Table 1.
Pharmacokinetics and Pharmacodynamics Exposure and Minimum Inhibitory Concentration Breakpoints as Targets for Optimized Doses
| World Health Organization Classification | Drug | Hollow Fiber System Model of Tuberculosis and Monte Carlo Experiments Derived | Clinical Study Derived | Reference | ||
|---|---|---|---|---|---|---|
| PK/PD Exposure Target (Free Drug) in Lung | PK/PD MIC or Susceptibility Breakpoint, mg/L | PK or PK/PD Derived in Blood | MIC or Susceptibility Breakpoint, mg/L | |||
| First-line | ||||||
| Rifampin | AUC0-24/MIC >1360; peak/MIC >75 | 0.0625 | AUC0-24 >35.4 mg*h/L; peak >8.2 mg/L | 0.125; 0.0695 | [24] | |
| Isoniazid | AUC0-24/MIC >567 | 0.0312 | AUC0-24 >52 mg*h/L | 0.0312; 0.0334 | [24] | |
| Ethambutol | Peak/MIC >0.51; AUC0-24/MIC >119 | 4 | Peak/MIC >0.46 | 4 | [24] | |
| Pyrazinamide | AUC0-24/MIC >209 | 50 | AUC0-24 >363 mg*h/L; AUC0-24/MIC >11.3 | 50 | [25] | |
| Multidrug-Resistant Tuberculosis | ||||||
| Group A | ||||||
| Moxifloxacin | AUC0-24/MIC = 56a | 1 | … | … | [26] | |
| Levofloxacin | AUC0-24/MIC = 146; AUC0-24/MIC = 360a | 0.5 | AUC0-24/MIC = 160 | … | [13] | |
| Gatifloxacin | AUC0-24/MIC = 184 | 0.5/2 | AUC0-24 >50.29 | 0.5/2 | [12] | |
| Linezolid | AUC0-24/MIC = 119 | 2 | ... | ... | [27] | |
| Bedaquiline | ... | ... | ... | ... | … | |
| Group B | ||||||
| Clofazimine | ... | ... | … | … | … | |
| Cycloserine | Time above MIC = 30% | 64 | ... | ... | [28] | |
| Group C | ||||||
| Delamanid | ... | ... | ... | ... | … | |
| Imipenem/cilastatin | ... | ... | ... | ... | … | |
| Meropenem | ... | ... | ... | ... | … | |
| Amikacin | Peak/MIC = 10.13 | ... | Peak >67 mg/L | ... | [19, 29] | |
| Ethionamide | AUC0-24/MIC >56.2 | 2.5 | ... | 2.5 | [14] | |
| P-aminosalicylic acid | ... | ... | ... | ... | … |
Abbreviations: AUC, area under the concentration time curve; MIC, minimum inhibitory concentration; PD, pharmacodynamics; PK, pharmacokinetics.
aResistance suppression target.