Plasma Drug Research Articles

DESIGN AND CHARACTERIZATION OF NATEGLINIDE ORAL DISPERSIBLE TABLETS BY SOLID DISPERSION TECHNIQUE

An ideal dosage regimen in the drug therapy of any disease is the one which immediately attains the desired therapeutic concentration of drug in plasma and maintains it constant for the entire duration of treatment. The main objective of the present work is to investigate the possibility of obtaining an immediate release tablet of Nateglinide with improved dissolution using the Solid dispersion technique. Solid dispersions preparations containing different weight ratios of Nateglinide in PEG6000 (1:1, 1:3, 1:5) were prepared by the melting method and characterized for drug content, phase solubility study, and dissolution study. Immediate release tablets were prepared using various polymers, and the prepared tablets were evaluated for weight variation, friability, assay, hardness, thickness, disintegration test and dissolution test. The Nateglinide immediate release tablet (F2) showed 58.72% drug release within the first 5 min. and 99.50% drug release within 30 min. The results showed that the formulation satisfied the objective of fast disintegration, dissolution, % friability, hardness, wetting time, water absorption ratio, ease of administration and safety. The success of the present study recommends a detailed investigation into in-vivo studies for its effective use in clinical practice.

Sex-Based Evaluation of Lipid Profile in Postoperative Adjuvant Mitotane Treatment for Adrenocortical Carcinoma.

Background: A wide interindividual variability in mitotane concentrations and treatment-related dyslipidemia have been reported. Here, we aimed to underline the sex-related differences in the lipid profile in patients that underwent radical surgery of adrenocortical carcinoma during treatment with adjuvant mitotane. Methods: A chromatographic method was used to quantify the drug in plasma collected from adult patients with complete tumor resection, also considering active metabolite o,p’-DDE. Results: We observed different lipid profiles between males and females and between pre- and post-menopausal women. Considering the mitotane-related effects on lipid levels, we observed that higher drug concentrations were correlated with higher HDL in all the considered groups (p < 0.001), with total cholesterol both in males (p = 0.005) and females (p = 0.036), with triglycerides in postmenopausal females (p = 0.002) and with LDL in male patients (p < 0.001). Increases in o,p’-DDE were positively correlated with HDL levels in all the groups (p < 0.001) and negatively with LDL in all the groups (males p = 0.008, pre- and post-menopausal females p < 0.001), with total cholesterol in pre- (p = 0.016) and post-menopausal women (p = 0.01) and with triglycerides in premenopausal females (p = 0.005). Conclusions: This is the first study designed to evaluate sex differences in lipoprotein and lipid levels during mitotane adjuvant treatment; the results suggest that a gender and personalized approach could be useful to prevent and manage alterations in the lipid profile.

Therapeutic potential of interleukin-2 in autoimmune diseases.

Autoimmune diseases are characterized by dysregulation and aberrant activation of cells in the immune system. Therefore, restoration of the immune balance represents a promising therapeutic target in autoimmune diseases. Interleukin-2 (IL-2) can promote the expansion and differentiation of different immune cell subsets dose-dependently. At high doses, IL-2 can promote the differentiation and expansion of effector and memory T cells, whereas at low doses, IL-2 can promote the differentiation, survival, and function of regulatory T (Treg) cells, a CD4+ T cell subset that is essential for the maintenance of immune homeostasis and immune tolerance. Therefore, IL-2 exerts immunostimulatory and immunosuppressive effects in autoimmune diseases. The immunoregulatory role of low-dose IL-2 has sparked excitement for the therapeutic exploration of modulating the IL-2-Treg axis in the context of autoimmune diseases. In this review, we discuss recent advances in the therapeutic potential of IL-2 or IL-2-derived molecules in the treatment of autoimmune diseases.

Review on Characterization, Properties, and Analytical Methods of Cefepime.

