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Marc H Weiner - One of the best experts on this subject based on the ideXlab platform.
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decreased plasma Rifapentine concentrations associated with aadac single nucleotide polymorphism in adults with tuberculosis
Journal of Antimicrobial Chemotherapy, 2021Co-Authors: Marc H Weiner, Melissa Engle, Jon Gelfond, Teresa L Johnsonpais, John L Johnson, William C Whitworth, Erin Blivensizemore, P Nsubuga, Susan E DormanAbstract: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.
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Rifapentine population pharmacokinetics and dosing recommendations for latent tuberculosis infection
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Je Hibma, Kelly E Dooley, Marc H Weiner, Helen Mcilleron, Susan E Dorman, Amina Jindani, Kendra K Radtke, Radojka M. SavicAbstract:Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms, but clarity on the optimal dosing approach is lacking.Objectives: To characterize Rifapentine popu...
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xpert mtb rif assay shows faster clearance of mycobacterium tuberculosis dna with higher levels of Rifapentine exposure
Journal of Clinical Microbiology, 2016Co-Authors: A Jayakumar, Marc H Weiner, Debra Benator, Radojka M. Savic, Charles M Heilig, Charles K Everett, David Alland, Sven O Friedrich, Neil A Martinson, Amy KerriganAbstract:CITATION: Jayakumar, A. et al. 2016. Xpert MTB/RIF assay shows faster clearance of Mycobacterium tuberculosis DNA with higher levels of Rifapentine exposure. Journal of Clinical Microbiology, 54(12):3028 –3033, doi:10.1128/JCM.01313-16.
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quantification of Rifapentine a potent antituberculosis drug from dried blood spot samples using liquid chromatographic tandem mass spectrometric analysis
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Teresa L. Parsons, Marc H Weiner, Mark A. Marzinke, William Mac R Kenzie, Erin Blivensizemore, Susan E Dorman, Thuy Hoang, Kelly E DooleyAbstract:ABSTRACT The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the 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 chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying Rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of Rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The analyte was stable on the cards for 11 weeks with a desiccant at room temperature and protected from light. The 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 acceptable correlation between plasma and whole-blood DBS (Passing-Bablok regression corrected for hematocrit; y = 0.98 x + 356). Concentrations of Rifapentine may be determined from whole-blood DBS collected via venipuncture after normalization in order to account for the dilutional effects of red blood cells. Additional studies are focused on the application of this methodology to capillary blood collected by finger stick. The simplicity of processing, storage, shipping, and low blood volume makes whole-blood DBS attractive for Rifapentine pharmacokinetic evaluations, especially in international and pediatric trials.
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protein binding of Rifapentine and its 25 desacetyl metabolite in patients with pulmonary tuberculosis
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Eric F Egelund, Marc H Weiner, Rajendra P Singh, Thomas J Prihoda, Jonathon A L Gelfond, Hartmut Derendorf, William Mac R Kenzie, Charles A. PeloquinAbstract:Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of Rifapentine in 41 patients with tuberculosis. We found a lower total Rifapentine concentration but significantly higher free Rifapentine levels in African patients of black race compared to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free Rifapentine in relation to microbiological and clinical outcomes.
Eric L. Nuermberger - One of the best experts on this subject based on the ideXlab platform.
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treatment shortening effect of a novel regimen combining clofazimine and high dose Rifapentine in pathologically distinct mouse models of tuberculosis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Vikram Saini, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Richard E Chaisson, Nicole C Ammerman, Yong Seok Chang, Jacques H. GrossetAbstract:Clofazimine and high-dose Rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose Rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where Rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose Rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a Rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose Rifapentine and clofazimine in clinical trials.
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treatment shortening effect of a novel regimen combining high dose Rifapentine and clofazimine in pathologically distinct mouse models of tuberculosis
bioRxiv, 2019Co-Authors: Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Richard E Chaisson, Vikram Saini, Nicole C Ammerman, Yong Seok Chang, Jacques H. GrossetAbstract:ABSTRACT High-dose Rifapentine and clofazimine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose Rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where Rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose Rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a Rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose Rifapentine and clofazimine in clinical trials.
