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摘要
Objective: To develop a population pharmacokinetic (PK) model of recombinant human growth hormone (rhGH) treatment in patients with end-stage renal disease (ESRD) and healthy volunteers (HVs), to support future study design. Design: This was an open, non-randomized, single-centre parallel-group study lasting 8-9 days. Various compartment models with first-order and Michaelis-Menten absorption and elimination were explored. Eleven adult ESRD patients and 10 matched HVs received 50 mu g/kg/day rhGH (subcutaneous (s.c.) injection) for 8 or 7 days, respectively. Blood samples were drawn every 30 min for 24 h following dosing on Days 0, 7 and 8 (ESRD patients). Influence of the covariates subject group (ESRD/HV), gender, weight, and dialysis flow-rate on model parameters was examined. Results: The final model was one-compartmental with Michaelis-Menten absorption and elimination. The following estimates were obtained: maximum absorption rate (VMA) - 11.3 mu g/kg/h (both groups); amount of drug corresponding to half-maximum absorption rate (KMA) - 1.06 and 18.8 mu g/kg (ESRD patients and HVs, respectively; P < 0.001); maximum elimination rate (VM) - 9.37 and 13.0 mu g/kg/h (ESRD patients and HVs, respectively; P < 0.001); amount of drug corresponding to half-maximum elimination rate - 18.9 mu g/kg (both groups). Significant differences in KMA and VM between HVs and ESRD patients corresponded to higher absorption and lower elimination rates in ESRD, but all GH profiles were back to baseline by 20-22 h and no overall accumulation Occurred. Simplified posterior predictive checks indicated that the model satisfactorily captured PK. All non-compartmental estimates for AUC(0-24h) and C-max lay within 95% confidence limits of the simulated distributions. Conclusions: A population PK model was established, which showed acceptable performance for trial-simulation purposes.
- 出版日期2009-12
