.73 m2) renal function.ResultsThe time-course of mean plasma concentration of dotinurad had similar profiles across the groups. Regarding PK, there was no significant difference between the renal dysfunction groups and normal renal function group. Regarding PD, the maximum reduction rate in serum uric acid levels and the fractional uric acid excretion (FE) ratio (FE0–24/FE−24–0) were significantly lower in the moderate renal dysfunction group than in the normal renal function group. However, other PD parameters were not significantly different among the groups. No notable adverse events or adverse drug reactions were observed in this study.ConclusionThese results suggested that no dose adjustment might be necessary when administering dotinurad to patients with mild-to-moderate renal dysfunction.ClinicalTrials.gov Identifier: NCT02347046.

WHAT NEXT FOR THE PGC? WHAT NEXT FOR PSYCHIATRIC GENETICS?

Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [11C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ± 21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.

Pharmacokinetics of Micafungin in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis With High Cutoff Membranes.

An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO). Prospective observational study performed in critically ill patients treated with 100 mg/d of micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and micafungin concentrations were determined using HPLC-UV. Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model. This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of micafungin, and that standard doses of this antifungal can be used.