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population pharmacokinetics of Rifapentine and desacetyl Rifapentine in healthy volunteers nonlinearities in clearance and bioavailability
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Radojka M. Savic, Eric L. Nuermberger, Marc H Weiner, Erin Blivensizemore, Susan E Dorman, William Burman, Kelly E DooleyAbstract:ABSTRACT 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. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.)
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reply to contradictory results with high dosage rifamycin in mice and humans
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Eric L. Nuermberger, Charles A. Peloquin, Rokeya Tasneen, Ian M. Rosenthal, Khisimuzi Mdluli, Petros C Karakousis, Jacques H. GrossetAbstract:We thank Coates and colleagues for their interest in our recent paper demonstrating in two pathologically distinct murine models of tuberculosis (TB) that Rifapentine (RPT) is approximately 4 times more potent (on a mg/kg body weight basis) than rifampin (RIF) when used alone and in combination with
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dose ranging comparison of rifampin and Rifapentine in two pathologically distinct murine models of tuberculosis
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Ian M. Rosenthal, Charles A. Peloquin, Rokeya Tasneen, Jacques H. Grosset, Ming Zhang, Deepak V Almeida, Khisimuzi Mdluli, Petros C Karakousis, Eric L. NuermbergerAbstract:In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of Rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to Rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and Rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and Rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.
Richard E Chaisson - One of the best experts on this subject based on the ideXlab platform.
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pharmacogenetic interactions of Rifapentine plus isoniazid with efavirenz or nevirapine
Pharmacogenetics and Genomics, 2021Co-Authors: David W Haas, Anthony T. Podany, Khuanchai Supparatpinyo, Noluthando Mwelase, Yajing Bao, Susan Swindells, Richard E Chaisson, Lerato Mohapi, Amita Gupta, Constance A BensonAbstract:OBJECTIVES The effect of Rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine. METHODS A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily Rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and Rifapentine pharmacokinetics were assessed. RESULTS Of 128 participants, 101 were evaluable for associations with Rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of Rifapentine (P = 2.6 × 10) and 25-desacetyl Rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics. CONCLUSIONS Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated Rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater Rifapentine and 25-desacetyl Rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.
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cost effectiveness of one month of daily isoniazid and Rifapentine versus three months of weekly isoniazid and Rifapentine for prevention of tuberculosis among people receiving antiretroviral therapy in uganda
Journal of the International AIDS Society, 2020Co-Authors: Olivia Ferguson, Richard E Chaisson, Jeff Pennington, Karl Johnson, Gavin J Churchyard, David W DowdyAbstract:Introduction Preventive therapy is essential for reducing tuberculosis (TB) burden among people living with HIV (PLWH) in high-burden settings. Short-course preventive therapy regimens, such as three-month weekly Rifapentine and isoniazid (3HP) and one-month daily Rifapentine and isoniazid (1HP), may help facilitate uptake of preventive therapy for latently infected patients, but the comparative cost-effectiveness of these regimens under different conditions is uncertain. Methods We used a Markov state-transition model to estimate the incremental costs and effectiveness of 1HP versus 3HP in a simulated cohort of patients attending an HIV clinic in Uganda, as an example of a low-income, high-burden setting in which TB preventive therapy might be prescribed to PLWH. Our primary outcome was the incremental cost-effectiveness ratio, expressed as 2019 US dollars per disability-adjusted life year (DALY) averted. We estimated cost-effectiveness under different conditions of treatment completion and efficacy of 1HP versus 3HP, latent TB prevalence and Rifapentine price. Results Assuming equivalent clinical outcomes using 1HP and 3HP and a Rifapentine price of $0.21 per 150 mg, 1HP would cost an additional $4.66 per patient treated. Assuming equivalent efficacy but 20% higher completion with 1HP versus 3HP, 1HP would cost $1,221 per DALY averted relative to 3HP. This could be reduced to $18 per DALY averted if 1HP had 5% greater efficacy than 3HP and the price of Rifapentine were 50% lower. At a Rifapentine price of $0.06 per 150 mg, 1HP would become cost-neutral relative to 3HP. Conclusions 1HP has the potential to be cost-effective under many realistic circumstances. Cost-effectiveness depends on Rifapentine price, relative completion and efficacy, prevalence of latent TB and local willingness-to-pay.