Infection is one of the most important reasons for the increase in the number of deaths worldwide; it can be a bacterial or viral infection. As a result, there are many effective drugs against this infection, especially bacterial ones. Cefepime (CP) is one of the fourth generations of cephalosporins and is distinguished from others in that it can kill both positive and negative bacteria. Therefore, this study focused on the chemical properties of the drug, its uses, and its stability against bacteria. All analysis methods for this drug in pharmaceutical preparations, blood, or plasma were also presented. One of the important problems in these methods is using toxic solvents, which poses a danger to society and the environment. The presentation of these solvents will allow companies to manufacture and use more effective and less toxic solvents.

A Simple and Sensitive UPLC-UV Method for Simultaneous Determination of Isoniazid, Pyrazinamide, and Rifampicin in Human Plasma and Its Application in Therapeutic Drug Monitoring.

As the first-line clinical drugs for tuberculosis (TB), isoniazid (INH), pyrazinamide (PZA), and rifampicin (RMP) are playing important roles for preventing the rapid spread of TB. Precise quantification of these drugs in biological samples is crucial to evaluate or improve the efficacy of advanced TB drug delivery systems, which are designed for reducing drug resistance, minimizing side effects, etc. Herein, a simple and sensitive method based on UPLC–UV was established and investigated for simultaneous quantification of PZA, INH, and RMP in human plasma and was applied to anti-TB drug therapeutic drug monitoring. The analytes were implemented on an HSS T3 C18 column at 40°C. The separation was performed with a gradient elution with methanol–acetonitrile–water (3:3:94) at 0.1 ml/min. The analysis only involved plasma with a small volume of 100 µL and a rapid one-step protein precipitation with methanol–acetonitrile (1:1). The results showed that the calibration curves for INH, PZA, and RMP were linear in a range of 0.5–20 μg/ml, 5–60 μg/ml, and 5–60 μg/ml, respectively. The intra- and inter-day precisions were both smaller than 15%, and the lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.5 μg/ml for INH and 5 μg/ml for both PZA and RMP, respectively. The target drugs in plasma were stable after 21 days of storage at −80°C. The results indicated that our developed method is suitable for the simultaneous monitoring of INH, PZA, and RMP in human plasma.

Development and evaluation of a simple and easy high-performance liquid chromatography-ultraviolet system simultaneously suitable for determination of 24 anti-epileptic drugs in plasma.

We aim to establish a simple and easy high-performance liquid chromatography system coupled with an ultraviolet detector suitable for simultaneous determination of 24 antiepileptic drugs in human plasma. Optimized chromatographic separation was performed on a ZORBAX Eclipse Plus-C18 (4.6 × 150mm2 , 3.5 μm) column with acetonitrile and 5mM potassium dihydrogen phosphate water solution as mobile phase. Note that, 24 antiepileptic drugs were divided into three groups and eluted with different gradient procedures, respectively. The column temperature was maintained at 35°C and the detection wavelength was set at 210nm. Plasma was processed with ethyl acetate or acetonitrile. The calibration curves of 24 antiepileptic drugs demonstrated good linearity within the test range (r>0.996). The intra- and inter-batch precision and accuracy were all less than 15%, while extraction recoveries were in the range of 74.57-90.89% with the relative standard deviation values less than 15%. The validated methods have been successfully applied to determination of some antiepileptic drugs in rat or patient plasma. Those results indicated that the developed methods were simple and easy, and could be suitable for the determination of 24 antiepileptic drugs in plasma just by changing the gradient elution procedures of mobile phase.

Evaluation of Impact of Concomitant Drugs in Human Plasma on LC-MS/MS Based Quantification of Olmesartan and Hydrochlorothiazide

Liquid chromatography tandem mass spectrometer (LC-MS/MS) is an advanced analytical technique, which requires a validated method for a particular drug, prior to analysis of study samples. The analytical method must be selective with ability to distinguish between analyte of interest and endogenous or exogenous interferents (salts, proteins, lipids, metabolites, and concomitant medications). Concomitant medications are general treatment taken by subject population. Regulatory guidelines advocate evaluation of effects of co-medication on analytical methods, but detailed description of experiment designs is not yet reported. In the present study, a simple procedure to evaluate the co-medication effects on LC-MS/MS based simultaneous quantitation of Olmesartan and hydrochlorothiazide is explained. This is the first report that provides details on experimental design for assessing effects of co-medications on LC-MS/MS based quantitation of drugs in biological samples. This experimental design is likely to facilitate assessment of effect of co-medications on analytical methods applied in pharmacokinetics, drug development, and therapeutic monitoring.

Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment.

ABSTRACTTebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).

Simultaneous determination of novel β-lactamase inhibitor WCK 4234 and Meropenem in dog plasma by LC-MS/MS and its application to preclinical pharmacokinetic study.

A precise and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) bioanalytical method has been developed and validated for the simultaneous quantification of WCK 4234 and meropenem (MEM) in dog plasma. Protein precipitation using acetonitrile was employed as a sample preparation approach. Cefepime was used as an internal standard. The developed method was selective, sensitive (limit of quantification, 0.075 μg/ml for both drugs), accurate (recovery > 90%), precise (CV <10%) and linear (r2 ≥0.99, concentration range 0.075-120 μg/ml for both analytes). The developed method was successfully applied for the determination of both drugs in plasma to assess the pharmacokinetics in beagle dogs. WCK 4234 + MEM in a 1:1 ratio at 15 + 15 and 30 + 30 mg/kg doses were administered by the intravenous route. The mean plasma concentration and area under the concentration-time curve of WCK 4234 ranged from 38.3 to 77.4μg/ml and from 47.8 to 77.1μg h/ml, respectively, and the values for MEM ranged from 52.2 to 115.3μg/ml and 70.5 to 133.6μg h/ml respectively. The elimination half-life of WCK 4234 and MEM was around 0.8h.

Protein-Induced Fluorescence Enhancement and Quenching in a Homogeneous DNA-Based Assay for Rapid Detection of Small-Molecule Drugs in Human Plasma.

Homogeneous assays for determining the concentration of small molecules in biological fluids are of importance for monitoring blood levels of critical drugs in patients. We have developed a strand displacement competition assay for the drugs dabigatran, methotrexate, and linezolid, which allows detection and determination of the concentration of the drugs in plasma; however, a surprising kinetic behavior of the assay was observed with an initial rapid change in apparent FRET values. We found that protein-induced fluorescent enhancement or quenching (PIFE/Q) caused the initial change in fluorescence within the first minute after addition of protein, which could be exploited to construct assays for concentration determination within minutes in the low nanomolar range in plasma. A kinetic model for the assay was established, and when taking the new finding into account, the in silico simulations were in good agreement with the experimentally observed results. Utilizing these findings, a simpler assay was constructed for detection of dabigatran, which allowed for detection within minutes without any time dependencies.

Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

Development of a Next-Generation Ionisation Technique in Mass Spectrometry

Mass spectrometry (MS) has a wide range of applications. Assistant Professor I-Chung Lu, Department of Chemistry, National Chung Hsing University, Taiwan, is working to improve and better understand aspects of MS in order to further broaden its possible applications. A particular focus for Lu and his team is on developing novel techniques or improving conventional ionisation methods to overcome application difficulties in MS, specifically in the detection of labile and unstable species. Those techniques extend the MS as a powerful tool to study critical reaction intermidiates and mechanisms. A novel ionisation technique called matrix-assisted ionisation (MAI) is another research focus for Lu and is something that he wants to shed greater light on due to its unclear ionisation process and potential for MS. Lu is seeking to enhance fundamental knowledge of spontaneously charge separation by studying ionisation processes in MAI. Lu and the team have combined a portable spectrometer and dedicated MAI source that has proven to directly detect drugs in urine and blood plasma rapidly. This fast-screen platform also has potential application to the diagnosis and clinical fields.

Preclinical evaluation of LCK as a novel therapeutic target in YAP-activated and FGFR2-altered cholangiocarcinoma.

