A Pharmacokinetics and Pharmacodynamics (PK/PD) Guided Approach to Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents

Currently used treatment strategies for tuberculosis (TB) involve administration of multiple drug combinations for a minimum of 6-9 months. However, these prolonged regimens do not always achieve sterilization, as evidenced by post-therapy relapse in a subgroup of treated individuals. In an effort to develop novel therapeutic agents for TB a new class of chemical agents, nitrofuranylamides, is being developed at the University of Tennessee Health Science Center. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of nitrofuranylamide lead compounds suitable for further development. First, we examined the biopharmaceutic properties and preclinical PK of nitrofuranylamide lead compounds. The first tested lead compound, Lee 562, exhibited a high systemic clearance, short terminal half-life, and low oral bioavailability of 15.9%. These observations were further supported by the poor metabolic stability of Lee 562. Thus, two second generation follow-up compounds, Lee 878 and Lee 952 were tested that included structural modifications for increased metabolic stability. Both compounds showed improved metabolic stability compared to Lee 562. As expected, this in vitro observation translated into an increased in vivo stability (lower plasma clearance) of Lee 878 compared to Lee 562 and Lee 952, with a 20- and 10-fold higher systemic exposure, respectively. As a consequence, oral bioavailability of Lee 878 reached ~27% compared to 16% for Lee 952 and Lee 562. We then tested a new set of nine third generation compounds for microsomal metabolic stability to guide selection of a stable compound with even higher oral bioavailability. From this panel Lee 1106 was selected for further PK evaluation in rats. Lee 1106 exhibited favorable PK properties such as a low systemic clearance and a long terminal half-life. However, oral bioavailability of Lee 1106 was poor (4.6%). Biopharmaceutic evaluation of the compound showed that the compound has poor aqueous solubility and a high clogP. Further, the plasma protein binding of the compound was found to be high underlining the hydrophobicity of the molecule. Based on these results, a PK guided screening paradigm was developed for optimization of the nitrofuranylamide lead compounds. In order to add pharmacodynamic considerations to the lead optimization approach, we developed a novel in vitro PK/PD model and validated the model by studying the activity of a first line anti-TB drug, isoniazid (INH) against M. bovis BCG as a model organism. M. bovis BCG in the model was treated with multiple doses of INH mimicking concentration-time profiles encountered during multiple dosing in vivo. The time-kill data was analyzed using a semi-mechanistic PK/PD model that included an adaptive IC50 function for explaining the re-growth of bacteria observed over the course of treatment. The PK/PD model was able to describe the data well. The PK/PD index AUC0-24/MIC was found to be the most explanatory of antimicrobial effect of INH. These findings are in agreement with the previously published studies and suggest that the in vitro PK/PD model can be used for assessing the antimycobacterial activity of lead compounds. Thus, the in vitro PK/PD model was subsequently applied to establish time-kill curves for dosing regimens of lead compound Lee 1106. Lee 1106 showed exposure-dependent killing of M. bovis BCG. A semi-mechanistic PK/PD model was developed to describe the Lee 1106 mediated killing of bacteria. The model was subsequently used for numerical simulation experiments to predict the killing effect of different untested multiple dose regimens of Lee 1106 in mice. It was found that the once daily regimen is most adequate for further studies in the mouse model of TB. The information gained from the PK/PD evaluation and the simulation experiments illustrate the utility of the PK/PD guided approach for the selection of compounds with favorable properties for a high likelihood of in vivo efficacy. In summary, we have successfully developed an iterative PK/PD guided process for lead optimization of nitrofuranylamides that uses a set of biopharmaceutic, pharmacokinetic and pharmacodynamic evaluations as criteria for compound and dose selection to move to subsequent development levels

Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage

Gastric Reacidification with Betaine HCl in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions

Population repeated time-to-event analysis of exacerbations in asthma patients : A novel approach for predicting asthma exacerbations based on biomarkers, spirometry, and diaries/questionnaires

Identification of covariates, including biomarkers, spirometry, and diaries/questionnaires, that predict asthma exacerbations would allow better clinical predictions, shorter phase II trials and inform decisions on phase III design, and/or initiation (go/no-go). The objective of this work was to characterize asthma-exacerbation hazard as a function of baseline and time-varying covariates. A repeated time-to-event (RTTE) model for exacerbations was developed using data from a 52-week phase IIb trial, including 502 patients with asthma randomized to placebo or 70 mg, 210 mg, or 490 mg astegolimab every 4 weeks. Covariate analysis was performed for 20 baseline covariates using the full random effects modeling approach, followed by time-varying covariate analysis of nine covariates using the stepwise covariate model (SCM) building procedure. Following the SCM, an astegolimab treatment effect was explored. Diary-based symptom score (difference in objective function value [dOFV] of -83.7) and rescue medication use (dOFV = -33.5), and forced expiratory volume in 1 s (dOFV = -14.9) were identified as significant time-varying covariates. Of note, time-varying covariates become more useful with more frequent measurements, which should favor the daily diary scores over others. The most influential baseline covariates were exacerbation history and diary-based symptom score (i.e., symptom score was important as both time-varying and baseline covariate). A (nonsignificant) astegolimab treatment effect was included in the final model because the limited data set did not allow concluding the remaining effect size as irrelevant. Without time-varying covariates, the treatment effect was statistically significant (p < 0.01). This work demonstrated the utility of a population RTTE approach to characterize exacerbation hazard in patients with severe asthma

The Use of Betaine HCl to Enhance Dasatinib Absorption in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions

The Use of Betaine HCl to Enhance Dasatinib Absorption in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib C(max) and AUC(0-∞) by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib C(max) and AUC(0-∞) by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions