Dataset Information

Pretomanid dose selection for pulmonary tuberculosis: An application of multi-objective optimization to dosage regimen design.

ABSTRACT: 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.

SUBMITTER: Lyons MA

PROVIDER: S-EPMC7965837 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pretomanid dose selection for pulmonary tuberculosis: An application of multi-objective optimization to dosage regimen design.

Lyons Michael A MA

CPT: pharmacometrics & systems pharmacology 20210213 3

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 evolvi ...[more]

PMID: 33440076

Similar Datasets

Project description:BackgroundThe sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization.Methods and findingsA total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts.ConclusionsOur results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Dataset Information

Pretomanid dose selection for pulmonary tuberculosis: An application of multi-objective optimization to dosage regimen design.

Publications

Pretomanid dose selection for pulmonary tuberculosis: An application of multi-objective optimization to dosage regimen design.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets