The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform
Pierre Mugabo - One of the best experts on this subject based on the ideXlab platform.
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steady state population pharmacokinetics of Terizidone and its metabolite cycloserine in patients with drug resistant tuberculosis
British Journal of Clinical Pharmacology, 2019Co-Authors: Mwila Mulubwa, Pierre MugaboAbstract: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.
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amount of cycloserine emanating from Terizidone metabolism and relationship with hepatic function in patients with drug resistant tuberculosis
Drugs in R & D, 2019Co-Authors: Mwila Mulubwa, Pierre MugaboAbstract:The dosing of cycloserine and Terizidone is the same, as both drugs are considered equivalent or used interchangeably. Nevertheless, it is not certain from the literature that these drugs are interchangeable. Therefore, the amount of cycloserine resulting from the metabolism of Terizidone and the relationship with hepatic function were determined. This prospective clinical study involved 39 patients with drug-resistant tuberculosis admitted for an intensive phase of treatment. Cycloserine pharmacokinetic parameters for individual patients, like area under the curve (AUC), clearance (CLm/F), peak concentration (Cmax) and trough concentration (Cmin), were calculated from a previously validated joint population pharmacokinetic model of Terizidone and cycloserine. Correlation and regression analyses were performed for pharmacokinetic parameters and unconjugated bilirubin (UB), conjugated bilirubin (CB), albumin, the ratio of aspartate transaminase to alanine aminotransferase (AST/ALT), or binding affinity of UB to albumin (Kaf), using R statistical software version 3.5.3. Thirty-eight patients took a daily dose of 750 mg Terizidone, while one took 500 mg. The amount of cycloserine [median (range)] that emanated from Terizidone metabolism was 51.6 (0.64–374) mg. Cmax (R2 = 22%, p = 0.003) and Cmin (R2 = 10.6%, p = 0.044) were significantly associated with increased CB concentration. Cmax was significantly associated with increased Kaf (R2 = 10.1%, p = 0.048), while high CLm/F was significantly associated with decreased AST/ALT (R2 = 21%, p = 0.003). Cycloserine is not interchangeable with Terizidone, as amounts are lower than expected. Cycloserine may be a predisposing factor to the development of hyperbilirubinaemia, as CLm/F is affected by hepatic function.
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analysis of Terizidone in plasma using hplc uv method and its application in a pharmacokinetic study of patients with drug resistant tuberculosis
Biomedical Chromatography, 2018Co-Authors: Mwila Mulubwa, Pierre MugaboAbstract:A chromatographic method has been developed and validated for the first time for analysis of Terizidone in plasma. Terizidone was extracted from plasma by protein precipitation using a mixture of acetonitrile and methanol (1:1, v/v). The chromatographic separation was achieved with a gradient of acetonitrile and water both containing 0.1% formic acid on a Supelco Discovery® HS C18 (150 × 4.6 mm, 5 μm) reversed-phase column. Propranolol was used as the internal standard. The total run-time was 18 min. The calibration standard concentrations ranged between 3.125 and 200 μg/mL and calibration curves were linear with coefficient of determination values in the range of 0.9988-0.9999. The inter- and intra-day assay precision (percentage relative standard error) was <15% while mean accuracy was 107%. The mean extraction efficiencies of Terizidone and IS were 76 and 89%, respectively. The validation results demonstrated that the method was selective and sensitive, and that Terizidone was stable under the studied conditions. The method was successfully applied in a population pharmacokinetic study. The mean plasma concentration of Terizidone in patients at all sampling time points was 51.8 ± 28 μg/mL. The method was simple, cheap and hence suitable for therapeutic drug monitoring of Terizidone.
Mwila Mulubwa - One of the best experts on this subject based on the ideXlab platform.
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steady state population pharmacokinetics of Terizidone and its metabolite cycloserine in patients with drug resistant tuberculosis
British Journal of Clinical Pharmacology, 2019Co-Authors: Mwila Mulubwa, Pierre MugaboAbstract: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.
