Pharmacokinetic Allometric Scaling of Oligonucleotides

Mahmood, Iftekhar

doi:10.1089/nat.2011.0299

Cited by 11 publications

(10 citation statements)

References 26 publications

(15 reference statements)

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“…Mahmood 13 also attempted to predict previously published observed mean human plasma clearance values for phosphorothioate oligodeoxynucleotides and 2′-MOE ASOs, utilizing previously published mean clearance data of the same compounds from several tested animal species, including mouse, rat, dog, and monkey, and applying various allometric scaling approaches. In this publication, human plasma clearance predictions were based on scaling data from one, two, or three animal species and the findings demonstrated mixed success.…”

Section: Discussionmentioning

confidence: 99%

“… 11 , 12 An article describing some initial evaluations of the predictive performance of several different interspecies scaling approaches for ASOs was recently published. 13 In the case of 2′-MOE ASOs, the most common animal species tested are mice and monkeys. Therefore, it is an important question to ask what dose-adjusted comparisons between these toxicology species and human best estimate the relative systemic exposure ratio.…”

Section: Introductionmentioning

confidence: 99%

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Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

Grundy

Henry

et al. 2015

Molecular Therapy - Nucleic Acids

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Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

Grundy

Henry

et al. 2015

Molecular Therapy - Nucleic Acids

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“…The aim of this investigation was to develop a PK model to predict the CL and exposure of the oligonucleotide LNA-i-miR-221 in humans and to anticipate human plasma levels in the absence of other human data. Quantitative modeling approaches based on allometry for oligonucleotides have provided encouraging results, but may not be always straightforward [19]. For this reason, in our approach, different scaling methods were used in parallel, based on the available preclinical PK information, and the mean of the different estimates was finally used to predict the CL of LNA-i-miR-221 (and its exposure) in humans.…”

Section: Protein Bindingmentioning

confidence: 99%

“…Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medical Products" [29]. The human PK parameters were predicted using different allometric approaches based on two-species allometry (rat and monkey) and single-species allometry [19].…”

Section: Protein Bindingmentioning

confidence: 99%

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

Martino

Arbitrio

Fonsi³

et al. 2019

Cancers

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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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“…Allometric scaling is regularly used to predict pharmacokinetic parameters such as clearance, volume of distribution, and half‐life from animals to humans (interspecies scaling) . Allometric scaling can also be used to predict pharmacokinetic parameters from adults to children and can be a very useful tool during pediatric drug development . Allometric scaling based on body weight or age is simple and can be used to predict drug clearance in children by allometric extrapolation of adult clearance .…”

mentioning

confidence: 99%

Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children ≤2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models

Mahmood

2015

The Journal of Clinical Pharma

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The objective of this study was to evaluate the predictive performance of 4 allometric models to predict clearance in pediatric ages ranging from premature neonates to children ≤2 years of age. Four allometric models were used to predict clearances of 28 drugs in children from preterm neonates to 2 years of age (n = 564). The 4 models are (1) basal metabolic rate-dependent model; (2) age-dependent exponent model; (3) an allometric model based on kidney and liver weights as well as kidney and liver blood flow; and (4) an allometric model based on a fixed exponent of 0.75. The predictive performance of these models was evaluated by comparing the predicted clearance of the studied drugs with the observed clearance in an individual child. The results of the study indicated that the 3 new proposed models predicted the mean clearance of the drugs with reasonable accuracy (≤50% prediction error). On the other hand, the exponent of 0.75 produced substantial prediction error. Predicted individual clearance values were ≥50% in approximately 30% of the children by the proposed 3 methods and 73% by exponent 0.75. The 3 new proposed allometric models can predict mean clearances of drugs in children from premature neonates to ≤2 years of age with reasonable accuracy and are of practical value during pediatric drug development.

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Pharmacokinetic Allometric Scaling of Oligonucleotides

Cited by 11 publications

References 26 publications

Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

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

Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children ≤2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models

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