Olivier Boutaud

Background/Objectives: VU0467319 (VU319), an M1 muscarinic positive allosteric modulator evaluated in Phase 1 studies, exhibits subproportional dose-exposure scaling typical of poorly soluble compounds. This study applies physiologically based pharmacokinetic (PBPK) modeling to investigate the sources of divergence between IVIVE-based predictions and observed single ascending dose (SAD) clinical pharmacokinetics. Methods: A whole-body PBPK model was developed in Simcyp Simulator V24 using in vitro ADME and physicochemical inputs. Clinical pharmacokinetic data were used for sequential, hypothesis-driven model refinement of distribution, clearance, and absorption parameters. Model performance was evaluated at 60–600 mg fasted using virtual populations demographically matched to their corresponding clinical cohort. Results: A K_p scalar of 0.125 recovered model V_ss within the observed V_z/F bound; a 10.7-fold downward CL_int correction (32.2 to 3 µL/min/mg) reconciled clearance; and a 1 µm particle radius recovered AUC_0–∞ within 6% across 60–240 mg. The model met predefined performance thresholds across the four independent verification doses (geometric mean fold error 1.45 for AUC and 1.56 for C_max; three of four doses within 2-fold), with progressive underprediction at the highest doses (≥400 mg). Supersaturation-ratio analysis indicated that, within the model, sustained supersaturation was unlikely to explain the high-dose underprediction. The refined model reproduced the observed sub-proportional dose-exposure relationship through 240 mg, but underpredicted exposure at 400 and 600 mg. Conclusions: Structured PBPK refinement identified dissolution-limited absorption as the most likely primary contributor to IVIVE–observed divergence for VU319, with secondary contributions from clearance and distribution. These model-derived mechanisms remain hypotheses that require experimental confirmation. The workflow may provide a structured refinement framework for other low-solubility compounds where IVIVE assumptions diverge from observed pharmacokinetics.

Background: 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer’s disease. Methods: This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. Results: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10–3.27 h, and an accumulation ratio of 1.38–1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. Conclusions: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. Trial registration: Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18).

2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer’s disease. In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers. Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1–2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level. 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement. This study is registered at ClinicalTrials.gov (NCT03176940).

Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. Bid-/- mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid’s membrane binding domain, Bid^M148T, associates with MI predisposition. Furthermore, Bid but not Bid^M148T associates with Mcl-1^Matrix, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.

The total synthesis of hemiketal E₂ (HKE₂) has been accomplished using a gold(I)-mediated cycloisomerization followed by oxidation of the enol ether product to introduce a unique keto-hemiketal, the core structure of HKE₂. Synthetic hemiketal E₂ reproduced biosynthetically derived HKE₂ in the inhibition of human platelet aggregation.

Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)–derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2 biosynthesis. We show that low-dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet–tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855–65. ©2016 AACR.