Correlation of the Plasma Concentration of Eltrombopag With Efficacy in the Treatment of Refractory Aplastic Anemia: A Single-Centre Study in China

Background and purpose: Eltrombopag (ELT) can be effective in the treatment of relapse/refractory aplastic anemia (AA) patients. Responses and adverse drug reactions (ADRs) differed greatly among individuals treated at the same dosage of ELT.Methods: Patients diagnosed with nonsevere aplastic anemia (NSAA) between January 2018 and January 2019 in Peking Union Medical Colleague Hospital who were refractory to immunosuppressive therapy were treated with ELT and followed up for at least 6 months. Plasma concentrations of ELT were detected by high-performance liquid chromatography-mass spectrometry after at least two months of ELT treatment and treatment at the same dosage for at least 2 weeks. The dose-concentration, concentration-response and concentration-ADR relationships were evaluated.Results: Among the 72 patients treated with ELT during the study period, 44 patients with complete data were enrolled. Six (13.6%) were males, and 38 were females (86.4%), with a median age of 54 years [interquartile range (IQR): 38.5–63]. At the time the ELT plasma concentration was detected, the median dosage of ELT was 75 (IQR 50–100) mg/d, the median time of total ELT exposure was 3 (IQR 2.0–6.0) months, and 37 (70.5%) patients had responded to ELT. The median concentration of ELT was 10.4 μg/ml (IQR 3.7–24.4 μg/ml). The concentration of ELT was positively correlated with the daily dose of ELT (r = 0.68, p < 0.001). Multivariate logistic regression analysis showed that the risk of inefficacy of ELT at a concentration between 11.2 and 15.2 μg/ml was 0.028-fold (95% CI: 0.001–0.864; p = 0.041) of that at a concentration between 3.2 and 7.2 μg/ml. The cutoff value for the concentration of ELT showing efficacy was 12.50 μg/ml according to the receiver operation characteristic curve. A higher risk of ADR was related to a longer total exposure to ELT (p = 0.012). Although the correlation was not significant, the odds ratio increased with the ELT concentration, suggesting that it was possible that an elevated risk of ADR was correlated with the ELT blood concentration.Conclusion: ELT is effective for the treatment of NSAA and has acceptable side effects. The plasma concentration of ELT was correlated with the dose and the effects of ELT.

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Plasma Concentration of Eltrombopag Correlated with the Efficacy in the Treatment of Refractory Aplastic Anemia: A Single-Center Study in China

Blood ◽

10.1182/blood-2020-134626 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-9

Author(s):

Wei Zuo ◽

Bo Zhang ◽

Jing Ruan ◽

Miao Chen ◽

Jian Li ◽

...

Keyword(s):

Plasma Concentration ◽

Aplastic Anemia ◽

High Performance ◽

Conflicts Of Interest ◽

Characteristic Curve ◽

Plasma Concentrations ◽

Multivariate Logistic Regression Analysis ◽

National Medical ◽

Dose Concentration ◽

The Usa

Background and purpose: Eltrombopag (ELT) was effective in the treatment of relapse/refractory aplastic anemia (AA) patients. Response and adverse drug reaction (ADR) differed greatly among individuals even at the same dosage of ELT. Methods: Patients diagnosed with non-severe aplastic anemia (NSAA) between January 2018 to January 2019 in Peking Union Medical Colleague Hospital who were refractory to immunosuppressive therapy were treated with ELT and followed up for at least 6 months. Plasma concentrations of ELT were detected by the high-performance liquid chromatography-mass spectrometry after at least two months of ELT treatment and staying for that dosage for at least two weeks. Dose-concentration, concentration-response and concentration- ADR relation were evaluated. Results: Among the 72 patients treated with ELT during that period, 44 patients with complete data were enrolled. 6 (13.6%) were males and 38 were females (86.4%) with a median age of 54 years (IQR: 38.5-63). By the time of plasma concentration detected, the median dosage of ELT was 75(IQR 50-100) mg/d and median time for total ELT exposure was 3 (IQR 2.0-6.0) months, and 37 (70.5%) patients responded to ELT. The median concentration of ELT was 10.4μg/ml (IQR 3.7-24.4μg/ml). The concentration of ELT was positively correlated with the daily dose of ELT (r = 0.68, p < 0.001). Multivariate logistic regression analysis showed that the risk of inefficacy of ELT with a concentration between 11.2-15.2 μg/ml was 0.028-fold (95% CI: 0.001-0.864; P=0.041) to those with a concentration between 3.2-7.2μg/ml. The cutoff value of concentration for ELT efficacy was 12.50μg/ml by receiver operation characteristic curve. A higher risk of ADR was related to a longer total exposure to ELT (P=0.012). Although not significant, odd ratio (OR) increased with ELT concentration, suggesting a possible elevated risk of ADR correlated with blood concentration. Conclusions: ELT is effective for the treatment of NSAA with accepTable side effects. Plasma concentration of ELT correlated with the dose and the effects of ELT. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Eltrombopag (ELT) has been proven to induce trilinear hematopoietic responses in relapse/refractory AA patients and has been approval as a monotherapy in relapsed/refractory SAA in the USA and Europe. However, the use of ELT is only approved for idiopathic thrombocytopenic purpura (ITP) in China by the National Medical Products Administration (NMPA), for AA it is still "off-label".

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High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction

Cancers ◽

10.3390/cancers13143425 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3425

Author(s):

Takayuki Takahashi ◽

Hideyuki Terazono ◽

Takayuki Suetsugu ◽

Hideki Sugawara ◽

Junko Arima ◽

...

Keyword(s):

Plasma Concentration ◽

Adverse Effects ◽

Dose Reduction ◽

Roc Curve ◽

High Performance ◽

Kinase Inhibitor ◽

Plasma Concentrations ◽

Laboratory Data ◽

Trough Plasma Concentration ◽

Trough Plasma

Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.

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First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j37s4k ◽

2015 ◽

Vol 18 (3) ◽

pp. 256

Author(s):

Wang Ping ◽

Yin Tao ◽

Ma HongYing ◽

Liu DanQi ◽

Sheng Yanghao ◽

...

Keyword(s):

Cytochrome P450 ◽

Plasma Concentration ◽

Genetic Polymorphisms ◽

High Performance ◽

Permutation Test ◽

Plasma Concentrations ◽

Nucleotide Polymorphisms ◽

Abcb1 Gene ◽

Epileptic Patients

Purpose: Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). Methods: Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). Results: In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. Conclusion: CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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HPLC Method for Quantification of Caffeine and Its Three Major Metabolites in Human Plasma Using Fetal Bovine Serum Matrix to Evaluate Prenatal Drug Exposure

Journal of Analytical Methods in Chemistry ◽

10.1155/2018/2085059 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Rosa del Carmen Lopez-Sanchez ◽

Victor Javier Lara-Diaz ◽

Alejandro Aranda-Gutierrez ◽

Jorge A. Martinez-Cardona ◽

Jose A. Hernandez

Keyword(s):

