TY - JOUR
T1 - PA-824 exhibits time-dependent activity in a murine model of tuberculosis
AU - Ahmad, Zahoor
AU - Peloquin, Charles A.
AU - Singh, Rajendra P.
AU - Derendorf, Hartmut
AU - Tyagi, Sandeep
AU - Ginsberg, Ann
AU - Grosset, Jacques H.
AU - Nuermberger, Eric L.
PY - 2011/1
Y1 - 2011/1
N2 - PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T>MIC (R2 = 0.87) and correlated with the free drug AUC/MIC (R2 = 0.60), but not with the free drug Cmax/MIC (R2 = 0.17), where T>MIC is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T>MIC and the AUC/MIC values fit the data well. Free drug T>MIC of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T >MIC values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T>MIC, in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.
AB - PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T>MIC (R2 = 0.87) and correlated with the free drug AUC/MIC (R2 = 0.60), but not with the free drug Cmax/MIC (R2 = 0.17), where T>MIC is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T>MIC and the AUC/MIC values fit the data well. Free drug T>MIC of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T >MIC values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T>MIC, in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.
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U2 - 10.1128/AAC.00849-10
DO - 10.1128/AAC.00849-10
M3 - Article
C2 - 20937781
AN - SCOPUS:78650642282
SN - 0066-4804
VL - 55
SP - 239
EP - 245
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 1
ER -