Development and validation of ultra-performance liquid chromatography-tandem mass spectrometric methods for simultaneous and rapid determination of contezolid and its major metabolite M2 in plasma and urine samples and its application to a study in subjects with moderate liver impairment.

Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment.

Nonclinical Evaluation of Antibacterial Oxazolidinones Contezolid and Contezolid Acefosamil with Low Serotonergic Neurotoxicity.

Linezolid, the principal oxazolidinone antibiotic for therapy of Gram-positive infections, is limited by its myelosuppression and monoamine oxidase (MAO) inhibition, with the latter manifested as serotonergic neurotoxicity. The oral oxazolidinone contezolid and its injectable prodrug contezolid acefosamil are developed to overcome the above limitations. Serotonergic profiles for contezolid in vitro and for orally administered contezolid acefosamil in rodents are reported. Contezolid exhibited 2- and 148-fold reduction over linezolid reversible inhibition of MAO-A and MAO-B human enzyme isoforms. In the mouse head-twitch model, contezolid acefosamil was devoid of neurotoxicity at supratherapeutic oral doses of 40, 80, and 120 mg/kg. In the rat tyramine challenge model, no significant increase in arterial blood pressure was observed for contezolid acefosamil up to 120 mg/kg oral dosing. In these tests, the comparator linezolid has elicited serotonergic responses. Thus, contezolid and contezolid acefosamil exhibited an attenuated propensity to induce MAO-related serotonergic neurotoxicity. The data support a continued clinical evaluation of these agents, with potential to expand oxazolidinone therapies to patient populations on concurrent selective serotonin reuptake inhibitor medications or where MAO inhibitors are contraindicated.

Safety and Efficacy of Oral and/or Intravenous Tedizolid Phosphate From a Randomized Phase 3 Trial in Adolescents With Acute Bacterial Skin and Skin Structure Infections.

BACKGROUND: Tedizolid phosphate is an oxazolidinone prodrug approved in 2014 for treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs); however, efficacy has not previously been evaluated in children. This study compared the safety and efficacy of tedizolid (administered as tedizolid phosphate) with active antibacterial comparators for the treatment of ABSSSIs in adolescents. METHODS: This was a randomized, assessor-blind, global phase 3 study of tedizolid versus active comparators for the treatment of Gram-positive ABSSSIs in adolescents (12 to <18 years of age; NCT02276482). Enrolled participants were stratified by region and randomized 3:1 to receive tedizolid phosphate 200 mg (oral and/or intravenous) once daily for 6 days or active comparator, selected by investigator from an allowed list per local standard of care, for 10 days. The primary endpoint was safety; blinded investigator's assessment of clinical success at the test-of-cure visit (18-25 days after the first dose) was a secondary efficacy endpoint. Statistical comparisons between treatment groups were not performed. RESULTS: Of the 121 participants enrolled, 120 were treated (tedizolid, n = 91; comparator, n = 29). Treatment-emergent adverse events were balanced between treatment groups (tedizolid, 14.3%; comparator, 10.3%). Overall, 3 participants (3.3%) in the tedizolid group and 1 (3.4%) in the comparator group experienced a single drug-related TEAE. Clinical success rates were high in both treatment groups: 96.7% and 93.1% at the test-of-cure visit for the tedizolid and comparator groups, respectively. CONCLUSIONS: Tedizolid demonstrated safety and efficacy similar to comparators for the treatment of ABSSSIs in adolescents.

Tedizolid-Cyclodextrin System as Delayed-Release Drug Delivery with Antibacterial Activity.

Progressive increase in bacterial resistance has caused an urgent need to introduce new antibiotics, one of them being oxazolidinones with their representative tedizolid. Despite the broad spectrum of activity of the parent tedizolid, it is characterized by low water solubility, which limits its use. The combination of the active molecule with a multifunctional excipient, which is cyclodextrins, allows preservation of its pharmacological activity and modification of its physicochemical properties. Therefore, the aim of the study was to change the dissolution rate and permeability through the model membrane of tedizolid by formation of solid dispersions with a cyclodextrin. The research included identification of tedizolid-hydroxypropyl-ß-cyclodextrin (tedizolid/HP-ß-CD) inclusion complex by thermal method (Differential Scanning Colorimetry), spectroscopic methods (powder X-ray diffraction, Fourier-Transform Infrared spectroscopy), and molecular docking. The second part of the research concerned the physicochemical properties (dissolution and permeability) and the biological properties of the system in terms of its microbiological activity. An increase in the dissolution rate was observed in the presence of cyclodextrin, while maintaining a high permeation coefficient and high microbiological activity. The proposed approach is an opportunity to develop drug delivery systems used in the treatment of resistant bacterial infections, in which, in addition to modifying the physicochemical properties caused by cyclodextrin, we observe a favorable change in the pharmacological potential of the bioactives.

