Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen
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ABSTRACT:
SUBMITTER: Strydom N
PROVIDER: S-EPMC11344811 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:The medium-dose etoposide (VP16) added on cyclophosphamide (CY)/total body irradiation (TBI) is one of the intensified myeloablative conditioning regimens used in allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL). However, the patient subgroups who can actually benefit from VP16/CY/TBI compared to CY/TBI have not been precisely defined. Therefore, we conducted a multi-center retrospective study using the Japanese nationwide registry database to elucidate the efficacy of VP16/CY/TBI on post-transplant prognosis. Biological and clinical distinct subtypes (i.e., Philadelphia chromosome-positive (Ph+) and -negative (Ph-) ALL) were evaluated separately, which included 820 Ph+ and 1463 patients with Ph- ALL, respectively. Compared with the CY/TBI group, the VP16/CY/TBI group showed superior progression-free survival (PFS) in patients with Ph+ ALL (65% vs. 57% at 3 years after HSCT; adjusted hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55-0.98; p = 0.03), along with significantly reduced incidence of relapse (adjusted HR, 0.58; 95% CI, 0.37-0.90; p = 0.02) without the increase of non-relapse mortality (NRM). By contrast, in patients with Ph- ALL, VP16/CY/TBI did not improve PFS nor incidence of relapse; addition of VP16 reduced relapse (HR, 0.65; p = 0.06) in patients with Ph- ALL transplanted at CR1, while improved PFS was not observed (HR, 0.90; p = 0.52) due to increased NRM. This study demonstrated that VP16/CY/TBI is a more effective and well-tolerated regimen in comparison with CY/TBI in patients with myeloablative allo-HSCT for adult Ph+ ALL. Our findings can provide a novel algorithm for conditioning regimen selection in patients with adult ALL.
| S-EPMC10084153 | biostudies-literature
Project description:BackgroundTuberculous meningitis is difficult to diagnose and is associated with high mortality. Recently, several studies evaluated the intensified regimen containing higher dose rifampin to treat tuberculous meningitis. However, this topic remains to be concluded. Therefore, this systematic review and meta-analysis was conducted to evaluate pharmacokinetics parameters, safety, and survival benefits of high-dose rifampin for tuberculous meningitis.MethodData were searched from PubMed, EMBASE, The Cochrane Library, and Web of Science for studies describing an antituberculosis regimen including a higher dose of rifampin for patients with tuberculous meningitis. The quality of eligible studies was evaluated via The Cochrane Risk of Bias Tool. The meta-analysis was performed by Review Manager 5.3 software, the synthesis of the data was shown in mean difference (MD) or relative risk (RR), and 95% confidence intervals (CIs).ResultsThere were six randomized control trails included in this meta-analysis. The results showed that the concentration in plasma and cerebrospinal fluid (CSF) were significantly higher in the intervention group than the standard group [MD = 22.08, 95%CI (16.24, 27.92), p < 0.00001; MD = 0.74, 95%CI (0.42, 1.05), p < 0.00001], as well as the area under the time concentration curve between 0 and 24 h (AUC0-24) of rifampin [MD 203.56, 95%CI (153.07, 254.05), p < 0.00001] in plasma, but the overall survival did not improve [RR = 0.92, 95%CI (0.67, 1.26), p = 0.61]. For adverse events, the results showed a statistically significant lower incidence of hypersensitivity compared with the intervention group [RR = 1.72, 95%CI (1.13, 2.62), p = 0.01]. Fortunately, other common adverse drug reactions such as liver injury, neurological events, myelosuppression, and cardiotoxicity had no significant increase [RR = 0.98, 95%CI (0.77, 1.26), p = 0.90; RR = 1.10, 95%CI (0.94, 1.30), p = 0.23; RR = 0.82, 95%CI (0.59, 1.13), p = 0.22; RR = 1.11, 95%CI (0.66, 1.86), p = 0.70].ConclusionThis meta-analysis suggested that the intensified treatment regimen including a higher dose of rifampin significantly increased the rifampin concentration both in the plasma and CSF, and it was safe in patients with tuberculous meningitis, but resulted in no improvement in survival rates.