Plasma Concentration ◽

Analytical Method ◽

Bovine Serum ◽

High Performance ◽

Drug Exposure ◽

Fetal Bovine Serum ◽

Plasma Concentrations ◽

Prenatal Drug Exposure ◽

Biological Matrix ◽

Fetal Bovine

Caffeine is recognized as the first-line therapeutic agent for apnea of prematurity. The dosage regimen is 10 mg/kg loading dose and 2.5 mg/kg maintenance dose. However, the plasma concentration achieved, not always, is therapeutically useful. It makes necessary to increase the doses to reach plasma concentration up to 30 or 35 μg/mL or even higher to attain therapeutic effect. To study why neonates have these differences, and whether these effects are linked to prenatal caffeine exposure, we had to develop an analytical method for an accurate measurement of caffeine and metabolites concentration. The analysis was carried out using fetal bovine serum (FBS) as biological matrix in a high-performance liquid chromatography with an ultraviolet detector method. This method allows acceptable chromatographic resolution between analytes in 15 minutes. It was validated and proved to be linear in the 0.1–40 µg/mL range for caffeine, paraxanthine, theobromine, and theophylline in the same chromatographic analysis. Accuracy for quality control samples for intra- and interday assays was ranged from 96.5 to 105.2% and 97.1 to 106.2%. Precision had CV no more than 10% in all concentration levels for all analytes. No differences were observed between quantification in human and FBS. This method was applied to quantify plasma drug concentration in mothers and their newborns in a Mexican northeast population. In our study, we confirmed self-reported caffeine maternal intake in 85.2% (n=23); meanwhile, in their newborn’s plasma, it was detected only in 78% (n=21). Caffeine plasma concentrations in mother and newborn had a linear relationship, and no differences were observed between groups (mothers versus children). These results suggest that our analytical method and substitution of biological matrix was linear, precise, and accurate for caffeine quantification and could be used for measuring prenatal exposure and let us to study, in the future, concentration differences observed during apnea clinical treatment.

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Effect of CYP2D6 polymorphisms on plasma concentration and therapeutic effect of risperidone

BMC Psychiatry ◽

10.1186/s12888-020-03034-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jinjun Lu ◽

Ye Yang ◽

Jian Lu ◽

Zuqing Wang ◽

Yiping He ◽

...

Keyword(s):

Plasma Concentration ◽

Side Effects ◽

High Performance ◽

Rating Scale ◽

Psychiatric Symptoms ◽

Plasma Concentrations ◽

Density Lipoprotein ◽

Chronic Schizophrenia ◽

Metabolic Effects ◽

Adverse Side Effects

Abstract Background This study aimed to investigate the influence of CYP2D6 polymorphisms on risperidone plasma concentrations in patients with schizophrenia. Based on pharmacogenomics, we examined whether plasma concentration of risperidone is associated with clinical response and adverse side-effects. Methods We recruited patients with chronic schizophrenia who were then treated with risperidone. The CYP2D6 genotypes were determined using targeted sequencing. All high-frequency mutation sites of the nine exons of the gene were assayed in the present study. Plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-RIS) were measured using high-performance liquid chromatography (HPLC). Psychiatric symptoms were monitored using The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Adverse effects were evaluated using the Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS). Follow-up visits were scheduled at weeks 2,4, and 8 after treatment initiation. Results Among the 76 patients, 100 C > T (rs1065852), 1038 C > T (rs1081003), 1662 G > C (rs1058164), 2851 C > T (rs16947), and 4181G > C (rs1135840) variants were detected. The most common allele was CYP2D6*10 (81.6%), whereas CYP2D6*2 (9.2%) and CYP2D6*5 (17.1%) were relatively rare. Plasma levels of risperidone and the risperidone/9-OH risperidone ratio (R/9-OH) were significantly increased in individuals with CYP2D6*10 (P < 0.05). The change in PANSS score, weight, high-density lipoprotein (HDL) level, prolactin (PRL) level, and ESRS were significantly different from baseline, between the different genotypes (P < 0.01). Moreover, individuals with CYP2D6*10 homozygous (TT) mutations were associated with higher risperidone concentration and R/9-OH ratio than those with heterozygous mutations (CT) (P < 0.01). A change from baseline in BPRS scores was observed only during week 8 and was different between heterozygous and homozygous mutations. As for the C2851T polymorphism, the incidence of adverse metabolic effects was significantly different between the C/C and C/T genotypes (P < 0.01). Regarding the G4181C polymorphisms, the changes from baseline in GLU and TG, were different between the C/C and C/G genotypes (P < 0.01). Conclusions The genotype of CYP2D6 significantly influences the plasma concentration of risperidone and may subsequently influence the adverse side-effects following risperidone treatment, while also exerting a slight influence on clinical outcomes.

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Risk Factors for Higher-than-Expected Residual Rivaroxaban Plasma Concentrations in Real-Life Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1639585 ◽

2018 ◽

Vol 118 (05) ◽

pp. 808-817 ◽

Cited By ~ 9

Author(s):

Andreas Schedler ◽

Alexander Jetter ◽

Burkhardt Seifert ◽

Donat Spahn ◽

Philipp Stein ◽

...