Effect of Anacetrapib on Cholesterol Efflux Capacity: A Substudy of the DEFINE Trial.

Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24-week follow-up using J774 macrophages, boron dipyrromethene difluoride-labeled cholesterol, and apolipoprotein B-depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard ß, 0.23; 95% CI, 0.05-0.41). This CEC-raising effect was seen only in men (P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1-1 haptoglobin genotype (standard ß, 0.42; 95% CI, 0.16-0.69) but not the dysfunctional 2-1/2-2 genotypes (P interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high-density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.

Quality by Design Approach for Preparation of Zolmitriptan/Chitosan Nanostructured Lipid Carrier Particles - Formulation and Pharmacodynamic Assessment.

PURPOSE: Zolmitriptan (ZT) is a selective serotonin agonist that is used for the treatment of migraine. It belongs to BCS class III with high solubility and low permeability. Besides, the drug is subjected to pre-systemic metabolism. Accordingly, new Zolmitriptan/chitosan nanostructured lipid carriers (ZT/CT NLCs) coated with Tween 80 (stealthy layer) have been developed to overcome such demerits. METHODS: The NLCs were developed by combining ultrasonication and double emulsion (w/o/w) techniques. The lipids were Gelucire and Labrasol. Herein, the quality by design (23 full factorial design) was scrupulously followed, where critical process parameters and critical quality attributes were predefined. The optimized formulation (F8) was fully characterized with respect to entrapment efficiency (%EE), percentage yield (% yield), particle size, size distribution (PDI), zeta potential (ZP), morphological appearance (TEM). In vitro release, stability study and pharmacodynamic evaluations were also assessed. The optimized freeze dried formula was dispensed in in situ gelling hard gelatin capsule encompassing pectin and guar gum for further in vitro and pharmacodynamic evaluations. RESULTS: The optimized spherical nanoparticles experienced high percentage EE and yield (78.14% and 60.19%, respectively), low particle size and PDI (343.87 nm and 0.209, respectively), as well as high negative ZP (-25.5 mV). It showed good physical stability at refrigerated conditions. The NLCs dispensed in in situ gelling hard gelatin capsule comprising pectin and guar gum experienced sustained release for 30 h and significantly maintained the pharmacological effect in mice up to 8 h (p < 0.001). CONCLUSION: ZT, a BCS class III drug that suffers from poor permeability and pre-systemic metabolism, was successfully maneuvered as nanostructured lipid carrier particles (NLCs). The incorporation of the NLCs in in situ gelling hard gelatin capsules fulfilled a dual function in increasing permeability, as well as sustaining the pharmacodynamic effect. This result would open new vistas in improving the efficacy of other class III drugs.

Population Pharmacokinetics Study of Contezolid (MRX-I), a Novel Oxazolidinone Antibacterial Agent, in Chinese Patients.

PURPOSE: Contezolid (MRX-I) is a novel oxazolidinone with potent in vitro activity against gram-positive pathogens. The aim of this study was to establish the dose-pharmacokinetic (PK) exposure-pharmacodynamic (PD)-response relationship and to quantitatively evaluate the variability of MRX-I after continuous oral administration of 600 mg BID and 800 mg BID for 14 days under fed conditions in patients with skin and skin structure infections. Another goal was to evaluate the 2 dosing regimens against methicillin-resistant Staphylococcus aureus infections based on PK/PD analysis. METHODS: PK data from healthy volunteers and patients were pooled to develop a population PK model using a nonlinear mixed effect modeling method. Monte Carlo simulations were used to predict probability of target attainment (PTA) and cumulative fraction of response after single oral administration of 600 and 800 mg of MRX-I under fed conditions. FINDINGS: The PK profile of oral administration of MRX-I was described by using a 2-compartment model with first-order elimination. Absorption of MRX-I may be affected by food intake. Type of volunteers could affect absorption constant rate and volume of distribution in the peripheral compartment, and weight could affect volume of distribution in the central department. No obvious effect on PK parameters was identified for other factors such as age, sex, creatinine clearance, concomitant medicine, and baseline diseases. Based on Monte Carlo simulation, MRX-I 600 or 800 mg BID up to 14 days on ordinary fed status could produce satisfactory efficacy against methicillin-resistant S aureus, with cumulative fraction of response >90% for fAUC0-24/MIC targeted at 2.3. At MIC ≤2.0 µg/mL for MRX-I 600 mg BID, or at MIC ≤4.0 µg/mL for MRX-I 800 mg BID, with continuous administration for 14 days at fed status, both regimens could obtain satisfactory clinical and antibacterial efficacy, with PTA >90%. Hence, the MRX-I regimen of 800 mg BID for 7-14 days can be recommended for confirmative clinical trials in patients with skin and skin structure infections. IMPLICATIONS: PK profiles of MRX-I were well captured by using a 2-compartment PK model, and disease status, food intake, and weight were found to significantly affect PK profiles. A dosing regimen of 800 mg BID for 7-14 days with ordinary food intake was recommended for pivotal study based on simulated fAUC0-24/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.