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amount of cycloserine emanating from Terizidone metabolism and relationship with hepatic function in patients with drug resistant tuberculosis
Drugs in R & D, 2019Co-Authors: Mwila Mulubwa, Pierre MugaboAbstract:The dosing of cycloserine and Terizidone is the same, as both drugs are considered equivalent or used interchangeably. Nevertheless, it is not certain from the literature that these drugs are interchangeable. Therefore, the amount of cycloserine resulting from the metabolism of Terizidone and the relationship with hepatic function were determined. This prospective clinical study involved 39 patients with drug-resistant tuberculosis admitted for an intensive phase of treatment. Cycloserine pharmacokinetic parameters for individual patients, like area under the curve (AUC), clearance (CLm/F), peak concentration (Cmax) and trough concentration (Cmin), were calculated from a previously validated joint population pharmacokinetic model of Terizidone and cycloserine. Correlation and regression analyses were performed for pharmacokinetic parameters and unconjugated bilirubin (UB), conjugated bilirubin (CB), albumin, the ratio of aspartate transaminase to alanine aminotransferase (AST/ALT), or binding affinity of UB to albumin (Kaf), using R statistical software version 3.5.3. Thirty-eight patients took a daily dose of 750 mg Terizidone, while one took 500 mg. The amount of cycloserine [median (range)] that emanated from Terizidone metabolism was 51.6 (0.64–374) mg. Cmax (R2 = 22%, p = 0.003) and Cmin (R2 = 10.6%, p = 0.044) were significantly associated with increased CB concentration. Cmax was significantly associated with increased Kaf (R2 = 10.1%, p = 0.048), while high CLm/F was significantly associated with decreased AST/ALT (R2 = 21%, p = 0.003). Cycloserine is not interchangeable with Terizidone, as amounts are lower than expected. Cycloserine may be a predisposing factor to the development of hyperbilirubinaemia, as CLm/F is affected by hepatic function.
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analysis of Terizidone in plasma using hplc uv method and its application in a pharmacokinetic study of patients with drug resistant tuberculosis
Biomedical Chromatography, 2018Co-Authors: Mwila Mulubwa, Pierre MugaboAbstract:A chromatographic method has been developed and validated for the first time for analysis of Terizidone in plasma. Terizidone was extracted from plasma by protein precipitation using a mixture of acetonitrile and methanol (1:1, v/v). The chromatographic separation was achieved with a gradient of acetonitrile and water both containing 0.1% formic acid on a Supelco Discovery® HS C18 (150 × 4.6 mm, 5 μm) reversed-phase column. Propranolol was used as the internal standard. The total run-time was 18 min. The calibration standard concentrations ranged between 3.125 and 200 μg/mL and calibration curves were linear with coefficient of determination values in the range of 0.9988-0.9999. The inter- and intra-day assay precision (percentage relative standard error) was <15% while mean accuracy was 107%. The mean extraction efficiencies of Terizidone and IS were 76 and 89%, respectively. The validation results demonstrated that the method was selective and sensitive, and that Terizidone was stable under the studied conditions. The method was successfully applied in a population pharmacokinetic study. The mean plasma concentration of Terizidone in patients at all sampling time points was 51.8 ± 28 μg/mL. The method was simple, cheap and hence suitable for therapeutic drug monitoring of Terizidone.
Richard Court - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of cycloserine and pharmacokinetic pharmacodynamic target attainment in multidrug resistant tuberculosis patients dosed with Terizidone
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Maxwell Chirehwa, Richard Court, Mariana De Kock, Lubbe Wiesner, Nihal De Vries, Joseph Harding, Tawanda Gumbo, Gary Maartens, R M Warren, Paolo DentiAbstract:Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis (TB). Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as Terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine when administered as Terizidone and predict the doses of Terizidone attaining cycloserine exposures associated with efficacy. The plasma cycloserine level was measured 2 to 6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. The pretreatment MICs of cycloserine were determined for the clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. The median pretreatment MIC was 16 mg/liter. A one-compartment disposition model with two clearance pathways, nonrenal (0.35 liters/h) and renal (0.43 liters/h), described cycloserine pharmacokinetics well. Nonrenal clearance and the volume of distribution were allometrically scaled using fat-free mass. Smoking increased nonrenal clearance by 41%. Simulations showed that with daily doses of Terizidone (750 mg and 1,000 mg for patients weighing ≤45 kg and >45 kg, respectively), the probability of maintaining the plasma cycloserine concentration above the MIC for more than 30% of the dosing interval (30% T >MIC) (which is associated with a 1.0-log10-CFU/ml kill in vitro) exceeded 90% at MIC values of ≤16 mg/liter, but the proportion of patients achieving 100% T >MIC (which is associated with the prevention of resistance) was more than 90% only at MICs of ≤8 mg/liter. Based on a target derived in vitro, the WHO-recommended doses of Terizidone are effective for cycloserine MICs of ≤8 mg/liter, and higher doses are required to prevent the development of resistance.
