Modelling pharmacokinetic and pharmacodynamic properties of second generation antisense-oligonucleotides (ASOs).
Callies Sophie, Andre Valerie, Vick Andrew-Mark, Graff Jeremy, Patel Bharvin, Brail Leslie, Lahn Michael
Eli Lilly and Company
Acknowledgement: Richard Geary, Rosie Yu (ISIS pharmaceuticals, Inc)
Introduction: One example of targeted therapy is the development of ASOs against a variety of mRNA coding for proteins involved in the pathogenesis of various diseases. By inhibiting the expression of the proteins, ASOs treatment may stop or slow down the disease process.
Objectives: A platform based plasma-tissue PK model was developed for three ASOs (A, B & C). This model was used to select the dose regimen for ASOs B & C.
Material and modelling strategy: NONMEM version V was used to model the data. A six compartments PK model with elimination from the distribution compartments was fitted to ASO PK data. Four compartments corresponded to plasma, liver, kidney and lung and two empirical compartments were included for the remaining tissues. Finally the pharmacodynamic parameters derived from preclinical in vivo and in vitro target inhibition data were used in the PK/PD model which link ASO tissue exposure to mRNA and protein concentration using two consecutive indirect response models. ASOs A was in phase I clinical development, and ASO B and C were between candidate selection and clinical development.
Results: The PK model adequately fitted ASO C monkey and human PK data. This model built using ASO A was predictive of ASO B and C preclinical and clinical PK and confirmed that allometric scaling per body weight is appropriate for ASOs (coefficient 0.922 and 1.19 for clearance and volume, respectively). ASOs are rapidly distributed into tissues following intravenous administration with the distribution half-lives of approximately 30-60 minutes and 2-3 h accounting for approximately 45%, 46% of the plasma exposure, respectively. The plasma clearance varies from 2 to 5 L/h. Following tissue distribution ASOs are cleared (metabolism via endo-exonucleases), with a long half- life in tissue matching the terminal elimination half-life in the plasma (about 20 days accounting for 9 % of plasma AUC). The total tissue clearance and tissue volume of distribution were high (approximately 150 L/h and 65000 L). From the preclinical target inhibition data, ASOs A and B IC50 in tissue and the target mRNAs and protein half-lives were determined.
Conclusion: This model supported the dosing in the clinic for ASOs: a loading dose over three days followed by maintenance weekly dosing regimen in order to achieve and maintain relevant tissue concentration. The PK/PD allowed simulating target down inhibition following dosing regimen and help predict the biological effective dose range.