Abstract: Spermidine/spermine N(1)-acetyltransferase (SAT1) is a critical enzyme in the polyamine pathway and the rate-limiting enzyme in the catabolism of polyamines. Under normal conditions, SAT1 has a relatively low expression and short half-life. However, SAT1 is inducible and expression of SAT1 is increased in a number of cancers. The increased expression of SAT1 in tumor tissue suggests that acetylated metabolites produced by SAT1 could be used as blood or urine biomarkers for the detection of a variety of cancers. The antiviral drug amantadine undergoes selective SAT1-mediated acetylation to a stable metabolite that is eliminated in the urine. In this regard, amantadine may be a more sensitive cancer biomarker than the endogenous acetylated polyamines. Evidence for the application of acetyl amantadine as an early biomarker for lung cancer will be presented. In addition, using physiologically-based pharmacokinetic (PBPK) modeling of amantadine and acetyl amantadine, predictions concerning SAT1 expression and activity within the tumor compartment and potential applications in early tumor detection will be presented.

Abstract: Clinical dose-ranging studies and exposure-response analyses provide key data underpinning dose selection and defense in development programs. Recent experience from the pembrolizumab programs suggests that monoclonal antibody (mAb) programs may face additional complexity in interpreting data with respect to dose due to strong associations of clearance with patient health factors. For pembrolizumab, randomized dose-ranging studies (2 vs. 10 mg/kg) in melanoma and NSCLC provided key data (including Overall Survival (OS)) for exposure-response analyses and dose selection decisions. No significant difference in OS was found between the doses studied for pembrolizumab, but trends suggestive of exposure-dependency were identified. These trends derived from a clearance-OS association, rather than a true exposure relationship, which likely reflects the patients’ overall catabolic state which may be tied to health factors such as cachexia which directly affect patient outcomes. To support dose selection in future mAb programs (and avoid confounding of patient health effects on clearance), it is recommended to include dose-ranging studies with associated exposure-response analyses, avoid single-dose studies prior to establishment of dose, and collect robust PK data and catabolism biomarkers.

Abstract: NBMI ((N1,N3-bis(2-mercaptoethyl) isophthalamide, Emeramide) is a mercuric chelator developed for the treatment of mercury intoxication. Chelation therapy for mercury toxicity varies throughout the world and is generally encompassed by treatments for toxic metal poisoning. Conducting field studies that yield meaningful results is, not surprisingly, a challenge since the toxic effects of mercury have been known since antiquity and its use in uncontrolled settings is often illegal. One set of biomarkers that are easy to apply are subject evaluations of their physical (e.g., “always lack energy”) and mental (e.g., “problems with memory”) well-being improving or not during 15 days of treatment. While the original statistical analysis was good, it did not explore a few issues: 1) the duration of dosing on improvement of scores, 2) that the individual scores were not independent, and 3) observations were not coupled with plasma measurements of drug and total mercury. A mathematical model was applied using longitudinal discrete outcomes (improvement by day over 15 days) with the generalized estimating (GEE) and the generalized (non-linear) mixed effects modeling (GLMM) approaches. An example of the probability for improvement over time is shown below:

Subject weight, drug and mercury concentration, treatment (dose) and day on study almost always had significant effects on improving GEE and GLMM models, though the use of some covariates, especially mercury concentrations, introduced instabilities in modeling. Depending on the metric (again, “always lack energy”), the odds of a person achieving a “good” physical or mental effect with the drug could be as much as 4 times the odds of the same person with placebo.