Lesson 5 – Pharmacokinetics of PS ASOs

Introduction

As is the case for drugs of all classes, for phosphorothioate (PS) ASOs, it is essential to understand their pharmacokinetic properties. 

Drug-Drug Interactions 

Because PS ASOs distribute and are metabolized by mechanisms that differ from small molecule drugs (cytochrome P450 metabolism vs nuclease metabolism), there are few pharmacokinetic drug-drug interactions. 

Of course, pharmacological and toxicological drug-drug interactions can occur, and a good example is our SCN2A ASO and Dilantin. The SCN2A ASO reduces the level of a sodium channel that is critical in CNS electrical signaling while Dilantin is a sodium channel inhibitor that is used to reduce seizures. As we increase the dose of the SCN2A ASO, it is necessary (and desired because Dilantin has many side effects) to reduce the dose of Dilantin. 

Conclusions

Thanks to 35 years of research, a great deal is known about the pharmacokinetic (PK) and pharmacodynamic (PD) properties of PS ASOs, including the sub-organ PK/PD for organs like the liver, kidney, and CNS. Importantly, for PS ASOs in a specific chemical class, PK behavior is quite consistent enabling the selection of dose, dose frequency, and route of delivery based on results obtained with other PS ASOs of the same class. There is also a strong correlation between PK and PD properties of PS ASOs of the same chemical class. However, optimal PD behavior (what the drug does to the body) is achieved only if rigorous multi-step screening processes are used to identify an optimal PS ASO. 

How and when one can extrapolate from the behavior of previously studied PS ASOs, however, is challenging and requires meaningful experience with the technology and a commitment to rigorous screening processes that weed out problematic PS ASOs and identify optimal PS ASOs. 

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