Pharmacokinetics and bioavailability of rhIGF-I/IGFBP-3 in the rat and monkey.

Circulating IGF-I exists primarily as part of a ternary 150 kDa complex comprising equimolar amounts of IGF-I, IGFBP-3 and acid labile subunit (ALS). It is also known that in contrast to IGF-I and IGFBP-3 there exists a substantial quantity of unbound ALS in the circulation. As part of our preclinical development program, we have investigated the pharmacokinetic properties of a complex of human recombinant IGF-I and IGFBP-3. Systematic administration of rhIGF-I/IGFBP-3 results in binding of this binary complex to endogenous free ALS and thus leads to increased circulating levels of 150 kD ternary complex (IGF-I/IGFBP-3/ALS). In contrast to the administration of free IGF-I, IGF-I/IGFBP-3 dosing leads to increased systemic IGF-I exposure (i.e. increased area under the time vs. serum concentration curve or AUC) and decreased clearance (CL). Upon administration of equimolar doses of IGF-I/IGFBP-3 to the rat and monkey, it was found that in the monkey AUC was increased and CL decreased when compared to the rat. In addition, the pharmacokinetic profile suggests that saturation of excess ALS occurs at considerably lower doses of rhIGF-I/IGFBP-3 in the monkey than in the rat. Finally, the bioavailability of rhIGF-I/IGFBP-3 was assessed in the rat and found to be approximately 85% and 50% after intramuscular and sub-cutaneous administration, respectively. It was concluded that the formation of the 150 kD ternary complex had a significant impact on increasing the systemic exposure to rhIGF-I when administered as the binary complex (rhIGF-I/IGFBP-3). In addition, IGFBP-3 increases the therapeutic index of rhIGF-I even at doses that significantly exceed the saturation of ALS.