Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs

Goutelle, Sylvain; Bourguignon, Laurent; Maire, Pascal; Guilder, Michael Van; Conte, John E.; Jelliffe, Roger W.

doi:10.1128/aac.01520-08

Cited by 94 publications

(85 citation statements)

References 29 publications

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“…The resulting estimated ELF concentrations (Fig. 1C) were similar to those described in a recent intrapulmonary pharmacokinetic study of rifampin (13,22).…”

Section: Bacterialsupporting

confidence: 81%

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

Wiskirchen

Koomanachai

Nicasio

et al. 2011

Antimicrob Agents Chemother

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Multidrug-resistant Klebsiella pneumoniae strains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). An in vitro pharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time-kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU-h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of <2 g/ml and meropenem MICs of <16 g/ml (P < 0.001) but added no additional activity when the meropenem MIC was 64 g/ml (P ‫؍‬ 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P ‫؍‬ 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms.

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“…The resulting estimated ELF concentrations (Fig. 1C) were similar to those described in a recent intrapulmonary pharmacokinetic study of rifampin (13,22).…”

Section: Bacterialsupporting

confidence: 81%

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

Wiskirchen

Koomanachai

Nicasio

et al. 2011

Antimicrob Agents Chemother

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“…Emergence appears to be a time-dependent process, which cannot be suppressed after a few days in vitro, even with very high levels of INH exposure. Therefore, the best way to prevent the emergence of INH resistance is the optimal use of companion drugs, especially rifampin (51,52).…”

Section: Discussionmentioning

confidence: 99%

Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Lalande

Bourguignon

Bihari

et al. 2015

Antimicrob Agents Chemother

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Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

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“…Monte Carlo simulations were performed using a semi-parametric sampling methodology 14,20 that generated a simulated population of 5000 neonates receiving a given teicoplanin regimen. For each simulated patient, the weight-based dose of teicoplanin (in mg/kg) was administered to each neonate (30 min infusion) as an absolute dose of teicoplanin (in mg) by multiplying the rate of infusion (in mg/h) by the simulated weight.…”

Section: Monte Carlo Simulationmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

Ramos-Martín

Neely

McGowan

et al. 2016

J. Antimicrob. Chemother.

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Objectives: There is uncertainty about the optimal teicoplanin regimens for neonates. The study aim was to determine the population pharmacokinetics (PK) of teicoplanin in neonates, evaluate currently recommended regimens and explore the exposure-effect relationships.Methods: An open-label PK study was conducted. Neonates from 26 to 44 weeks post-menstrual age were recruited (n ¼ 18). The teicoplanin regimen was a 16 mg/kg loading dose, followed by 8 mg/kg once daily. Therapeutic drug monitoring and dose adjustment were not conducted. A standard two-compartment PK model was developed, followed by models that incorporated weight. A PK/pharmacodynamic (PD) model with C-reactive protein serial measurements as the PD input was fitted to the data. Monte Carlo simulations (n¼ 5000) were performed using Pmetrics. The AUCs at steady state and the proportion of patients achieving the recommended drug exposures (i.e. C min .15 mg/L) were determined. The study was registered in the European Clinical Trials Database Registry (EudraCT: 2012-005738-12).Results: The PK allometric model best accounted for the observed data. The PK parameters medians were:). The individual time-course of C-reactive protein was well described using the Bayesian posterior estimates for each patient. The simulated median AUC 96-120 was 302.3 mg . h/L and the median C min at 120 h was 12.9 mg/L; 38.8% of patients attained a C min .15 mg/L by 120 h.Conclusions: Teicoplanin population PK is highly variable in neonates, weight being the best descriptor of PK variability. A low percentage of neonates were able to achieve C min .15 mg/L. The routine use of therapeutic drug monitoring and improved knowledge on the PD of teicoplanin is required.

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Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs

Cited by 94 publications

References 29 publications

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

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