Dataset Information

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis.

ABSTRACT: Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250?mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h^-1; elimination rate constant, 0.69 (0.46) h^-1; volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500?mg or more was needed for ?90% attainment of the 1.0-log kill target at a MIC of 1?mg/liter, and 2,250?mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5?mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting the current recommendations for ETA deprioritization.

SUBMITTER: Al-Shaer MH

PROVIDER: S-EPMC7449188 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis.

Al-Shaer Mohammad H MH Märtson Anne-Grete AG Alghamdi Wael A WA Alsultan Abdullah A An Guohua G Ahmed Shahriar S Alkabab Yosra Y Banu Sayera S Houpt Eric R ER Ashkin David D Griffith David E DE Cegielski J Peter JP Heysell Scott K SK Peloquin Charles A CA

Antimicrobial agents and chemotherapy 20200820 9

Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were tw ...[more]

PMID: 32631828

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Project description:ObjectiveTo study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.MethodsMicafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations.ResultsA two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016.ConclusionsThe licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Project description:Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

Dataset Information

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis.

Publications

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis.

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