| S-EPMC8916538 | biostudies-literature
Project description:Sirolimus is an effective oral treatment for pediatric patients with lymphangioma. The present clinical study in 15 children (0.12-16.39 years of age) examines the effects of underlying factors on sirolimus concentrations through application of a population pharmacokinetic model. Using Monte Carlo simulation, an initial dose regimen for sirolimus in pediatric patients with lymphangioma is presented. It is found that the lower the body weight, the higher the clearance rate and sirolimus clearances are 0.31-0.17 L/h/kg in pediatric patients with lymphangioma whose weights are 5-60 kg, respectively. The doses of sirolimus, 0.07, 0.06, 0.05 mg/kg/day are recommended for weights of 5-10, 10-24.5 and 24.5-60 kg in children with lymphangioma. This study is the first to establish a population pharmacokinetic model for sirolimus and to recommend initial doses in pediatric patients with lymphangioma. Large scale, prospective studies are needed in the future.
| S-EPMC8606893 | biostudies-literature
Project description:Changes in physiological factors may result in large pharmacokinetic variability of vancomycin in pediatric patients, thereby leading to either supratherapeutic or subtherapeutic exposure and potentially affecting clinical outcomes. This study set out to characterize the disposition of vancomycin, quantify the exposure target and establish an optimal dosage regimen among the Southern Chinese pediatric population. Routine therapeutic drug monitoring data of 453 patients were available. We performed a retrospective population pharmacokinetic analysis of hospitalized children prescribed intravenous vancomycin using NONMEM® software. A one-compartment PPK model of vancomycin with body weight and renal functions as covariates based on a cutoff of 2 years old children was proposed in this study. Both internal and external validation showing acceptable and robust predictive performance of the model to estimate PK parameters. The value of area under the curve over 24 h to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 260 was a significant predictor for therapeutic efficacy. Monte Carlo simulations served as a model-informed precision dosing approach and suggested that different optimal dose regimens in various scenarios should be considered rather than flat dosing. The evaluation of vancomycin exposure-efficacy relationship indicated that lower target level of AUC0-24/MIC may be needed to achieve clinical effectiveness in children, which was used to derive the recommended dosing regimen. Further prospective studies will be needed to corroborate and elucidate these results.
| S-EPMC11247118 | biostudies-literature
Project description:Contrast-enhanced MRI (CE-MRI) is the most sensitive technique for breast cancer detection. Contrast-enhanced mammography (CEM) is emerging as a possible alternative to CE-MRI.PurposeTo evaluate the diagnostic performance of a low radiation dose contrast-enhanced mammography (L-CEM) in women with suspicious findings on conventional imaging compared to CE-MRI of the breast.Study typeProspective, single center.PopulationWomen with suspicious findings on mammography, tomosynthesis, or ultrasound, and no contraindications for L-CEM or CE-MRI. Eighty women were included.Field strength/sequence1.5 and 3T CE-MRI, standard protocol for breast, with dedicated coils, according to international guidelines. L-CEM was performed using a dedicated prototype.AssessmentThree, off-site, blinded readers evaluated the images according to the BI-RADS lexicon in a randomized order, each in two separate reading sessions. Histology served as a gold standard.Statistical testLesion detection rate, sensitivity, specificity, and negative and positive predictive values (NPV, PPV) were calculated and compared with multivariate statistics.ResultsIncluded were 80 women (mean age, 54.3 years ±11.2 standard deviation) with 93 lesions (32 benign, 61 malignant). The detection rate was significantly higher with CE-MRI (92.5-94.6%; L-CEM 79.6-91.4%, P = 0.014). Sensitivity (L-CEM 65.6-90.2%; CE-MRI 83.6-93.4%, P = 0.086) and NPV (L-CEM 59.6-71.4%; CE-MRI 63.0-76.5%, P = 0.780) did not differ between the modalities. Specificity (L-CEM 46.9-96.9%; CE-MRI 37.5-53.1%, P = 0.001) and PPV (L-CEM 76.4-97.6%; CE-MRI 73.3-77.3%, P = 0.007) were significantly higher with L-CEM. Variations between readers were significant for sensitivity and NPV. The accuracy of L-CEM was as good as CE-MRI (75.3-76.3% vs. 72.0-75.3%, P = 0.514).Data conclusionL-CEM showed a high sensitivity and accuracy in women with suspicious findings on conventional imaging. Compared to CE-MRI, L-CEM has the potential to increase specificity and PPV. L-CEM might help to reduce false-positive biopsies while obtaining sensitivity comparable to that of CE-MRI LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:589-595.