Keyword(s):

Plasma Concentration ◽

Kidney Function ◽

Medical Records ◽

Pharmacokinetic Model ◽

Elective Surgery ◽

Plasma Concentrations ◽

Real Life ◽

Factor Xa ◽

Single Centre Study

Introduction Rivaroxaban (RXA) is a direct oral factor Xa (Xa) antagonist with a short half-life and a fast onset and offset of effect. Before elective surgery, discontinuation is recommended with an interval of at least > 24 hours. In clinical practice, this is, however, not always sufficient to achieve a residual RXA plasma concentration deemed appropriate for surgery, defined as ≤ 50 mcg/L. Our study aimed at identifying factors associated with a higher-than-expected residual RXA plasma concentration in a large group of real-life patients. Materials and Methods This retrospective single-centre study included all patients taking RXA between 2012 and 2016 where RXA plasma concentration was determined by pharmacodynamic anti-Xa assay (518 measurements in 368 patients). Medical records were reviewed. Residual RXA plasma concentrations were then compared with expected values according to a pharmacokinetic model. Results Residual RXA plasma concentration was significantly higher-than-expected in patients with atrial fibrillation, impaired kidney function (glomerular filtration rate [GFR] < 60 mL/min), CYP3A4-, CYP2J2- and PGP-inhibitory co-medication including amiodarone. Impaired kidney function (odds ratio [OR], 2.22, 95% confidence interval [CI], 1.30–3.78, p = 0.003) and concomitant amiodarone intake (OR, 1.97, 95% CI, 1.04–3.72, p = 0.036) were significantly associated with RXA plasma concentrations > 50 mcg/L at 24 to 48 hours after the last RXA intake. Conclusion In our group of real-life patients, impaired kidney function (GFR < 60 mL/min) and co-medication with amiodarone were independently associated with higher-than-expected residual RXA plasma concentrations. In these patients, standard intervals of RXA discontinuation may not always be sufficient before elective surgery and routine pre-operative determination of the residual RXA concentration could be advisable.

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Comparative Study between Propofol in a Long-chain Triglyceride and Propofol in a Medium/Long-chain Triglyceride during Sedation with Target-controlled Infusion

Anaesthesia and Intensive Care ◽

10.1177/0310057x0503300301 ◽

2005 ◽

Vol 33 (3) ◽

pp. 351-355 ◽

Cited By ~ 3

Author(s):

M. Yamakage ◽

S. Iwasaki ◽

S-W. Jeong ◽

S-I. Ishiyama ◽

A. Namiki

Keyword(s):

Plasma Concentration ◽

High Performance ◽

Plasma Concentrations ◽

Pharmacokinetics And Pharmacodynamics ◽

Blood Concentrations ◽

Arterial Blood ◽

Target Controlled Infusion ◽

Long Chain Triglycerides ◽

Long Chain ◽

Long Chain Triglyceride

This study was performed to compare the pharmacological characteristics of propofol in an emulsion of both medium- and long-chain triglycerides (MCT/LCT) with those of propofol in an LCT emulsion, by measuring the sedative level and the plasma concentration of propofol during sedation using a target-controlled infusion (TCI) technique. Forty ASA 1 or 2 adult patients who required spinal anaesthesia for surgery were enrolled in this study. The patients were divided into two groups: a propofol LCT group (n=20) and a propofol MCT/LCT group (n=20). Propofol was injected intravenously at target blood concentrations of 2.0, 3.0 and 4.0 μg.ml–1. The bispectral (BIS®) index was recorded, and arterial blood was drawn to measure the actual plasma concentrations of propofol at each predicted concentration. Propofol was assayed by high-performance liquid chromatography. Propofol MCT/LCT was associated with significantly less pain than propofol LCT (P<0.05). There were no significant differences between the two groups in BIS® index or in plasma concentration of propofol at each predicted concentration. Computer-generated TCI of propofol MCT/LCT during sedation is comparable with that of propofol LCT with respect to pharmacokinetics and pharmacodynamics. The formulation of MCT/LCT has a beneficial effect with respect to less pain on injection.

