Last data update: Jun 03, 2024. (Total: 46935 publications since 2009)
Records 1-10 (of 10 Records) |
Query Trace: Bliven-Sizemore E [original query] |
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Optimising pyrazinamide for the treatment of tuberculosis
Zhang N , Savic RM , Boeree MJ , Peloquin C , Weiner M , Heinrich N , Bliven-Sizemore E , Phillips PP , Hoelscher M , Whitworth W , Morlock G , Posey J , Stout JE , Mac Kenzie W , Aarnoutse R , Dooley KE . Eur Respir J 2021 58 (1) Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from TBTC Studies 27 and 28 and PanACEA MAMS-TB, multi-center Phase 2 trials in which participants received rifampicin (range 10-35 mg·kg(-1)), pyrazinamide (range 20-30 mg·kg(-1)), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK/PD) and PK-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of two-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin Cmax (p-value<0.01). Modeling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with Grade 3 or higher liver function tests, LFT), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiologic efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel. |
Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.
Weiner M , Gelfond J , Johnson-Pais TL , Engle M , Johnson JL , Whitworth WC , Bliven-Sizemore E , Nsubuga P , Dorman SE , Savic R . J Antimicrob Chemother 2020 76 (3) 582-586 BACKGROUND: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. OBJECTIVES: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. METHODS: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. RESULTS: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). CONCLUSIONS: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups. |
Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI
Bliven-Sizemore EE , Sterling TR , Shang N , Benator D , Schwartzman K , Reves R , Drobeniuc J , Bock N , Villarino ME . Int J Tuberc Lung Dis 2015 19 (9) 1039-44 SETTING: Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. OBJECTIVES: To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity. DESIGN: Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. RESULTS: Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. CONCLUSION: The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred. |
Quantification of rifapentine, a potent anti-tuberculosis drug, from dried blood spot samples using liquid chromatographic-tandem mass spectrometric analysis
Parsons TL , Marzinke MA , Hoang T , Bliven-Sizemore E , Weiner M , Mac Kenzie W , Dorman SE , Dooley KE . Antimicrob Agents Chemother 2014 58 (11) 6747-57 Quantifying anti-tuberculosis drug concentrations in multinational trials currently requires collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into Tuberculosis Trials Consortium Study 29B, a Phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for quantification of rifapentine in whole blood from dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in trials. Paired plasma and whole blood samples were collected by venipuncture; whole blood was spotted on Whatman 903(R) cards. Methods were optimized for plasma and then validated for DBS. The analytical measuring range was 50 to 80,000 ng/ml in whole blood DBS. Analytes were stable on cards for 11 weeks with desiccant at room temperature protected from light. Method concordance for paired plasma and whole blood DBS samples was determined after correcting for participant hematocrit or population-based estimates of bias from Bland-Altman plots. The application of either correction factor resulted in excellent correlation between plasma and whole blood DBS (Passing-Bablok regression corrected for hematocrit; y=0.98x+356). Concentrations of rifapentine may be determined from whole blood DBS collected via venipuncture after normalization to account for dilutional effects of red blood cells; additional studies are focused on the application of this methodology to capillary blood collected by finger stick. Simplicity of processing, storage, shipping and low blood volume makes whole blood DBS attractive for rifapentine pharmacokinetic evaluations, especially in international and pediatric trials. |
Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability
Savic RM , Lu Y , Bliven-Sizemore E , Weiner M , Nuermberger E , Burman W , Dorman SE , Dooley KE . Antimicrob Agents Chemother 2014 58 (6) 3035-3042 Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters . h-1, respectively, after a single dose to 2.2 and 5.0 liters . h-1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. |
Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis
Nahid P , Bliven-Sizemore E , Jarlsberg LG , De Groote MA , Johnson JL , Muzanyi G , Engle M , Weiner M , Janjic N , Sterling DG , Ochsner UA . Tuberculosis (Edinb) 2014 94 (3) 187-96 BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Ralpha, HSP70, Galectin-8, alpha2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study. |
Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers
Dooley KE , Bliven-Sizemore EE , Weiner M , Lu Y , Nuermberger EL , Hubbard WC , Fuchs EJ , Melia MT , Burman WJ , Dorman SE . Clin Pharmacol Ther 2012 91 (5) 881-8 Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration-time curve (AUC(0-24)) and maximum concentration (C(max)) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC(0-12) of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust. |
Effect of HIV infection on tolerability and bacteriologic outcomes of tuberculosis treatment
Bliven-Sizemore EE , Johnson JL , Goldberg S , Burman WJ , Villarino ME , Chaisson RE , Tuberculosis Clinical Trials Consortium . Int J Tuberc Lung Dis 2012 16 (4) 473-9 SETTING: Two international, multicenter Phase 2 clinical trials examining fluoroquinolone-containing regimens in adults with smear-positive pulmonary tuberculosis (TB), conducted from July 2003 to March 2007. Both trials enrolled human immunodeficiency virus (HIV) infected participants who were not receiving antiretroviral therapy (ART) at TB treatment initiation. OBJECTIVE: To assess the impact of HIV infection on TB treatment outcomes in Phase 2 clinical trials. DESIGN: Cross-protocol analysis comparing the safety, tolerability and outcomes of anti-tuberculosis treatment by HIV status. RESULTS: Of 750 participants who received at least one dose of study treatment, 123 (16%) were HIV-infected. Treatment completion rates were similar by HIV status (81% infected vs. 85% non-infected), as were rates of week 8 culture conversion (66% infected vs. 63% non-infected), and treatment failure (5% infected vs. 3% non-infected). Among HIV-infected participants, treatment failure detected using liquid media was more frequent in those treated thrice weekly (14% thrice weekly vs. 2% daily, P = 0.03). HIV-infected participants more frequently experienced an adverse event during the intensive phase treatment than non-HIV-infected participants (30% vs. 15%, P < 0.01). CONCLUSION: HIV-infected persons not receiving ART had more adverse events during the intensive phase of anti-tuberculosis treatment, but tolerated treatment well. Failure rates were higher among HIV-infected persons treated with thrice-weekly intensive phase therapy. |
Tuberculosis biomarker and surrogate endpoint research roadmap
Nahid P , Saukkonen J , Mac Kenzie WR , Johnson JL , Phillips PPJ , Andersen J , Bliven-Sizemore E , Belisle JT , Boom WH , Luetkemeyer A , Campbell TB , Eisenach KD , Hafner R , Lennox JL , Makhene M , Swindells S , Villarino ME , Weiner M , Benson C , Burman W . Am J Respir Crit Care Med 2011 184 (8) 972-979 The Centers for Disease Control and Prevention and National Institutes of Health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. The goals were to assess recent surrogate marker research and to provide specific recommendations for (1) the qualification and validation of biomarkers of treatment outcome; (2) the standardization of specimen and data collection for future clinical trials, including a minimum set of samples and collection time points; and (3) the creation of a specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation. |
The effects of tuberculosis, race and human gene SLCO1B1 polymorphisms on rifampin concentrations
Weiner M , Peloquin C , Burman W , Luo CC , Engle M , Prihoda TJ , MacKenzie WR , Bliven-Sizemore E , Johnson JL , Vernon A . Antimicrob Agents Chemother 2010 54 (10) 4192-200 BACKGROUND: Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However marked inter-subject variation of rifampin concentrations occur. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of human transporter genes SLCO1B1, SLCO1B3 and MDR1. MATERIALS & METHODS: Seventy-two adults with pulmonary tuberculosis from Africa, North America and Spain were evaluated during multi-drug intensive-phase therapy, and compared to 16 healthy controls from North America. RESULTS: Rifampin pharmacokinetics values were similar between tuberculosis patients versus controls (geometric mean [GM] area under the concentration-time curve (AUC0-24) 40.2 vs. 40.9 mcg*h/ml, P=.9). However in multivariable analyses, rifampin AUC0-24 was significantly affected by rifampin dosage (mg/kg), polymorphisms in the SLCO1B1 gene, and presence of tuberculosis by geographic region. Adjusted rifampin AUC0-24 was lowest in patients with tuberculosis from Africa compared to non-African patients or control subjects. Adjusted rifampin AUC0-24 was also 36% lower among participants with SLCO1B1 c.463CA versus c.463CC genotype (adjusted GM 29.8 vs. 46.7 mcg*h/ml, P=.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among subjects of Black race. CONCLUSIONS: Marked inter-subject variation of rifampin AUC0-24 was observed, but means of AUC0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease. |
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