Interspecies scaling of receptor-mediated pharmacokinetics and pharmacodynamics of type I interferons

Abstract

Purpose: To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD).

Methods: PK and PD profiles of human IFN-beta1a, IFN-beta1b, and IFN-alpha2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters.

Results: PK/PD profiles of IFN-beta1a in humans and monkeys were successfully characterized by utilizing the same rate constant parameters and scaling the volume of the central compartment to body weight using an allometric exponent of 1. Concentration and effect profiles of other IFNs were also well described by changing only the affinity of the drug to its receptor. PK profiles in rodents were simulated using an allometric exponent of -0.25 for the first-order elimination rate constant, and no receptor-binding was included given the lack of cross-reactivity.

Conclusions: An integrated TMDD PK/PD model was successfully combined with classic allometric scaling techniques and showed good predictive performance. Several parameters obtained from one IFN can be effectively shared to predict the kinetic behavior of other IFN subtypes.

Fig. 1

Integrated model used to characterize PK and PD of different IFNs in humans and monkeys. For rodents, it is assumed that there is no binding of human interferon to receptor in those species, so the model reduces to a two-compartmental PK model.

Fig. 2

Flowchart of the data analysis approach. TMDD—target-mediated drug disposition, 2CM—two-compartment.

Fig. 3

Allometric scaling of clearances and volumes for IV dose of human IFNs. A Systemic clearances (Cl) and B volumes of distribution at steady state (Vss) calculated by non-compartmental analysis. C Distributional clearances (Cl_D) and D central compartment volumes (Vc) calculated by two-compartmental model. Symbols represent values from each study group (IFN-β1a—○; IFN-β1b—□; IFN-α2a—△). Lines represent regression lines (Eq. 1).

Fig. 4

Time-course of IFN-β1a concentrations in humans (A) and monkeys (B) after IV bolus administration. The symbols represent data extracted from references (23) and (8), and lines are model-predicted profiles after simultaneous fitting of IFN-β1a PK data for both species. Doses in humans are 14.8 pmole/kg (▼; dashed line), 29.6 pmole/kg (○; dotted line), and 44.4 pmole/kg (●; solid line). Doses in monkeys are 148 pmole/kg (▼; dashed line), 444 pmole/kg (○; dotted line), and 1,481 pmole/kg (●; solid line).

Fig. 5

Time-course of plasma neopterin following IFN-β1a bolus IV administration in humans (A) and monkeys (B). The symbols represent data extracted from references (23) and (8), and lines are model-predicted profiles after simultaneous fitting of PD data for both species. IFN-β1a doses in humans are 14.8 pmole/kg (▼; dashed line), 29.6 pmole/kg (○; dotted line), and 44.4 pmole/kg (●; solid line). IFN-β1a doses in monkeys are 148 pmole/kg (▼; dashed line), 444 pmole/kg (○; dotted line), and 1,481 pmole/kg (●; solid line).

Fig. 6

Time-course of IFN-β1b and IFN-α2a concentrations following IV administration to humans (A) and monkeys (B). The symbols represent experimental data extracted from references (7,32) for IFN-β1b and (40,41) for IFN-α2a; lines are model-predicted profiles after fitting of PK data (stage 3). The doses in humans are IFN-β1b 335 pmole/kg (●; solid line), and a 148 pmole/kg IV infusion over 40 min IFN-α2a (○; dashed line). The doses in monkeys are IFN-β1b 300 pmole/kg (■; solid line), and a 947 pmole/kg IV infusion over 40 min IFN-α2a (□; dashed line).

Fig. 7

Time-course of plasma neopterin concentrations following IFN-β1b bolus IV administration (335 pmole/kg) in humans. The symbols represent data extracted from reference (32), and the line is a PD modelpredicted profile using PK and PD parameters determined at stages 1, 2, and 3.

Fig. 8

Time-course of IFN concentrations following IV administration to mice and rats. The symbols represent experimental data extracted from the literature; lines are model-simulated profiles using scaled parameters estimated at stage 1. The volume of distribution (V_C) and the rate constant of linear elimination (k_el) were scaled to body weight using allometric exponents of 1 and −0.25. Doses are IFN-β1a 4,867 pmole/kg in rats (▼; dashed line) (39), IFN-α2a 947 pmole/kg in rats (■, dash-dot-dot line) (42), IFN-β1a 578 pmole/kg in mice (●; solid line) (39), and IFN-β1a 71 pmole/kg in mice (○; dotted line) (38).