Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis

Abstract

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of anti-tuberculosis agents, and lead spectinamide 1810 has demonstrated excellent efficacy, safety and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of M. tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of colony-forming units in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by fC max /MIC and fAUC/MIC rather than f%T MIC . A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis .

Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis

“…8 A similar plateau effect for efficacy under monotherapy has recently also been described for structurally closely related spectinamide-1810. 25 Similar efficacy has been observed after IPA administration of substantially lower doses: 50 and 100 mg/kg given 3 times per week. These observations suggest that the benefit of the spectinamide accumulation in the lungs under IPA therapy is not a higher efficacy, but that substantially lower IPA doses seem to be necessary for the same maximum efficacy as observed under SC monotherapy.…”

“…In addition, the maximum efficacy of spectinamide-1599 after SC administration as 4-week monotherapy in the chronic infection model in BALB/c mice has consistently been reported as a ∼1.2–1.5 log 10 CFU reduction in lung (with dosing performed in 5 of 7 days per week): 1.2 for 150 mg/kg once daily, 1.2 for 200 mg/kg once daily, and 1.5 for 200 mg/kg twice daily . A similar plateau effect for efficacy under monotherapy has recently also been described for structurally closely related spectinamide-1810 . Similar efficacy has been observed after IPA administration of substantially lower doses: 50 and 100 mg/kg given 3 times per week.…”

“…Examples of which include tobramycin and amikacin. In chemostat-based in vitro experiments, spectinamide-1599 also exhibited concentration-dependent mycobacterial killing, , and in vivo studies in mouse models of chronic Mtb infection indicate the same PK/PD behavior for spectinamides in vivo . ELF exposures were similar or in some cases even slightly higher than lung homogenate exposures, suggesting that spectinamide-1599 does not remain sequestered in substructures of lung tissue but is able to maintain high ELF concentrations.…”

“…The overall observation of a ceiling effect of spectinamide monotherapy can be explained by the coexistence of multiple bacterial subpopulations with different metabolic states in infected animals in vivo, and a preferential killing of some of these populations, but not all of them by the spectinamide. 25 Moreover, we believe that the therapeutic window of inhaled spectinamide-1599 is substantially improved when administered with pyrazinamide. Pyrazinamide is a critical component in TB chemotherapy and is a drug that has played an essential role in shortening the standard treatment regimen from nine to six months, 37 although its mechanism of action is still not wellunderstood.…”

“…These observations suggest that the benefit of the spectinamide accumulation in the lungs under IPA therapy is not a higher efficacy, but that substantially lower IPA doses seem to be necessary for the same maximum efficacy as observed under SC monotherapy. The overall observation of a ceiling effect of spectinamide monotherapy can be explained by the coexistence of multiple bacterial subpopulations with different metabolic states in infected animals in vivo , and a preferential killing of some of these populations, but not all of them by the spectinamide …”