Case Study 2 Preclinical Pharmacokinetics and Pharmacodynamics of PEGylated IFNP1a Following Subcutaneous Administration in Monkeys

The purpose of this study was to characterize the PK/PD properties of a new polyethylene glycol (PEG) conjugate formulation of interferon-pia (IFN-pia) following subcutaneous (SC) administration in monkeys [26]. Single SC injections of 0.3, 1, and 3 MIU/kg of PEG-IFN-pia were administered to three

Figure 5 PK/PD model for the effect of IFN- pia on neopterin. (From ref. 26 , by permission of Springer Science and Business Media.)

groups of cynomolgus monkeys. Plasma concentrations of drug and neopterin, a classic biomarker for IFN-pia, were measured at various time points after dosing using an ELISA assay. PK/PD profiles were first described by noncom-partmental methods, and then a pooled analysis was performed using an integrated mathematical model, where fixed and delayed concentration-time profiles were used as a driving function in an indirect stimulatory response model as presented in Figure 5.

The PK component of IFN-pia was assessed using a standard linear two-compartment model with a first- order rate constant for absorption to and elimination from the central compartment of IFN-pia. The PD model was a modified stimulatory indirect response model, with a zero-order rate constant of neopterin production (kin), a first-order rate constant of neopterin elimination (kout), where the driving function (i.e., concentrations of IFN-pia) was delayed by a time -- ag parameter (-). Neopterin concentrations followed a typical dose-dependent biphasic pattern. Pooled PD profiles were well described by the PK/PD model, and the neopterin elimination rate was consistent with previous estimates. The PEG modification of IFN-pia provided enhanced drug exposure and comparable pharmacodynamics to unpegylated IFN -p ia.

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