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

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.Cancers 2020, 12, 27 2 of 15 against multiple myeloma (MM) and other malignancies [5], and rescues tumor sensitivity to alkylating agents [6]. On these bases, LNA-i-miR-221 has been selected and recently approved for a dose-escalation phase I clinical trial in humans (2017). However, at present, little information is yet available on the pharmacokinetics (PK) of LNA-oligonucleotides after systemic injection. In our previous studies on LNA-i-miR-221 PK properties in different animal species [2,4], we found that it reaches the targeted biphase already described for these "second generation" antisense oligonucleotides (ASOs), which relies on their systemic distribution and retention by tissues. Such processes involve surface protein interactions and endocytosis, which finally lead to cell internalization and excretion [7].We have already developed a full GLP-compliant ion-pair reversed-phase LC-MS/MS method for accurate quantification of LNA-i-miR-221 in preclinical animal models that was recently validated for a GLP rat study [8]. This LNA-i-miR-221 detection method was applied to analysis of plasma samples from both preliminary toxicity studies in mice and monkeys [2], and for regulatory toxicity study in rats [4]. All the PK studies performed showed similar profiles in the tested species, showing a large systemic volume of distribution and extensive tissue penetration [2,4], supporting the results reported for other ASOs with a PS backbone [9]. Moreover, LNA-i-miR-221 showed rapid tissue distribution, followed by systemic clearance with low renal excretion [2], suggesting a favorable clearance reduction due to large binding to plasmatic proteins.The aim of safe animal dose extrapolation is to estimate appropriate human dose and exposure levels to ensure drug safety. This approach is required for the initial dose selection in the clinical phase. In cross...

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