Population Pharmacokinetic Model for Human Growth Hormone in Adult Patients in Chronic Dialysis vs. Healthy Subjects
T Klitgaard , JN Nielsen, MS Fitsios, and M Lange
Novo Nordisk A/S Denmark; Novo Nordisk Inc. USA
Objectives: To develop a population pharmacokinetics (popPK) model of human growth hormone (hGH) in patients with end-stage renal disease (ESRD) and healthy volunteers (HVs), after s.c. administration of rhGH, to explore and to support the design of future clinical trials.
Methods: The analysis was performed using NONMEM, based on samples from 11 patients (pts.) with ESRD and 10 healthy volunteers (HVs). Subjects received 7 (HVs) or 8 (ESRD pts.) daily doses of 50 µg/kg rhGh. Samples for PK were drawn every 30 minutes for 24 h, following dosing on days 0, 7 and 8 (ESRD pts. only). On day 9, ESRD pts. underwent 3-4 h of dialysis. Various compartment models with both first order and Michaelïs-Menten (MM) type of absorption and elimination were explored. Influence of covariates subject group (ESRD/HV) , gender, weight, and dialysis flow rate on key model parameters was examined. Finally, a visual posterior predictive check of the model was performed, to assess its predictive performance.
Results: The final model was one-compartmental with MM-absorption and MM-elimination. S.c. volume of distribution was 0.45 L/kg, baseline hGH was 0.52 µg/L, maximum absorption rate was 11.3 µg/kg/h, and the amount corresponding to half-maximum elimination rate was 18.9 µg/kg. Only the covariate ESRD/HV was significant (p<0.001), on parameters KMA (amount in depot corresponding to half-maximum absorption rate) and VM (maximum elimination rate), leading to different estimates in these 2 groups. Hence, KMA was estimated at 18.8 and 1.06 µg/kg, and VM at 13.0 and 9.37 µg/kg/h, in HVs and ESRD pts., respectively. The differences in KMA and VM corresponded to a smaller elimination rate and higher absolute rate of absorption in ESRD pts. compared with HVs, in turn corresponding to a faster ascent and higher peak level of hGH for the former. Inter-subject variation, particularly of absorption parameters, was high. Visual predictive checks showed that the model seemed to capture the overall PK for the 2 groups quite well. For example, the non-compartmental estimates of AUC0-24h and Cmax lay within the 95% confidence limits of the simulated distributions.
Conclusion: A popPK model of hGH was developed for ESRD pts. and HVs. Absorption and elimination were found to be different in the 2 groups. Visual posterior predictive checks of the model showed an acceptable performance for simulation purposes.
