Premium
P1‐055: E2027, A NOVEL PHOSPHODIESTERASE‐9 (PDE9) INHIBITOR IN DEVELOPMENT FOR TREATMENT OF DEMENTIA WITH LEWY BODIES (DLB), SHOWED NO CLINICALLY SIGNIFICANT DRUG INTERACTION WITH DILTIAZEM
Author(s) -
Landry Ishani,
Lai Robert YK.,
Boyd Peter,
Aluri Jagadeesh,
Chang Min-Kun,
Schuck Edgar L.,
Luthman Johan
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.057
Subject(s) - diltiazem , cmax , pharmacokinetics , pharmacology , medicine , phosphodiesterase , chemistry , calcium , enzyme , biochemistry
effect of short vs long forms of Ab on glutamate and nicotinic neurotransmission. Results: Both the 5-HTTLPR and COMT genotype substantially affect the cognitive trajectory in placebo patients. The beneficial effect of 5HT-6 antagonism is reduced by donepezil or other AChE-I; other negative pharmacodynamic interactions are observed with some antipsychotics and anti-depressants. Aweak 5HT4 agonist while ineffective in mild-to-moderate AD patients shows benefit in the more severe AD case. The cognitive effect of both 5-HT4 and 5-HT6 modulators is heavily dependent upon the baseline state of b-amyloid. Conclusions: Quantitative Systems Pharmacology, when applied to clinical trial design has the capacity to identify and mitigate negative pharmacodynamic interactions that otherwise could reduce the clinical signal of a novel drug, resulting in a negative trial. This would suggest that many trials have failed due to imbalance of comedications, genotypes and b-amyloid status over the different treatment arms.