Tedizolid (torezolid) for the treatment of complicated skin and skin structure infections.

INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSSI) are among the most frequent infectious diseases. Recently, several new antibiotics with activity against MRSA have been approved. Tedizolid, a second-generation oxazolidinone approved for ABSSSI offers theoretical advantages over first-generation oxazolidinones. AREAS COVERED: A comprehensive online search of Medline, ClinicalTrials.gov, and conference presentations was made, selecting articles between January 2000 and April 2020. In this review, the authors discuss the chemical and microbiological properties of tedizolid, summarize its efficacy, safety, and potential role in the treatment of ABSSSI as well as the potential for future indications. EXPERT OPINION: Tedizolid has proven to be non-inferior compared to linezolid for the treatment of ABSSSI in two registrational phase III clinical trials, being well tolerated. Tedizolid exhibits antibacterial activity against the most important ABSSSI pathogens (including multidrug-resistant strains of MRSA), as well as mycobacteria and Nocardia. It appears to have a safe profile, including decreased myelotoxicity and no significant drug interactions. Preliminary studies with longer duration of therapy seem to confirm these potential benefits. Overall, tedizolid expands the newly acquired armamentarium to treat ABSSSI. The role of tedizolid for other indications is under investigation and has yet to be determined.

Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4/5 and P-Glycoprotein Inhibitor (Itraconazole).

The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open-label, single-sequence drug-drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug-drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUCinf ) of rovatirelin increased 3.05-fold and 2.82-fold, respectively, and the 90% confidence intervals of the ratios for Cmax (2.64-3.52) and AUCinf (2.47-3.23) did not fall within the 0.8-1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUCinf ratio with coadministration; however, renal clearance did not change. Cmax , AUCinf , and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco-2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P-gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4/5 and intestinal P-gp.

Neuropeptide S Displays as a Key Neuromodulator in Olfactory Spatial Memory.

Neuropeptide S (NPS) is an endogenous peptide recently recognized to be presented in the brainstem and believed to play an important role in maintaining memory. The deletion of NPS or NPS receptor (NPSR) in mice shows a deficit in memory formation. Our recent studies have demonstrated that central administration of NPS facilitates olfactory function and ameliorates olfactory spatial memory impairment induced by muscarinic cholinergic receptor antagonist and N-methyl-D-aspartate receptor antagonist. However, it remains to be determined if endogenous NPS is an indispensable neuromodulator in the control of the olfactory spatial memory. In this study, we examined the effects of NPSR peptidergic antagonist [D-Val5]NPS (10 and 20 nmol, intracerebroventricular) and nonpeptidergic antagonist SHA 68 (10 and 50 mg/kg, intraperitoneal) on the olfactory spatial memory using computer-assisted 4-hole-board olfactory spatial memory test in mice. Furthermore, immunofluorescence was employed to identify the distributions of c-Fos and NPSR immunoreactive (-ir) neurons in olfactory system and hippocampal formation known to closely relate to the olfactory spatial memory. [D-Val5]NPS dosing at 20 nmol and SHA 68 dosing at 50 mg/kg significantly decreased the number of visits to the 2 odorants interchanged spatially, switched odorants, in recall trial, and simultaneously reduced the percentage of Fos-ir in NPSR-ir neurons, which were densely distributed in the anterior olfactory nucleus, piriform cortex, subiculum, presubiculum, and parasubiculum. These findings suggest that endogenous NPS is a key neuromodulator in olfactory spatial memory.

Pharmacokinetic study and brain tissue analysis of Zolmitriptan loaded chitosan nanoparticles in rats by LC-MS method.

