Biology subjects

Zannoni, S.

Publications and source records attributed to Zannoni, S..

3 recordsLinked to original sources

bioRxiv2026

Impact of GPR39 Inhibition on Tissue Oxygen Tension in Acute Myocardial Infarction: Modeling Using an Indirect Response Pharmacokinetics/Pharmacodynamics Approach

In pre-clinal studies, VC108, a novel GPR39 inhibitor, increased myocardial O2 tension (mpO2) during different phases of acute myocardial infarction (AMI). The purpose of this work was to investigate the temporal effects of VC108 on mpO2 using a novel population PK/PD model developed from preclinical data using healthy animals and animals subjected to AMI protocols. PK/PD simulations were then performed to explore mpO2 dynamic in untested experimental scenarios. VC108 PK data fitted well to a two-compartment model with linear elimination with body weight, sex, and nominal dose identified as significant covariates influencing clearance and/or central compartment volume. Applying indirect effect model principles for representing mpO2 flux, a structural population PK/PD model was developed to capture mpO2 dynamics during different AMI phases: before and during coronary occlusion and after reperfusion. The model successfully captured basal mpO2 homeostasis, ischemic decline, and reperfusion overshoot, while quantifying the contribution of VC108 to collateral blood flow and functional recovery. Dose response relationships were simulated to measure the effect of different VC108 dose levels on permanent damage, i.e. a reduction in mpO2 at steady state after AMI. The probability of remaining below predefined damage thresholds (mpO2 reduction of 5% to 20%) increased with dose in both sexes, with females consistently achieving greater protection that plateaued around 1 mg/kg of VC108 for higher permanent damage. This model represents a valuable tool to describe, for the first time, VC108 efficacy data and pharmacokinetics with ischemia/reperfusion dynamics and quantify its effect in untested dose levels.

pharmacology and toxicology↗

bioRxiv2026

Next Generation TB Drug Combinations from the Pan-TB Consortium: Combination Efficacy and Contributions of Individual Agents, Evaluated in a BALB/c Mouse TB Model

The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) aims to accelerate development of shorter, simpler and safer pan-TB combinations. We previously identified 3 out of 25 first-generation novel PAN-TB 4-drug combinations, that cured 90% of mice in less than 3 months, at clinically relevant doses in the relapsing mouse model of TB. These regimens include BPa830Sut, BPa286Sut and BQSut286 (B: bedaquiline; Pa: pretomanid; 830: GSK3211830; 286: GSK2556286; Sut: sutezolid; Q: quabodepistat). Here, we assess the efficacy of these combinations where the original candidates are substituted next-generation or more advanced compounds (ganfeborole (656) for 830, sorfequiline, S for B, TBD09 for Sut and TBD11 for 286) and the individual contributions of specific agents. Six novel regimens demonstrated bactericidal activity more rapid than comparators PHMZ (Rifapentine P, Isoniazid H, Moxifloxacin M, Pyrazinamide Z) and BPaMZ. Modelled cure/relapse data showed that SPa286Sut, SPaSut and SPa656Sut cured 90% of mice in about 1 month, while SPa286, SPaQTBD11 and SPaTBD09 in less than 2 months, faster than PHMZ. Consistent with our previous findings, the fastest-curing regimens centered on a diarylquinoline (S), a nitroimidazole (Pa) and an oxazolidinone (TBD09 or Sut) together with an Rv1625c agonist (TBD11 or 286), DprE1 inhibitor (Q) or a LeuRS inhibitor (656). Notably, significant contributions to sterilizing efficacy were demonstrated for S in all combinations and for Pa, Sut, TBD09, Q and TBD11 or 286 in specific S-containing combinations. These findings suggest potential for these novel agents and combinations to improve treatment of both DS-and DR-TB.

pharmacology and toxicology↗

bioRxiv2026

Nonclinical pharmacokinetics and relative efficacy of the first 25 novel tuberculosis drug combinations from the PAN-TB consortium: Use of the BALB/c relapsing mouse model and combination pharmacokinetics within a modeling-based framework

The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) aims to accelerate development of shorter, simpler and safer pan-TB combinations, effective for use in both Drug Susceptible (DS)- and Drug Resistant (DR)- TB patients. Towards this aim, bactericidal and sterilizing activity of 25 priority 4-drug combinations was evaluated at doses targeting clinically relevant exposures, in the BALB/c relapsing mouse model of TB. The combinations comprised 8 PAN-TB drugs and candidates: bedaquiline (B), pretomanid (Pa), delamanid (Del), quabodepistat (Q), sutezolid (Sut), GSK2556286 (286), GSK3211830 (830) and ganfeborole (GSK3036656, (656)). Combination PK studies in infected mice enabled dose selection and a population-PK approach guided dosing so that compounds should achieve mean AUC0-24 within 2-fold of their clinical target exposures during the efficacy studies. All test combinations showed time-dependent bactericidal activity, with six regimens reducing lung bacterial burdens below the limit of detection with 8 weeks treatment, similar to the comparator BPaMZ (M is moxifloxacin and Z as pyrazinamide). Cure/Relapse data were modelled to derive population time to cure 90% mice (T90) values. Fifteen PAN-TB combinations had T90s of less than 5 months, sterilizing mice faster than the standard of care for drug susceptible TB, RHZE/RH. The best-performing PAN-TB combinations, BPa830Sut, BPa286Sut and BQSut286, cured 90% of mice in less than 3 months. These 3 top-ranked 4-drug combinations are all centered on a diarylquinoline (B)/oxazolidinone (Sut) core, together with the nitroimidazole (Pa) or a DprE1 inhibitor (Q) plus a novel agent such as the LeuRS inhibitor (830) or the Rv1625c agonist (286).

microbiology↗