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Pharmacological Endpoint Reduction of Target mRNA and Protein

Pharmacological Endpoint Reduction of Target mRNA and Protein [Pg.109]

One of the first reported applications of PK/PD modeling to characterize anti-sense PK/PD relationships was a study of a 2 -MOE partially modified ASO, ISIS 22023, targeting murine Fas mRNA expressed exclusively in hepatocytes [46, 47]. [Pg.109]

In this study, the PK/PD relationships of ISIS 22023 were characterized not only in the target organ (the mouse liver), but also in sub-organ levels within the liver. [Pg.109]

In the clinic, PK/PD relationships with the direct pharmacological effect, reduction of target mRNA and protein as the response measure, have been demonstrated in two studies with 2 -MOE partially modified ASOs [42, 50]. In a Phase Ila study in patients with rheumatoid arthritis, ISIS 104838 was targeted at the mRNA of TNF-a (a cytokine which is important in immune response and inflammation). The results showed that TNF-a mRNA and protein reduction in synovial tissue biopsies correlated positively with concentrations of ISIS 104838 in the synovial tissues [50]. Another investigation of PK/PD relationships was conducted in a Phase II doseranging study in prostate cancer patients treated with OGX-Oll, a 2 -MOE partially [Pg.111]




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Endpoints

MRNA

Protein mRNA and

Protein target

Protein targeting

Protein targeting proteins)

Proteins reductants

Proteins reduction

Proteins targeted

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