FIG 6.
Cumulative fraction of response. The dose of 1,200 mg per day achieved the target AUC0–24 of 96 mg · h/liter associated with 50% mitochondrial inhibition in >90% of patients, consistent with the high adverse event rate, validating the approach. The dose of 600 mg a day achieved this AUC in <20% of patients. The dose of 300 mg a day achieved this AUC0–24 of 96 mg · h/liter in ∼0% of patients. In terms of efficacy, the dose of 300 mg a day achieved EC80 just shy of 90% of patients with the more stringent assumption on poorer ELF-to-serum penetration. The dose of 600 mg a day achieved the cumulative fraction of response that none of the higher doses improved much on, even with sensitivity testing such as lower ELF-to-serum ratio. Given that this is an AUC/MIC-linked effect, intermittent therapy (1,200 mg every other day) would also be as effective as a 600-mg/day dose.