RESUMO
AIMS: The hollowfibre system for tuberculosis (HFSTB) is a preclinical model qualified by the European Medicines Agency to underpin the antiTB drug development process. It can mimic in vivo pharmacokinetic (PK)pharmacodynamic (PD) attributes of selected antimicrobials, which could feed into in silico models to inform the design of clinical trials. However, historical data and published protocols are insufficient and omit key information to allow experiments to be reproducible. Therefore, in this work, we aim to optimize and standardize various HFSTB operational procedures. METHODS: First, we characterized bacterial growth dynamics with different types of hollowfibre cartridges, Mycobacterium tuberculosis strains and media. Second, we mimicked a moxifloxacin PK profile within hollowfibre cartridges, in order to check drugfibres compatibility. Lastly, we mimicked the moxifloxacin total plasma PK profile in human after once daily oral dose of 400 mg to assess PKPD after different sampling methods, strains, cartridge size and bacterial adaptation periods before drug infusion into the system. RESULTS: We found that final bacterial load inside the HFSTB was contingent on the studied variables. Besides, we demonstrated that drugfibres compatibility tests are critical preliminary HFSTB assays, which need to be properly reported. Lastly, we uncovered that the sampling method and bacterial adaptation period before drug infusion significantly impact actual experimental conclusions. CONCLUSION: Our data contribute to the necessary standardization of HFSTB experiments, draw attention to multiple aspects of this preclinical model that should be considered when reporting novel results and warn about critical parameters in the HFSTB currently overlooked.
Assuntos
Antituberculosos , Moxifloxacina , Mycobacterium tuberculosis , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacocinética , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Tuberculose/tratamento farmacológico , Modelos Biológicos , Testes de Sensibilidade Microbiana , Administração OralRESUMO
BACKGROUND: Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy. METHODS: Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10-50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events. RESULTS: The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35 mg/kg daily. CONCLUSIONS: Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy.
Assuntos
Rifampina , Tuberculose , Humanos , Antituberculosos/uso terapêutico , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose/tratamento farmacológicoRESUMO
OBJECTIVES: Mycobacterium avium complex (MAC) bacteria can cause chronic pulmonary disease (PD). Current treatment regimens of azithromycin, ethambutol and rifampicin have culture conversion rates of around 65%. Dynamic, preclinical models to assess the efficacy of treatment regimens are important to guide clinical trial development. The hollow fibre system (HFS) has been applied but reports lack experimental details. METHODS: We simulated the human pharmacokinetics of azithromycin, ethambutol and rifampicin both in plasma and epithelial lining fluid (ELF) in a HFS, exposing THP-1 cells infected with M. avium to the triple-drug regimen for 3 weeks. We accounted for drug-drug interactions and protein-binding and provide all laboratory protocols. We differentiated the effects on the intracellular and extracellular mycobacterial population. RESULTS: The antibiotic concentrations in the HFS accurately reflected the time to peak concentration (Tmax), the peak concentration (Cmax) and half-life of azithromycin, rifampicin and ethambutol in plasma and ELF reported in literature. We find that plasma drug concentrations fail to hold the MAC bacterial load static (ΔLog10 CFU/mLControl:Regimen = 0.66 ± 0.76 and 0.45 ± 0.28 at 3 and 21 days); ELF concentrations do hold the bacterial load static for 3 days and inhibit bacterial growth for the duration of the experiment (ΔLog10 CFU/mLControl:Regimen = 1.1 ± 0.1 and 1.64 ± 0.59 at 3 and 21 days). DISCUSSION: In our model, the current therapy against MAC is ineffective, even when accounting for antibiotic accumulation at the site of infection and intracellularly. New treatment regimens need to be developed and be compared with currently recommended regimens in dynamic models prior to clinical evaluation. With the publication of all protocols we aim to open this technology to new users.
Assuntos
Pneumopatias , Infecção por Mycobacterium avium-intracellulare , Antibacterianos/farmacologia , Azitromicina/uso terapêutico , Quimioterapia Combinada , Etambutol/farmacologia , Etambutol/uso terapêutico , Humanos , Pneumopatias/tratamento farmacológico , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologiaRESUMO
The development of optimal treatment regimens in tuberculosis (TB) remains challenging due to the need of combination therapy and possibility of pharmacodynamic (PD) interactions. Preclinical information about PD interactions needs to be used more optimally when designing early bactericidal activity (EBA) studies. In this work, we developed a translational approach which can allow for forward translation to predict efficacy of drug combination in EBA studies using the Multistate Tuberculosis Pharmacometric (MTP) and the General Pharmacodynamic Interaction (GPDI) models informed by in vitro static time-kill data. These models were linked with translational factors to account for differences between the in vitro system and humans. Our translational MTP-GPDI model approach was able to predict the EBA0-2 days , EBA0-5 days , and EBA0-14 days from different EBA studies of rifampicin and isoniazid in monotherapy and combination. Our translational model approach can contribute to an optimal dose selection of drug combinations in early TB clinical trials.
Assuntos
Antibióticos Antituberculose/administração & dosagem , Antituberculosos/administração & dosagem , Desenvolvimento de Medicamentos , Isoniazida/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/administração & dosagem , Pesquisa Translacional Biomédica , Tuberculose/tratamento farmacológico , Antibióticos Antituberculose/farmacocinética , Antituberculosos/farmacocinética , Carga Bacteriana , Ensaios Clínicos Fase II como Assunto , Cálculos da Dosagem de Medicamento , Quimioterapia Combinada , Humanos , Isoniazida/farmacocinética , Testes de Sensibilidade Microbiana , Modelos Biológicos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Rifampina/farmacocinética , Tuberculose/microbiologiaRESUMO
BACKGROUND: The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing. METHODS: Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median area under the curve (AUC0-24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing. RESULTS: The difference of median AUC0-24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing. CONCLUSIONS: Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.