| S-EPMC7496227 | biostudies-literature
Project description:Vancomycin is a synthetic antibiotic effective against Gram-positive pathogens. Although the clinical applicability of vancomycin for infants has been increasing, the pharmacokinetic data for vancomycin in extremely low-birth-weight infants are limited. The aim of this study was to construct a population pharmacokinetics model for vancomycin in extremely-low-birth-weight infants and establish an optimal dosage regimen. We enrolled children aged less than 1 year with a birth weight of less than 1,000 g and body weight at vancomycin prescription of less than 1,500 g. Pharmacokinetic data from 19 patients were analyzed, and a population pharmacokinetics model was developed using nonlinear mixed-effects modeling software. Goodness-of-fit plots, a nonparametric bootstrap analysis, and a prediction-corrected visual predictive check were employed to evaluate the final model. The dosage regimen was optimized based on the final model. The pharmacokinetic data fit a one-compartment model with first-order elimination, and body weight and estimated serum creatinine level were used as significant covariates. In a simulation using the final model, the optimal dosage regimen, especially when the serum creatinine level (>0.6 mg/dl) was high, was 5.0 to 7.5 mg/kg of body weight twice a day every 12 h; this was required to reduce the dosage compared with that in previous studies. The recommended doses based on the current target time course concentration curves may not be appropriate for extremely-low-birth-weight infants.
| S-EPMC8092535 | biostudies-literature
Project description:Clinical development of combination chemotherapies for tuberculosis (TB) is complicated by partial or restricted phase II dose-finding. Barriers include a propensity for drug resistance with monotherapy, practical limits on numbers of treatment arms for component dose combinations, and limited application of current dose selection methods to multidrug regimens. A multi-objective optimization approach to dose selection was developed as a conceptual and computational framework for currently evolving approaches to clinical testing of novel TB regimens. Pharmacokinetic-pharmacodynamic (PK-PD) modeling was combined with an evolutionary algorithm to identify dosage regimens that yield optimal trade-offs between multiple conflicting therapeutic objectives. The phase IIa studies for pretomanid, a newly approved nitroimidazole for specific cases of highly drug-resistant pulmonary TB, were used to demonstrate the approach with Pareto optimized dosing that best minimized sputum bacillary load and the probability of drug-related adverse events. Results include a population-typical characterization of the recommended 200 mg once daily dosage, the optimality of time-dependent dosing, examples of individualized therapy, and the determination of optimal loading doses. The approach generalizes conventional PK-PD target attainment to a design problem that scales to drug combinations, and provides a benefit-risk context for clinical testing of complex drug regimens.
| S-EPMC7965837 | biostudies-literature
Project description:The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug-resistant or extensively drug-resistant TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile, but it lacks oral bioavailability. Here, we propose to replace L in the BPaL regimen with spectinamide (S) administered via inhalation and we demonstrate that inhaled spectinamide 1599, combined with BPa --BPaS regimen--has similar efficacy to that of the BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effects in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested the development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL and BPa, but not the BPaS treatment, also decreased myeloid to erythroid ratio suggesting the S in the BPaS regimen was able to recover this effect. Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen without L-associated AEs.
| S-EPMC11460978 | biostudies-literature
Project description:Melphalan at a dose of 200 mg/m2 (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database (n = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32-62) in favor or the BuMelVel group (95% CI; 23-37) (p = 0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44-0.97)(p = 0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.
| S-EPMC7786301 | biostudies-literature
Project description:The aim of this study was to create nanoparticles of human serum albumin immobilized with anti-TB drugs (rifampicin, isoniazid) using the desolvation method. Central Composite Design (CCD) was applied to study the effect of albumin, urea, L-cysteine, rifampicin and isoniazid concentration on particle size, polydispersity and loading degree of the drugs. The optimized nanoparticles were spherical in shape with an average particle size of 216.7 ± 3.7 nm and polydispersity of 0.286 ± 4.9. The loading degree of rifampicin and isoniazid in the optimized nanoparticles were 44% and 27%, respectively. The obtained nanoparticles were examined by Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC); the results showed the absence of drug-polymer interactions. The drug release from the polymer matrix was studied using dialysis membranes.
| S-EPMC10347201 | biostudies-literature