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treatment shortening effect of a novel regimen combining clofazimine and high dose Rifapentine in pathologically distinct mouse models of tuberculosis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Vikram Saini, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Richard E Chaisson, Nicole C Ammerman, Yong Seok Chang, Jacques H. GrossetAbstract:Clofazimine and high-dose Rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose Rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where Rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose Rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a Rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose Rifapentine and clofazimine in clinical trials.
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treatment shortening effect of a novel regimen combining high dose Rifapentine and clofazimine in pathologically distinct mouse models of tuberculosis
bioRxiv, 2019Co-Authors: Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Richard E Chaisson, Vikram Saini, Nicole C Ammerman, Yong Seok Chang, Jacques H. GrossetAbstract:ABSTRACT High-dose Rifapentine and clofazimine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose Rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where Rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose Rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a Rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose Rifapentine and clofazimine in clinical trials.
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exposure to latent tuberculosis treatment during pregnancy the prevent tb and the iadhere trials
Annals of the American Thoracic Society, 2018Co-Authors: Ruth N. Moro, Andrew Vernon, Nigel A Scott, Stefan V Goldberg, Neil W Schluger, Naomi K Tepper, Kevin Schwartzman, Chi Chiu Leung, Robert Belknap, Richard E ChaissonAbstract:Rationale: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus Rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy.Objectives: To asses...
Radojka M. Savic - One of the best experts on this subject based on the ideXlab platform.
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Rifapentine population pharmacokinetics and dosing recommendations for latent tuberculosis infection
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Je Hibma, Kelly E Dooley, Marc H Weiner, Helen Mcilleron, Susan E Dorman, Amina Jindani, Kendra K Radtke, Radojka M. SavicAbstract:Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms, but clarity on the optimal dosing approach is lacking.Objectives: To characterize Rifapentine popu...
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once weekly Rifapentine and isoniazid for tuberculosis prevention in patients with hiv taking dolutegravir based antiretroviral therapy a phase 1 2 trial
The Lancet HIV, 2020Co-Authors: Kelly E Dooley, Radojka M. Savic, Mark A. Marzinke, Nan Zhang, Akshay Gupte, Vinodh A Edward, Lisa Wolf, Modulakgotla Sebe, Morongwe LikotiAbstract:Summary Background Short-course preventive therapy with 12 doses of once-weekly Rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive. Methods DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load ( ClinicalTrials.gov , NCT03435146 . Findings Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35–48), CD4 cell count was 683 cells per μL (447–935), and body-mass index was 28·9 kg/m2 (24·0–32·9). Three grade 3 adverse events occurred; two elevated creatinine and one hypertension. Rifapentine–isoniazid increased dolutegravir clearance by 36% (relative standard error 13%) resulting in a 26% decrease in dolutegravir area under the curve. Overall geometric mean ratio of trough concentrations with versus without Rifapentine–isoniazid was 0·53 (90% CI 0·49–0·56) though this ratio varied by day after Rifapentine–isoniazid dose. All but one trough value was above the 90% maximal inhibitory concentration for dolutegravir and HIV viral loads were less than 40 copies per mL in all patients. Interpretation Our results suggest 12 doses of once-weekly Rifapentine–isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed. Funding UNITAID.
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Pharmacokinetics of Rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data
Science translational medicine, 2018Co-Authors: Dalin Rifat, Brendan Prideaux, Radojka M. Savic, Michael E. Urbanowski, Teresa L. Parsons, Brian Luna, Mark A. Marzinke, Alvaro A. Ordonez, Vincent P. Demarco, Sanjay K. JainAbstract:In clinical trials of two rifamycin antibiotics (rifampin and Rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from Rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or Rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site-of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients ≥1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for Rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant ( P −7 ). We propose that poor penetration of Rifapentine into lung cavitary lesions explains, in part, why Rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease.