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steady state pharmacokinetics of cycloserine in patients on Terizidone for multidrug resistant tuberculosis
International Journal of Tuberculosis and Lung Disease, 2018Co-Authors: Richard Court, Lubbe Wiesner, Nihal De Vries, Joseph Harding, Tawanda Gumbo, Gary Maartens, Annemie Stewart, Helen McilleronAbstract:SETTING Terizidone/cycloserine (TRD/CS) is included in standard treatment regimens for multidrug-resistant tuberculosis (MDR-TB) in many countries. The steady state pharmacokinetics (PKs) of CS after TRD administration are not known. OBJECTIVES AND DESIGN We recruited in-patients treated with 250-750 mg oral TRD daily as part of standard treatment regimens for pulmonary MDR-TB in Cape Town, South Africa. Plasma CS assays were performed in samples taken pre-dose and at 2, 4, 6, 8 and 10 h post-dose. CS concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Non-compartmental PK analyses were performed. RESULTS Of 35 participants enrolled, 22 were males, and 20 (57%) were infected with the human immunodeficiency virus; the median age was 37 years. The median duration on TRD at the time of sampling was 33 days (interquartile range [IQR] 28-39). The area under the concentration-time curve at 0-10 h (AUC0-10) was 319 μg.h/ml (IQR 267.5-378.7), and peak concentration was 38.1 μg/ml (IQR 32.6-47.2). On multiple regression, dose (mg/kg) was the only factor independently associated with AUC0-10. CONCLUSION Steady state concentrations of CS in patients treated with TRD for MDR-TB were higher than those reported with CS formulations. Our findings support once-daily dosing.
Sonali Phadke - One of the best experts on this subject based on the ideXlab platform.
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development and validation of hptlc and lc ms ms method for estimation of Terizidone in pharmaceutical dosage form
Thai Journal of Pharmaceutical Sciences (TJPS), 2018Co-Authors: Ritesh P Bhole, Sonali PhadkeAbstract:The estimation of Terizidone in pharmaceutical dosage form by using High Performance Thin Layer Chromatography was done using CAMAG HPTLC system. The separation was achieved using precoated silica gel 60 F 254 aluminium plates with mobile phase Toluene: n-Butanol 9:1 ml % v/v at wavelength 268 nm. The linearity range was found between 50-300 ng/ml-band having correlation coefficient 0.997. The recovery study of method showed the recovery between 99.3-101.6%. The LOD and LOQ values for method were 0.981 and 2.973 respectively. The R.S.D. of precision study was less than 2. The method parameters were validated as per ICH guidelines. The forced degradation studies revealed that the drug found stable in acidic, thermal and photo degradation. The LC-MS/MS study of degraded products gave the idea about the fragmentation patterns of degraded products.The developed method can be used for routine analysis of Terizidone and its formulations.
Helen Mcilleron - One of the best experts on this subject based on the ideXlab platform.
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steady state pharmacokinetics of cycloserine in patients on Terizidone for multidrug resistant tuberculosis
International Journal of Tuberculosis and Lung Disease, 2018Co-Authors: Richard Court, Lubbe Wiesner, Nihal De Vries, Joseph Harding, Tawanda Gumbo, Gary Maartens, Annemie Stewart, Helen McilleronAbstract:SETTING Terizidone/cycloserine (TRD/CS) is included in standard treatment regimens for multidrug-resistant tuberculosis (MDR-TB) in many countries. The steady state pharmacokinetics (PKs) of CS after TRD administration are not known. OBJECTIVES AND DESIGN We recruited in-patients treated with 250-750 mg oral TRD daily as part of standard treatment regimens for pulmonary MDR-TB in Cape Town, South Africa. Plasma CS assays were performed in samples taken pre-dose and at 2, 4, 6, 8 and 10 h post-dose. CS concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Non-compartmental PK analyses were performed. RESULTS Of 35 participants enrolled, 22 were males, and 20 (57%) were infected with the human immunodeficiency virus; the median age was 37 years. The median duration on TRD at the time of sampling was 33 days (interquartile range [IQR] 28-39). The area under the concentration-time curve at 0-10 h (AUC0-10) was 319 μg.h/ml (IQR 267.5-378.7), and peak concentration was 38.1 μg/ml (IQR 32.6-47.2). On multiple regression, dose (mg/kg) was the only factor independently associated with AUC0-10. CONCLUSION Steady state concentrations of CS in patients treated with TRD for MDR-TB were higher than those reported with CS formulations. Our findings support once-daily dosing.