INTRODUCTION: Migraine has recently become a major interest to the neuroscientists. Zolmitriptan is an effective medicine used in the treatment of migraine. The nasal spray was prepared from Zolmitriptan loaded chitosan nanoparticles and evaluated for pharmacokinetic properties. METHODS: In this study male Wistar albino rats weighing between 200 and 250 g were taken and divided into 4 groups with 6 rats in each group. Nasal spray containing Zolmitriptan loaded Chitosan nanoparticles were administered nasally (using specific inhalation mask) at a dose of 0.5 mg/kg as a test formulation and compared with the control groups which received either water for injection or marketed standard drug (Zolmist) or standard drug solution at a same dose. The pharmacokinetic parameters such as Cmax, Tmax, and brain tissue analyses for accumulation of drug were performed for Zolmitriptan by LC-MS method. RESULTS: Amount of drug in the plasma from the test formulation, standard marketed drug (Zolmist) and standard drug solution was found to be 41.37 ±â€¯2.31, 34.76 ±â€¯4.22 and 23.74 ±â€¯2.42 ng/ml at 10 min respectively, which indicated significantly (p < 0.05) greater amount of drug being delivered from the test formulation compared to the both standard groups. The amount of the drug (Zolmitriptan) present in brain tissue (Olfactory lobe) was found to be 15 ±â€¯0.08, 13 ±â€¯0.14 and 8 ±â€¯0.13 ng/g at 60 min for test formulation, marketed standard and standard drug solution respectively which indicates significantly (p < 0.05) higher amount of drug absorption in brain tissue from the test formulation compared to both the standard groups. CONCLUSION: Pharmacokinetics studies of nasal spray containing Zolmitriptan loaded chitosan nanoparticles proved rapid onset of action in animals and is promising in treatment of migraine.

Practical Approach to Modeling the Impact of Amorphous Drug Nanoparticles on the Oral Absorption of Poorly Soluble Drugs.

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.

Impact of drug distribution into adipose on tissue function: The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib as a test case.

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid-modifying agent that reduces LDL-cholesterol and increases HDL-cholesterol in hypercholesterolemic patients. Anacetrapib demonstrates a long terminal half-life and accumulates in adipose tissue, which contributes to a long residence time of anacetrapib. Given our previous report that anacetrapib distributes into the lipid droplet of adipose tissue, we sought to understand whether anacetrapib affected adipose function, using a diet-induced obese (DIO) mouse model. Following 20 weeks of treatment with anacetrapib (100 mg/kg/day), levels of the drug increased to approximately 0.6 mmol/L in white adipose tissue. This level of anacetrapib was not associated with any impairment in adipose functionality as evidenced by a lack of any reduction in biomarkers of adipose functionality (plasma adiponectin, leptin, insulin; adipose adiponectin, leptin mRNA). In DIO wild-type (WT) mice treated with anacetrapib for 2 weeks and then subjected to 30% food restriction during washout to induce weight loss (18%) and fat mass loss (7%), levels of anacetrapib in adipose and plasma were not different between food restricted and ad lib-fed mice. These data indicate that despite deposition and long-term residence of ~0.6 mmol/L levels of anacetrapib in adipose tissue, adipose tissue function appears to be unaffected in mice. In addition, these data also indicate that even with severe caloric restriction and acute loss of fat mass, anacetrapib does not appear to be mobilized from the fat depot, thereby solidifying the role of adipose as a long-term storage site of anacetrapib.

Assessment Of Spanlastic Vesicles Of Zolmitriptan For Treating Migraine In Rats.

OBJECTIVE: To develop and evaluate zolmitriptan spanlastics (Zol SLs) as a brain-targeted antimigraine delivery system. Spanlastics (SLs) prepared using span 60: tween 80 (70:30%, respectively) gave the highest percentage of entrapment efficiency (EE%). MATERIALS AND METHODS: A total of 60 adult male Wistar albino rats were divided into six groups (n=10 rats/group). Group 1 (Control) comprised rats serving as a negative control. Group 2 was treated with glyceryl trinitrate (NTG) and served as the positive control. Groups 3 (NTG+Zol com), Group 4 (NTG+Zol sol) and Group 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally. RESULTS: We found decreased Tmax, increased Cmax, AUC0-6, AUC0-∞ and ameliorated behaviour in rats (head scratching) treated with intranasal SLs compared to oral commercial zolmitriptan. CONCLUSION: Our study substantiates the enhanced efficacy of Zol SLs in brain targeting for migraine treatment.

Antibacterial Activity of Tedizolid, a Novel Oxazolidinone Against Methicillin-Resistant Staphylococcus aureus: A Systematic Review and Meta-Analysis.

