Endocrine Abstracts

Introduction: OPKO Biologics has produced a long-acting human growth hormone (hGH), MOD-4023, containing three copies of a naturally-occurring peptide (C-terminal peptide, CTP) that markedly increases growth hormone’s in vivo residence. We describe the development and validation of a pharmacokinetic (PK) and pharmacodynamic (PD) model to characterize the relationship between MOD-4023 dose, serum concentrations (Cserum), and IGF-1 responses in healthy adults, GHD adults, and GHD children.

Design/Methods: MOD-4023 PK and PD were studied following its administration to healthy adults (N=18), GHD adults (N=46), and GHD children (age 3–11, N=42). In children, doses were 0.25, 0.48, or 0.66 mg/kg weekly; Genotropin® hGH (N=11, 34 μg/kg daily) was the comparator. Data from healthy adults were used to develop PK/PD models; models were then applied to GHD adults and children. Serum concentrations were fit to a linear compartmental model with first-order absorption and an absorption lag. An indirect response PD model (1) (in which MOD 4023 increases input to IGF-1’s central compartment) was applied to serum IGF-1 data. Covariates (age, body size, gender, organ function) were entered into the PK/PD models if justified statistically. Analyses were performed using mixed-effects (population) methods.

Results: In adults and children, a two-compartment PK model fit Cserum well. The indirect response model generally fit IGF-1 well. In children, systemic parameters scaled allometrically; baseline IGF-1 increased with age. The MOD-4023 PK/PD models predict the relationship between administered dose, Cserum, and IGF-1 response with various dosing regimens.

Conclusion: A linear PK model with first-order absorption fit concentration data well. Systemic PK parameters varied with body size. The indirect response model generally fit IGF-1 data in GHD children. Based on the analysis, the model can assist in safety monitoring, and guide dose modifications. This model may be used to support dose selection and dose modification in future clinical studies.

Reference: 1. Sun et al. JPET 289:1523–1532, 1999