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Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis.

Maiga M, Ahidjo BA, Maiga MC, Cheung L, Pelly S, Lun S, Bougoudogo F, Bishai WR - EBioMedicine (2015)

Bottom Line: BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks.C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib.Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

View Article: PubMed Central - PubMed

Affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali.

ABSTRACT
The global tuberculosis (TB) epidemic and the spread of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host-directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

No MeSH data available.


Related in: MedlinePlus

A: Mouse serum concentrations of tofacitinib.Mouse serum concentrations of tofacitinib after dosing at 15, 22.5 and 30 mg/kg administered at t = 0 h and t = 6 h. A single dose of 10 mg/kg of rifampin was also administered at t = 6 h. The resulting tofacitinib area under curve concentrations (0–24 h) were 2380, 5074, and 5156 ng/ml·H, for the three respective doses. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.B: Mouse serum concentrations of rifampin.Mouse serum concentrations of rifampin after dosing at 10 mg/kg at t = 0 h with tofacitinib 15, 22.5 and 30 mg/kg given at t = − 6 h and t = 0 h. The resulting rifampin area under curve concentrations (0–18 h) were 77, 93, and 103 μg/ml·H for the respective co-administered tofacitinib dose. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.
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f0005: A: Mouse serum concentrations of tofacitinib.Mouse serum concentrations of tofacitinib after dosing at 15, 22.5 and 30 mg/kg administered at t = 0 h and t = 6 h. A single dose of 10 mg/kg of rifampin was also administered at t = 6 h. The resulting tofacitinib area under curve concentrations (0–24 h) were 2380, 5074, and 5156 ng/ml·H, for the three respective doses. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.B: Mouse serum concentrations of rifampin.Mouse serum concentrations of rifampin after dosing at 10 mg/kg at t = 0 h with tofacitinib 15, 22.5 and 30 mg/kg given at t = − 6 h and t = 0 h. The resulting rifampin area under curve concentrations (0–18 h) were 77, 93, and 103 μg/ml·H for the respective co-administered tofacitinib dose. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.

Mentions: Because of the known tofacitinib-rifampin drug-drug interaction due to rifampin-mediated CYP3A4 induction, we first conducted a PK study to establish effective rifampin and tofacitinib doses in mice for drug co-administration. The concentration of tofacitinib required to inhibit JAK tyrosine kinase activity is 100 nM (31.2 ng/mL), and treatment with recommended doses achieves an AUC0–24 of ~ 3250 nM·H (1014 ng/mL·H) with an elimination half-life of ~ 3 h (Dowty et al., 2014). First we assessed the effect of chronic rifampin exposure on tofacitinib levels. Rifampin was administered daily for seven days prior to a one-day co-administration of tofacitinib and rifampin. Since rifampin is only dosed once daily and tofacitinib twice, the first dose of tofacitinib was administered and followed 6 h later by the second dose in conjunction with rifampin. After steady state rifampin exposure, the peak serum concentration achieved by all three doses of tofacitinib tested was 500–800 ng/mL, well above the concentration required to inhibit JAK tyrosine kinase activity (100 nM or 31.2 ng/mL). With rifampin pre-treatment and co-administration, the 24-hour area under the curve (AUC0–24) values for tofacitinib were 2380 ng/ml·H, 5074 ng/ml·H, and 5156 ng/ml·H for 15, 22.5 and 30 mg/kg/day of tofacitinib, respectively (Fig. 1A). All of these tofacitinib AUC0–24 values compared favorably with typical human AUC0–24 achieved by the drug (1014 ng/mL·H). Interestingly, we observed increased tofacitinib levels in mouse serum on the second of the two daily doses, namely the dose that was co-administered with rifampin at t = 6 h. This may be due to relative saturation of the liver clearance enzymes by rifampin on this second dose.


Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis.

Maiga M, Ahidjo BA, Maiga MC, Cheung L, Pelly S, Lun S, Bougoudogo F, Bishai WR - EBioMedicine (2015)

A: Mouse serum concentrations of tofacitinib.Mouse serum concentrations of tofacitinib after dosing at 15, 22.5 and 30 mg/kg administered at t = 0 h and t = 6 h. A single dose of 10 mg/kg of rifampin was also administered at t = 6 h. The resulting tofacitinib area under curve concentrations (0–24 h) were 2380, 5074, and 5156 ng/ml·H, for the three respective doses. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.B: Mouse serum concentrations of rifampin.Mouse serum concentrations of rifampin after dosing at 10 mg/kg at t = 0 h with tofacitinib 15, 22.5 and 30 mg/kg given at t = − 6 h and t = 0 h. The resulting rifampin area under curve concentrations (0–18 h) were 77, 93, and 103 μg/ml·H for the respective co-administered tofacitinib dose. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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f0005: A: Mouse serum concentrations of tofacitinib.Mouse serum concentrations of tofacitinib after dosing at 15, 22.5 and 30 mg/kg administered at t = 0 h and t = 6 h. A single dose of 10 mg/kg of rifampin was also administered at t = 6 h. The resulting tofacitinib area under curve concentrations (0–24 h) were 2380, 5074, and 5156 ng/ml·H, for the three respective doses. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.B: Mouse serum concentrations of rifampin.Mouse serum concentrations of rifampin after dosing at 10 mg/kg at t = 0 h with tofacitinib 15, 22.5 and 30 mg/kg given at t = − 6 h and t = 0 h. The resulting rifampin area under curve concentrations (0–18 h) were 77, 93, and 103 μg/ml·H for the respective co-administered tofacitinib dose. All mice were pre-treated daily for seven days with 10 mg/kg/day of rifampin to induce CYP3A4.
Mentions: Because of the known tofacitinib-rifampin drug-drug interaction due to rifampin-mediated CYP3A4 induction, we first conducted a PK study to establish effective rifampin and tofacitinib doses in mice for drug co-administration. The concentration of tofacitinib required to inhibit JAK tyrosine kinase activity is 100 nM (31.2 ng/mL), and treatment with recommended doses achieves an AUC0–24 of ~ 3250 nM·H (1014 ng/mL·H) with an elimination half-life of ~ 3 h (Dowty et al., 2014). First we assessed the effect of chronic rifampin exposure on tofacitinib levels. Rifampin was administered daily for seven days prior to a one-day co-administration of tofacitinib and rifampin. Since rifampin is only dosed once daily and tofacitinib twice, the first dose of tofacitinib was administered and followed 6 h later by the second dose in conjunction with rifampin. After steady state rifampin exposure, the peak serum concentration achieved by all three doses of tofacitinib tested was 500–800 ng/mL, well above the concentration required to inhibit JAK tyrosine kinase activity (100 nM or 31.2 ng/mL). With rifampin pre-treatment and co-administration, the 24-hour area under the curve (AUC0–24) values for tofacitinib were 2380 ng/ml·H, 5074 ng/ml·H, and 5156 ng/ml·H for 15, 22.5 and 30 mg/kg/day of tofacitinib, respectively (Fig. 1A). All of these tofacitinib AUC0–24 values compared favorably with typical human AUC0–24 achieved by the drug (1014 ng/mL·H). Interestingly, we observed increased tofacitinib levels in mouse serum on the second of the two daily doses, namely the dose that was co-administered with rifampin at t = 6 h. This may be due to relative saturation of the liver clearance enzymes by rifampin on this second dose.

Bottom Line: BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks.C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib.Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

View Article: PubMed Central - PubMed

Affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali.

ABSTRACT
The global tuberculosis (TB) epidemic and the spread of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host-directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

No MeSH data available.


Related in: MedlinePlus