Allometric Scaling Approaches for Predicting Human Pharmacokinetic of a Locked Nucleic Acid Oligonucleotide Targeting Cancer-Associated miR-221

Maria Teresa Di Martino, Mariamena Arbitrio, Massimiliano Fonsi, Claudio Alberto Erratico, Francesca Scionti, Daniele Caracciolo, Pierosandro Tagliaferri, Pierfrancesco Tassone, Maria Teresa Di Martino, Mariamena Arbitrio, Massimiliano Fonsi, Claudio Alberto Erratico, Francesca Scionti, Daniele Caracciolo, Pierosandro Tagliaferri, Pierfrancesco Tassone

Abstract

: LNA-i-miR-221 is a novel phosphorothioate backbone 13-mer locked nucleic acid oligonucleotide-targeting microRNA-221 designed for the treatment of human malignancies. To understand the pharmacokinetic properties of this new agent, including unbound/total clearance, we investigated the LNA-i-miR-221 protein binding in three different species, including rat (Sprague-Dawley), monkey (Cynomolgus), and human. To this end, we generated a suitable ultrafiltration method to study the binding of LNA-i-miR-221 to plasma proteins. We identified that the fraction of LNA-i-miR-221 (at concentration of 1 and 10 µM) bound to rat, monkey, and human plasma proteins was high and ranged from 98.2 to 99.05%. This high protein binding of LNA-i-miR-221 to plasma proteins in all the species tested translates into a pharmacokinetic advantage by preventing rapid renal clearance. The integration of these results into multiple allometric interspecies scaling methods was then used to draw inferences about LNA-i-miR-221 pharmacokinetics in humans, thereby providing a framework for definition of safe starting and escalation doses and moving towards a first human clinical trial of LNA-i-miR-221.

Keywords: LNA-i-miR-221; PK; allometric method; first-in-human; locked nucleic acid; oligonucleotide; pharmacokinetic; phosphorothioate; plasma protein binding.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
plasma concentration versus time profiles (sparse sampling) following single intravenous (bolus) administration at 12.5 mg/kg to male and female Sprague-Dawley rats (semi logarithmic scale). Error bars represent standard deviations (n = 3).
Figure 2
Figure 2
plasma concentration versus time profiles following single intravenous (bolus) administration at 8.75 mg/kg to male Cynomolgus Monkey (semi logarithmic scale).
Figure 3
Figure 3
plasma concentration versus time profiles (sparse sampling) following single intravenous (bolus) administration at 25 mg/kg to NOD.SCID mice (semi logarithmic scale). Plasma concentrations at 12h and 24h were below the limit of quantification (LLQ = 25ng/mL). Mouse PK was not used for the allometric extrapolation (see main text for details).
Figure 4
Figure 4
Schematic representation of the methodological approaches and results discussed in the work. Arrows connect the input information used to estimate the corresponding output parameter; references to the applied methods are also cited. Based on the estimated parameters, a short conclusion is reported. Additional details are described in the main text.

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