463 Background: Molecularly targeted therapy is gaining traction in cholangiocarcinoma with the first FDA approval of a targeted agent in 2020, the FGFR inhibitor pemigatinib. Yet response rates and efficacy are modest, and most cholangiocarcinoma patients still lack targeted therapy options. The hippo pathway effector, YAP, is an oncogene that is activated in the majority of cholangiocarcinoma, yet attempts to develop YAP inhibitors have not yet been clinically successful. Recently, we described a novel mechanism of YAP regulation, via tyrosine phosphorylation by the Src-family kinase LCK. Therefore we hypothesized that LCK inhibition by may be therapeutic in cholangiocarcinoma through suppression of YAP activity. Methods: NTRC 0652-0 is a novel tyrosine kinase inhibitor with specificity for LCK. In vitro pharmacodynamics were defined. In cholangiocarcinoma cells, specificity for LCK inhibition was determined by mass spectrometry-based unbiased analysis of the tyrosine phosphoproteome following treatment with NTRC 0652-0 or genetic deletion of LCK. YAP phosphorylation and cotranscriptional activity, cell viability, and apoptosis were assessed. A panel of eight cholangiocarcinoma patient derived organoids (PDO) were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft (PDX) models bearing FGFR2-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. Results: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in cholangiocarcinoma cells. NTRC 0652-0 treatment led to YAP inhibition and apoptotic cell death in cholangiocarcinoma cell lines, associated with inhibition of MCL1 expression. PDOs demonstrated variable sensitivity to NTRC 0652-0, correlated with basal YAP tyrosine phosphorylation and drug-induced suppression of YAP co-transcriptional activity. FGFR2-altered cholangiocarcinoma was also identified as a subset with enrichment of YAP target genes. Cells from an FGFR2-altered PDX were sensitive to NTRC 0652-0 despite being primarily resistant to pemigatinib. In two PDX models of FGFR2-altered cholangiocarcinoma, daily oral treatment with NTRC 0652-0 inhibited YAP tyrosine phosphorylation, and resulted in stable plasma and tumor drug levels, acceptable toxicity, and significantly decreased tumor growth. Conclusions: A novel LCK inhibitor, NTRC 0652-0, reduced YAP signaling and demonstrated preclinical efficacy in multiple patient-derived models of cholangiocarcinoma. LCK is a novel therapeutic target in cholangiocarcinoma, and YAP activation or FGFR2-alteration are potential biomarkers for response.

Development and Validation of Highly Sensitive LC–ESI-MS/MS Method for Bortezomib and Its Applications for Plasma Levels and Drug Content of Branded and Generic Formulations in India

Development and Validation of Highly Sensitive LC–ESI-MS/MS Method for Bortezomib and Its Applications for Plasma Levels and Drug Content of Branded and Generic Formulations in India

Pharmacokinetics and Safety Studies in Rodent Models Support Development of EPICERTIN as a Novel Topical Wound-Healing Biologic for Ulcerative Colitis.

The novel wound-healing biologic EPICERTIN, a recombinant analog of cholera toxin B subunit, is in early development for the management of ulcerative colitis. This study established for the first time the pharmacokinetics (PK), bioavailability (BA), and acute safety of EPICERTIN in healthy and dextran sodium sulfate-induced colitic mice and healthy rats. For PK and BA assessments, single administrations of various concentrations of EPICERTIN were given intravenously or intrarectally to healthy and colitic C57BL/6 mice and to healthy Sprague-Dawley rats. After intravenous administration to healthy animals, the drug's plasma half-life (t 1/2) for males and females was 0.26 and 0.3 hours in mice and 19.4 and 14.5 hours in rats, respectively. After intrarectal administration, drug was detected at very low levels in only four samples of mouse plasma, with no correlation to colon epithelial integrity. No drug was detected in rat plasma. A single intrarectal dose of 0.1 µM (0.6 µg/mouse) EPICERTIN significantly facilitated the healing of damaged colonic epithelium as determined by disease activity index and histopathological scoring, whereas 10-fold higher or lower concentrations showed no effect. For acute toxicity evaluation, healthy rats were given a single intrarectal administration of various doses of EPICERTIN with sacrifice on Day 8, recording body weight, morbidity, mortality, clinical pathology, and gross necropsy observations. There were no drug-related effects of toxicological significance. The no observed adverse effect level (intrarectal) in rats was determined to be 5 µM (307 µg/animal, or 5.2 µg drug/cm2 of colorectal surface area), which is 14 times the anticipated intrarectally delivered clinical dose. SIGNIFICANCE STATEMENT: EPICERTIN is a candidate wound-healing biologic for the management of ulcerative colitis. This study determined for the first time the intravenous and intrarectal pharmacokinetics and bioavailability of the drug in healthy and colitic mice and healthy rats, and its acute safety in a dose-escalation study in rats. An initial therapeutic dose in colitic mice was also established. EPICERTIN delivered intrarectally was minimally absorbed systemically, was well tolerated, and induced epithelial wound healing topically at a low dose.

