Table 5

In vitro or animal studies regarding impact of dosing intermittency on efficacy of tuberculosis treatment

Authors, year of publicationMeasures of treatment efficacySource of study materialsStudy designMain findingsLikely impact of dosing intermittency on treatment efficacy of standard regimens
Weiner et al, 200551Acquired rifamycin resistanceUSAPK-PD study involving human subjectsLower AUC (0–24) of rifabutin and perhaps AUC (0–12) of isoniazid were associated with failure or relapse with acquired rifamycin resistance in HIV-related TB treated with twice-weekly therapy.Negative
Weiner et al, 200357RelapseUSAPK study involving human subjectsAmong HIV-negative patients given either H and R twice weekly or H and rifapentine once weekly in continuation phase, failure/relapse was associated with low H concentrations (AUC 0–12) rather than any rifamycin PK parameter. Dosing schedule of rifampicin appeared to be unrelated to relapse.No
Goutelle et al, 200958Not applicableFrancePopulation PK model for rifampicinAmong 34 human volunteers given 600 mg rifampicin, the proportions of subjects achieving target values for Cmax/MIC ratio and AUC (0–24)/MIC ratio in epithelial lining fluid were only 35.9% and 54.5%, respectively.Negative
Gupta et al, 200859Not applicableIndiaPK-PD studies in childrenCmax, elimination half-life and clearance for pyrazinamide 15 and 25 mg/kg per day differed non-significantly. This might suggest a difference in AUC/MIC (and hence sterilizing activity) between daily and intermittent treatment regimens.Negative with a caveat: the PAE of intermittent pyrazinamide may compensate for less sterilising activity due to lower AUC/MIC
Mitchison, 197922Not applicableUKGuinea pig experimentsWhen the same total drug amount is given as single dose or fractionated into multiple doses of different sizes, better efficacy is observed with high doses given at long intervals, especially for rifampicin and ethambutol.Positive
Rosenthal et al, 200852RelapseUSATB mouse modelMice with TB disease were treated daily or thrice-weekly with rifapentine, pyrazinamide, and either isoniazid or moxifloxacin. The duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampicin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.Negative
Rosenthal et al, 200753RelapseUSATB mouse modelReplacing rifampicin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. No relapse was observed after just 3 months of treatment with daily or thrice-weekly rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 months to prevent relapse.Negative
Rosenthal et al, 200654RelapseUSATB mouse modelStable cure was achieved after 4 months of twice-weekly rifapentine (15 mg/kg or 20 mg/kg) plus isoniazid- or moxifloxacin-containing therapy, but only after 6 months of standard daily therapy (10 mg/kg). Twice-weekly rifapentine displayed more favourable pharmacodynamics than did daily rifampicin.Negative
Veziris et al, 200555RelapseFranceTB mouse modelMice were treated with rifapentine, isoniazid and moxifloxacin given once a week during 5.5 months, preceded by 2 weeks of daily treatment with isoniazid, rifampicin, pyrazinamide, and moxifloxacin. When used at high dosages, such a regimen effectively achieved stable cure in mouse TB. The relapse rate increased from 0 to 11% when treatment was once-weekly throughout.Negative
Daniel et al, 200056Treatment failure, acquired drug resistanceFranceTB mouse modelReducing dosing frequency in the initial phase from daily to twice-weekly increased the risk of treatment failure with emergence of resistance to rifampicin or isoniazid.Negative
Jayaram et al, 200349Not applicableIndiaPK-PD study in a murine aerosol infection modelDose ranging and fractionation studies demonstrated that AUC (0–24)/MIC of rifampicin correlated best (r2=0.95) with a reduction in bacterial counts, followed by Cmax/MIC (r2=0.86) and the time that the concentration remained above the MIC (r2=0.44).Negative
Jayaram et al, 200460Not applicableIndiaPK-PD study in a murine aerosol infection modelDose fractionation studies demonstrated that AUC (0–24)/MIC of isoniazid correlated best (r2=0.83) with the bactericidal efficacy, followed by Cmax/MIC (r2=0.73).Negative with a caveat: AUC/MIC of isoniazid is probably comparable for daily and intermittent regimens
Gumbo et al, 200950USAIn vitro PK-PD studyThe sterilising effect of pyrazinamide was linked to AUC (0–24) to MIC ratio (r2=0.80–0.90), with 90% of the maximal effect being achieved by a ratio of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r2=0.73–0.91).Negative with a caveat: the PAE of intermittent pyrazinamide may compensate for less sterilising activity due to lower AUC/MIC
Gumbo et al, 200721USAIn vitro PK-PD modelThe PAE of rifampicin lasted for at least 5.2 days and closely related to free Cmax to MIC ratio (r2=0.96). The microbial killing of rifampicin was linked to AUC (0–24) to MIC ratio, and suppression of resistance was associated with free Cmax to MIC ratio.Negative
Budha et al, 200961Not applicableUSAIn vitro PK-PD studyThe time-kill data suggest that AUC (0–24)/MIC is the PK/PD index most explanatory of the antimicrobial effect of isoniazid.Negative with a caveat: AUC/MIC of isoniazid is probably comparable for daily and intermittent regimens
  • AUC, area under the curve; Cmax, peak serum concentration; H, isoniazid; MIC, minimum inhibitory concentration; PAE, post-antibiotic effect; PK-PD, pharmacokinetics-pharmacodynamics; R, rifampicin; TB, tuberculosis.