ESPE Abstracts

Background, objective, and hypotheses: OPKO Biologics has produced a long-acting human GH (hGH), MOD-4023, containing copies of a naturally-occurring C-terminal peptide (CTP) to markedly increase GH’s in vivo residence. We describe the construction and validation of a pharmacokinetic (PK)/pharmacodynamics (PD) model to characterise the relationship between MOD-4023 dose, MOD-4023 serum concentrations (Cserum), and IGF1 responses in healthy adults, GH-deficient (GHD) adults and GHD children. The model was used to characterise the PK and PD profile of MOD-4023 as part of the on-going paediatric GHD clinical studies.

Method: MOD-4023 PK and PD were studied following administration to healthy adults (n=18), GHD adults (n=46), and GHD children (3–11 years of age, n=53). In children, doses were 0.25, 0.48, or 0.66 mg/kg weekly; genotropin® (hGH 34 μg/kg daily) was the comparator. Data from healthy adults were used to develop PK and 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 was applied to IGF1 data. Covariates (age, body size, gender, and organ function) were entered into the PK and PD models if justified statistically.

Results: In adults and children, a two-compartment PK model fit Cserum data well. For PD modeling, the indirect response model generally fit IGF1 data well. Systemic parameters scaled allometrically; baseline IGF1 increased with age in GHD children.

Conclusion: We constructed and validated MOD-4023 PK and PD models which predict the relationship between administered dose, Cserum, and IGF1 response with various dosing regimens in paediatric GHD population. This model can assist in safety monitoring, including dose selection and dose modification in future clinical studies.