Transdermal Patches: A review of a new drug delivery system approach

Background: Transdermal patch is a transdermal delivery system that can overcome problems in conventional drug administration such as oral drug administration. Patches can provide controlled drug release and have advantages over oral administration such as avoiding first pass metabolism, increasing drug bioavailability, avoiding adverse effects on the gastrointestinal (GI) tract, minimizing patient variability, maintaining a constant drug in plasma, and providing a stable therapeutic effect. The effectiveness of a patch is determined by the ability of the drug to release from the patch matrix and penetrate into the stratum corneum. According to the method used to make the patches, they are divided into single layer, multi-layer, reservoir system, and matrix system patches. The basic components of a patch are polymer matrix, membrane, drug, permeation enhancer, pressure-sensitive adhesives, backing film, release liner, and plasticizer. Methods of review : This review refers to several previously published data regarding physical characteristics and transdermal drug release. This review also includes some explanations regarding the patch as a transdermal drug delivery system. Conclusion: This review focuses on patch analysis methods after the manufacturing process such as physical characteristics test, in vitro drug release test, in vitro skin permeation test, skin irritation test, and stability test as well as some explanations related to transdermal drug delivery system.

Development of UPLC-MS/MS method and its pharmacokinetic application for estimation of sertraline in rat plasma

The current research aims to develop a rapid, sensitive and robust UPLC-MS/MS method for quantitative estimation of sertraline in rat plasma following oral administration of lipid-based formulation. Different types of isocratic systems were tried for optimization of mobile phase to attain good resolution and appropriate retention time. The multiple reaction monitoring transitions of m/z 306.3 → 159.1 and 515.2 → 276.1 were used to quantify sertraline and internal standard, respectively. The method was validated for different parameters as per the guideline of the United States Food and Drug administration (USFDA). The validated linearity range of sertraline was found to be 1-1,00 ng/mL in rat plasma with 0.1 ng/mL as lower limit of quantification. The intra-day and inter-day precision (RSD%) were within 7.6-10.6% and the accuracies (RE%) were ± 8.0%. The results showed a good percentage recovery of analytes within acceptance limit. No significant degradation of drug in plasma was observed during the stability study. The method demonstrated short analytical run time (< 3 min), low sensitivity (0.1 ng/mL) and requirement of small amount of plasma (50 µL) for extraction procedure.Overall, this method•Results in an optimized and validated assay for estimation of sertraline in plasma.•Offers a cost effective mobile phase with excellent linearity, sensitivity, accuracy, and precision. The method suggested its application in pharmacokinetic study of sertraline administered via oral route.•The method can be used for therapeutic drug monitoring in drug designing. The method can also be used for toxicity and bioequivalence studies.

