Stefan Hecht

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. DOI: http://dx.doi.org/10.7554/eLife.20722.001

Changes in blood pressure after administration of hydroxocobalamin: Relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers

Objective. To assess the relationship between blood pressure changes following infusion of antidotal doses of hydroxocobalamin and plasma concentrations of total and free cobalamins-(III). Methods. Independent groups of healthy volunteers received single intravenous doses of 2.5, 5, 7.5, or 10 g hydroxocobalamin over 7.5 to 30 minutes. Results. In the pharmacokinetic population (n = 41), hydroxocobalamin caused short-lived mean blood pressure increases. Blood pressure increased shortly after initiation of infusion and returned nearly to baseline by 4 hours post-infusion. The time course of blood pressure changes coincided with that of changes in plasma total and free cobalamins-(III). Change in mean arterial pressure (MAP) was strongly correlated with plasma area-under-the-concentration-time curves (AUCs) of total and free cobalamins-(III) during infusion (r > 0.7) but not through 24 hours post-infusion (r ≤ 0.36). Conclusion. The short-lived increase in mean blood pressure during administration of antidotal doses of hydroxocobalamin is closely linked to initial exposure to total and free cobalamins-(III).

A novel PBPK modeling approach to assess cytochrome P450 mediated drug-drug interaction potential of the cytotoxic prodrug evofosfamide

Evofosfamide is a cytotoxic small‐molecule prodrug preferentially activated under hypoxic conditions. The cytotoxicity of evofosfamide impacted the generation of in vitro drug‐drug interaction (DDI) data, especially in vitro induction results. Therefore, a novel physiologically based pharmacokinetic (PBPK) approach was used, which involved available in vitro and clinical data of evofosfamide and combined it with induction data from the prototypical cytochrome P450 (CYP)3A inducer rifampicin. The area under the concentration‐time curve (AUC) ratios of midazolam were above 0.80, indicating that induction of CYP3A by evofosfamide administered weekly is unlikely to occur in humans. Moreover, static and PBPK modeling showed no clinically relevant inhibition via CYP2B6, CYP2D6, and CYP3A4. In conclusion, PBPK models were used to supplement in vitro information of a cytotoxic compound. This approach may set a precedent for future studies of cytotoxic drugs, potentially reducing the need for clinical DDI studies and providing more confidence in the clinical use of approved cytotoxic compounds for which DDI information is sparse.