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Study on the relationship between rivaroxaban and factor Xa activity in blood based on HPLC-MS/MS

Current Drug Metabolism ◽

10.2174/1389200222666211126093627 ◽

2021 ◽

Vol 22 ◽

Author(s):

Hongchuan Liu ◽

Zhixia Zhao ◽

Yingkai Wang ◽

Lihong Liu ◽

Yuanhua Yang ◽

...

Keyword(s):

Plasma Concentration ◽

High Performance ◽

Plasma Concentrations ◽

Factor Xa ◽

Bleeding Risk ◽

Tandem Mass ◽

Chromatography Tandem Mass Spectrometry ◽

Liquid Chromatography Tandem Mass ◽

The Relationship

Objective: The aim of the study was to investigate a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of rivaroxaban and evaluate the correlation between plasma concentration and anti-Xa activity in patients using oral rivaroxaban. Methods: In this study, the plasma concentration of rivaroxaban and anti-Xa factor activities was determined in 125 patients, and the relationship between the two variables was analysed by SPSS 21.0 software. Results: The results showed that the plasma concentrations of oral rivaroxaban patients were significantly correlated with the activity of the anti-Xa factor (Spearman’s r = 0.990, p <0.05). Conclusion: The plasma concentrations of rivaroxaban are a potentially useful monitoring indicator to assess the patient’s bleeding risk if testing for plasma anti-Xa activity is not available.

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Clinical Impact of Co-medication of Levetiracetam and Clobazam with Proton Pump Inhibitors: A Drug Interaction Study

Current Drug Metabolism ◽

10.2174/1389200221666200218121050 ◽

2020 ◽

Vol 21 (2) ◽

pp. 126-131

Author(s):

Bhuvanachandra Pasupuleti ◽

Vamshikrishna Gone ◽

Ravali Baddam ◽

Raj Kumar Venisetty ◽

Om Prakash Prasad

Keyword(s):

Plasma Concentration ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Plasma Concentrations ◽

Control Group ◽

Drug Concentrations ◽

Significant Difference ◽

Post Hoc ◽

Hydrolysis Of ◽

Cytochrome P 450

Background: Clobazam (CLBZ) metabolized primarily by Cytochrome P-450 isoenzyme CYP3A4 than with CYP2C19, Whereas Levetiracetam (LEV) is metabolized by hydrolysis of the acetamide group. Few CYP enzymes are inhibited by Proton Pump Inhibitors (PPIs) Pantoprazole, Esomeprazole, and Rabeprazole in different extents that could affect drug concentrations in blood. The aim of the present study was to evaluate the effect of these PPIs on the plasma concentrations of LEV and CLBZ. Methods: Blood samples from 542 patients were included out of which 343 were male and 199 were female patients and were categorized as control and test. Plasma samples analyzed using an HPLC-UV method. Plasma concentrations were measured and compared to those treated and those not treated with PPIs. One way ANOVA and games Howell post hoc test used by SPSS 20 software. Results: CLBZ concentrations were significantly 10 folds higher in patients treated with Pantoprazole (P=0.000) and 07 folds higher in patients treated with Esmoprazole and Rabeprazole (P=0.00). Whereas plasma concentration of LEV control group has no statistical and significant difference when compared to pantoprazole (P=0.546) and with rabeprazole and esomeprazole was P=0.999. Conclusion: The effect of comedication with PPIs on the plasma concentration of clobazam is more pronounced for pantoprazole to a greater extent when compared to esomeprazole and rabeprazole. When pantoprazole is used in combination with clobazam, dose reduction of clobazam should be considered, or significance of PPIs is seen to avoid adverse effects.

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Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

2020 ◽

Vol 16 ◽

Author(s):

Xi He ◽

Wenjun Hu ◽

Fanhua Meng ◽

Xingzhou Li

Keyword(s):

Plasma Concentration ◽

Broad Spectrum ◽

Plasma Concentrations ◽

Antiviral Drug ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Hydroxyl Group ◽

First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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