A Simple and Reliable RPLC Method for Simultaneous Determination of Five β-Blocker Drugs in Pharmaceuticals and Human Plasma

A simple and reliable simultaneous determination of β-blocker drugs (acebutolol, pindolol, atenolol, nadolol and oxprenolol) was accomplished by reversed phase liquid chromatography-ultraviolet detection (RPLC/UV). The chromatographic separation was achieved on a SB-C18 ZORBAX® column (250 mm × 4.6 mm i.d., 5 micron), using a mobile phase consisted of 0.02 mol L-1 phosphate buffer (pH = 3.5)-acetonitrile (70:30, v/v). Isocratic elution was used at a flow rate of 1.0 mL min-1. The UV detector was operated at 230 nm and the column temperature was maintained at 30 °C. Under optimal conditions, a good linearity in the range of 10-500 μg L–1 for five β-blocker drugs with the correlation of determinations (R2) higher than 0.9971 was achieved. The proposed method was successfully applied to routine analysis of several β-blockers in pharmaceutical tablets. Moreover, the results obtained from this study demonstrated that the validated method can be successfully used to routine analyze the therapeutic concentrations of several β-blockers in human plasma. The LOD and LOQ for selected β-blockers were ranged within 0.050-0.538 and 0.152-1.794 μg L-1 &amp; 0.192-0.845 and 0.641-2.562 μg L-1, respectively, for pharmaceutical and plasma samples. Results of intra-day and inter-day precision expressed in terms of %RSD were found to be less than 2.0. Accuracy of the RPLC method was assessed by performing replicate analyses of selected β-blockers in samples against a calibration curve indicating high recoveries within 96.7-110.5%. This new method could be used for analysis of large sample series of five β-blockers in routine laboratory work.

Partial Validation of Ultra Performance Liquid Chromatography Method for Quantification of Isoniazid-Pyrazinamide in Human Samples

Isoniazid (INH) and pyrazinamide (PZA) are first-line drugs in the treatment of meningitis of tuberculosis, in addition to rifampicin. The use of these drugs will determine the success of therapy to kill Mycobacterium tuberculosis in brain tissue that is difficult to penetrate by other drugs. Therefore, it is necessary to conduct research and monitor the use of this drug in plasma and cerebrospinal fluid (CSF) patients with TBM. This study aimed to determine the method of analysis of INH and PZA using Ultra Performance Liquid Chromatography Ultra Violet (UPLC-UV). The samples were taken from TBM patients who taken INH-PZA and others besides TBM patients who did not take INH-PZA. The analytic method carried out includes a comparison of the results of the analysis method for measuring levels of standard INH-PZA and INH-PZA in plasma and CSF samples. Analysis of INH-PZA in plasma and CSF can be performed using UPLC with UV detector, at least 100 uL plasma or CSF samples volume, with reproducible and accurate results.

Concentration-Response Model of Immediate Release Oxycodone Drug Liking by Different Routes of Abuse.

To understand the correlation between oxycodone concentration and drug liking response for immediate-release formulations as they relate to different doses and different routes of administration following manipulation involved in opioid misuse and nontherapeutic use. Concentration-response and noncompartmental analyses of drug liking and plasma oxycodone data from Category 3 human abuse potential studies (n = 15-29 per study) were conducted, using Phoenix 6.0 software. Time to onset of a set threshold of subjective effects (Tonset) and offset of subjective effects (Toffset) were estimated based on a baseline pharmacodynamic response set at 50 on a bipolar Drug Liking visual analog scale of 0-100 and the threshold for drug liking set at ≥65, based on study qualification criteria. Partial Area Under the Concentration (AUCTonset-Toffset) and Effect (AUETonset-Toffset) profiles were calculated and their correlation with individual partial AUE vs partial AUC was assessed. The oxycodone concentration-response (drug liking) was best described by a sigmoidal-effect Emax model (S-shaped). Using a defined threshold, drug liking was closely associated with the rate of rise in concentration and the onset of action for oxycodone administered via oral or intranasal route. Partial AUCTonset-Toffset and AUETonset-Toffset showed a strong linear correlation. Results indicate that oxycodone concentration-response and duration of drug liking following manipulation via different routes of administration may be an approach for further exploring drug liking effects of opioids.