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defining the optimal dose of Rifapentine for pulmonary tuberculosis exposure response relations from two phase ii clinical trials
Clinical Pharmacology & Therapeutics, 2017Co-Authors: Radojka M. Savic, Melissa Engle, John L Johnson, William C Whitworth, P Nsubuga, Michael W Weiner, William R Mackenzie, Payam Nahid, N V NguyenAbstract:Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare Rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with Rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high Rifapentine doses.
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defining the optimal dose of Rifapentine for pulmonary tuberculosis exposure response relations from two phase ii clinical trials
Clinical Pharmacology & Therapeutics, 2017Co-Authors: Radojka M. Savic, Melissa Engle, John L Johnson, William C Whitworth, P Nsubuga, William R Mackenzie, Payam Nahid, M Weiner, N V NguyenAbstract:Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare Rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with Rifapentine at 1200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high Rifapentine doses. This article is protected by copyright. All rights reserved.
Kelly E Dooley - One of the best experts on this subject based on the ideXlab platform.
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four month Rifapentine regimens with or without moxifloxacin for tuberculosis
The New England Journal of Medicine, 2021Co-Authors: Susan E Dorman, Kelly E Dooley, Melissa Engle, Payam Nahid, Stefan V Goldberg, Ekaterina V Kurbatova, Patrick C Phillips, Kia E Bryant, Ha T T Phan, James HakimAbstract:Abstract Background Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. Methods In an ope...
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Rifapentine population pharmacokinetics and dosing recommendations for latent tuberculosis infection
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Je Hibma, Kelly E Dooley, Marc H Weiner, Helen Mcilleron, Susan E Dorman, Amina Jindani, Kendra K Radtke, Radojka M. SavicAbstract:Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms, but clarity on the optimal dosing approach is lacking.Objectives: To characterize Rifapentine popu...
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once weekly Rifapentine and isoniazid for tuberculosis prevention in patients with hiv taking dolutegravir based antiretroviral therapy a phase 1 2 trial
The Lancet HIV, 2020Co-Authors: Kelly E Dooley, Radojka M. Savic, Mark A. Marzinke, Nan Zhang, Akshay Gupte, Vinodh A Edward, Lisa Wolf, Modulakgotla Sebe, Morongwe LikotiAbstract:Summary Background Short-course preventive therapy with 12 doses of once-weekly Rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive. Methods DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load ( ClinicalTrials.gov , NCT03435146 . Findings Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35–48), CD4 cell count was 683 cells per μL (447–935), and body-mass index was 28·9 kg/m2 (24·0–32·9). Three grade 3 adverse events occurred; two elevated creatinine and one hypertension. Rifapentine–isoniazid increased dolutegravir clearance by 36% (relative standard error 13%) resulting in a 26% decrease in dolutegravir area under the curve. Overall geometric mean ratio of trough concentrations with versus without Rifapentine–isoniazid was 0·53 (90% CI 0·49–0·56) though this ratio varied by day after Rifapentine–isoniazid dose. All but one trough value was above the 90% maximal inhibitory concentration for dolutegravir and HIV viral loads were less than 40 copies per mL in all patients. Interpretation Our results suggest 12 doses of once-weekly Rifapentine–isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed. Funding UNITAID.
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high dose Rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis study protocol for tbtc study 31 actg a5349 phase 3 clinical trial
Contemporary Clinical Trials, 2020Co-Authors: Susan E Dorman, William J. Burman, Payam Nahid, Stefan V Goldberg, Lorna Bozeman, Ekaterina V Kurbatova, Kwokchiu Chang, Michael Chen, Mark F Cotton, Kelly E DooleyAbstract:Abstract Introduction Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose Rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose Rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. Methods/Design S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose Rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. Discussion This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. Trial registration: NCT02410772 . Registered 8 April 2015, https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1
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novel dosing strategies increase exposures of the potent antituberculosis drug Rifapentine but are poorly tolerated in healthy volunteers
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Kelly E Dooley, Radojka M. Savic, Mark A. Marzinke, Jeonggun Park, Yoninah S Cramer, Richard Hafner, Evelyn Hogg, Jennifer Janik, Kristine B Patterson, Constance A BensonAbstract:Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase Rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, Rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg Rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking Rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC0-24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC0-24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase Rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. NCT01574638.).
