Model-Based Drug Development (MBDD) of Pegylated Growth Hormone (PEG-hGH) in the Treatment of Adult Growth Hormone Deficient (AGHD)
Rujia Xie (1), Tracy Higgins (1), Jaap Mandema (2)
(1)Pfizer, Sandwich, United Kingdom; (2)Quantitative Solutions Inc. CA, USA
Objectives: This presentation reviews the major MBDD activities and their influence on the early development of PEG-hGH and the inception of an expedited late development strategy.
Methods: There were three key influential MBDD activities undertaken in the early development of PEG-hGH.
A model-based literature meta-analysis (MBLMA) was conducted across the extensive prior literature available on the treatment of AGHD with recombinant human growth hormone (rhGH) (Genotropin). Summary level data was available on 135 trials (354 unique treatment arms) presenting 6395 patients and patient level data was available on 3 trials. The dose response relationships for the biomarker insulin growth factor-1 (IGF-1)  and outcome measures of body composition were characterised.
A semi-mechanistic PK/IGF-1 model to describe IGF-1 vs. time profiles after administration of PEG-hGH was developed , applied and updated across Phase 1 (56 males) and Phase 2a (7 males) The data were analysed by a nonlinear mixed effects modelling approach.
The computer added trial design (CATD) was performed to assist Phase 2a/b study designs using PK/IGF-1 model including variability and parameter uncertainty.
Results: The MBLMA approach allowed the relationship between IGF-1 and body composition for rhGH to be fully quantified. This result supported the rationale to use IGF-1 as a biomarker for early development and provided the confidence to select Phase 3 dose(s) based on the Phase 2 IGF-1 response; saving a dose body composition Phase 2 study. Females were less sensitive than males and this relationship was well quantified for all endpoints.
The equivalent clinical efficacious doses for PEG-hGH to rhGH were predicted based on simulated IGF-1 response. This approach was used to optimise the dose regimen for PEG-hGH and supported the early investment in the dose strength for Phase 3.
Clinical trial simulation (CTS) was undertaken to simulate IGF-1 response for various scenarios to select the optimal study design (doses and sample size) for PEG-hGH Phase 2a and 2b trials using the PK/IGF-1 models developed from phase 1 and Phase 2, respectively. Gender difference obtained from MBLMA was incorporated into the CTS under the assumption of similar gender effect on both drugs. The sample size (especially for placebo group), duration and arms for Phase 2b study were significantly reduced.
Conclusions: The application of MBDD has supported the efficient and cost-effective clinical drug development of PEG-hGH. The established quantitative linkage between IGF-1 and body composition has the potential to improve routine clinical practice with rhGH.
 Relationship between the Dose of Recombinant Human Growth Hormone (rhGH) and Insulin Growth Factor-1 (IGF-1) in Adult Patients with Growth Hormone Deficiency (AGHD). Poster for PAGE, Marseille, 2008.
 Population Pharmacokinetic/Pharmacodynamic Analysis for Pegylated Recombinant Human Growth Hormone (PHA-794428) in Male Healthy Volunteers. Abstract for Endocrine Society Meeting, Boston June 24-27, 2006.