Antibiotic resistance is an increasing phenomenon and has become a serious public health concern. Nowadays, limited therapeutic options exist for the treatment of invasive infections caused by drug-resistant strains, particularly methicillin-resistant Staphylococcus aureus (MRSA). The present study was conducted to analyze the published literature on the in vitro activity of tedizolid toward MRSA strains. A systematic literature search was conducted on the Web of Science, PubMed, Scopus, and Google Scholar electronic databases from January 2000 to December 2017 to cover all published articles relevant to our study. Then, 18 publications that met our inclusion criteria were selected for data extraction and analysis by the Comprehensive Meta-analysis software. The overall antibacterial activity of tedizolid on 10,119 MRSA isolates was estimated 0.25 and 0.5 µg/mL for MIC50 and MIC90 (minimum inhibitory concentration at which 50% and 90% of isolates were inhibited, respectively), respectively. The pooled prevalence of tedizolid susceptibility was estimated at 99.6% (95% confidence interval: 99.5-99.8%). Only 4 of 18 included publications have reported the antibacterial activity of tedizolid against linezolid-resistant isolates, of which the MIC range of tedizolid was 0.25-16 µg/mL. Of the four studies, all of the linezolid-resistant isolates were susceptible to tedizolid in one study, and in the other studies, the susceptibility rates were <50%. Based on the results of the systematic reviews, tedizolid had a promising antibacterial activity against MRSA isolates from different clinical sources. However, future studies are needed to provide clinical evidence to support these observations.

In-vitro and in-vivo respiratory deposition of a developed metered dose inhaler formulation of an anti-migraine drug.

Enhancement of zolmitriptan bioavailability through development of micronized zolmitriptan pressurized metered dose inhaler (MDI) as an alternative to its traditional drug delivery systems. A reversed phase HPLC method for zolmitriptan determination was developed and evaluated. Micronized zolmitriptan MDI formulations were prepared using two different propellants. The prepared formulations were evaluated for mean shot weight, drug content, and leakage rate in addition to in-vitro deposition using next generation impactor where mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle dose, fine particle fraction (FPF), emitted dose (ED), and dispersibility were determined. The selected formulation was evaluated for in-vivo bronchial absorption in rats. The physicochemical characters of the prepared formulations were found to be dependent mainly on the vapor pressure of the used propellant. MDI formulation prepared with HFA 134a propellant was found to have the lowest MMAD (3.47 ± 0.65) with GSD of 2.3 ± 0.4. It also had the highest FPF (41.9), ED (89.26 ± 2.35) with dispersibility of 46.9%. This formulation, when applied to rats, resulted in faster Tmax (27 ± 5 min) with higher Cmax (1236 ± 116 ng/mL) and AUC(0-12) (3375 ± 482 ng/mL·h) over the oral tablet. Its relative bioavailability was 72.7% which was 1.25 times higher than the oral tablet relative bioavailability. Zolmitriptan MDI formulation was developed using micronized zolmitriptan powder without further modification or particle engineering. The developed formulation using HFA 134a propellant could be favorable alternative, with enhanced bioavailability, to zolmitriptan oral tablet for acute migraine treatment.

Tolerability and Pharmacokinetics of Contezolid at Therapeutic and Supratherapeutic Doses in Healthy Chinese Subjects, and Assessment of Contezolid Dosing Regimens Based on Pharmacokinetic/Pharmacodynamic Analysis.

PURPOSE: This study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis. METHODS: A Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus, Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response. FINDINGS: Single-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC50 and MIC90 (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%). IMPLICATIONS: Contezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074.

Steady-state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug-resistant tuberculosis.

AIMS: Despite terizidone being part of the second-line recommended drugs for treatment of drug-resistant tuberculosis (DR-TB), information on its pharmacokinetics is scarce. The aim of this study was to describe the steady-state population pharmacokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients with DR-TB and determine the effect of patient characteristics. METHODS: This clinical study involved 39 adult DR-TB patients admitted to Brewelskloof Hospital in Cape Town, South Africa for intensive treatment phase. Blood samples were collected at predose and 0.5, 1, 2, 3, 3.5, 4, 8, 16 and 24 hours after drug administration. The estimation of PPK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R1. Free-fat mass was used to perform allometric scaling on disposition parameters. RESULTS: A 1-compartment model best described the pharmacokinetics of terizidone and cycloserine. A modified transit compartment model described the absorption of terizidone. The parameters of terizidone model were mean transit time (1.7 h), absorption rate constant (2.97 h-1 ), apparent volume of distribution (Vp/F: 13.4 L) and apparent total clearance (0.51 L h-1 ). In the joint model, apparent fraction of terizidone converted to cycloserine was 0.29 while apparent clearance of terizidone via other routes and apparent cycloserine clearance was 0.1 L h-1 and 2.94 L h-1 , respectively. Serum albumin had significant effect on Vp/F. CONCLUSIONS: The developed PPK model described well the concentration-time profile for terizidone and cycloserine in DR-TB patients. High albumin concentration was associated with low Vp/F.