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Inferring Half-Lives at the Effect Site of Oligonucleotide Drugs.

Knowledge of the kinetics of the active drug in biophase, that is, at the effect site, is fundamental to select dose and to reason about safety. Unfortunately, the kinetics is cumbersome to measure in vivo. We describe how dose-response-time (DRT) analysis estimates the biophase and the target-response half-lives from data of the circulating protein of the encoded messenger RNA for seven antisense oligonucleotides (ASOs) and four small interfering RNA (siRNA) drugs. The biophase half-lives were estimated with acceptable precision (relative standard error <26%). For ASOs, the estimates were similar to, or slightly longer than, the reported terminal plasma half-lives. Terminal plasma half-life was reported for only one siRNA, precluding any general comparison. The estimated half-lives of response were 0.5-12 days cross drugs and shorter than the biophase half-lives. We recommend DRT analysis when limited plasma pharmacokinetic data are available, or when the biophase half-life differs from the terminal plasma half-life.