Population pharmacokinetic model for human growth hormone in adult patients in chronic dialysis compared with healthy subjects.
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.


METHODS
This was an open, non-randomized, single-centre parallel-group study lasting 8-9 days. Various compartment models with first-order and Michaëlis-Menten absorption and elimination were explored. Eleven adult ESRD patients and 10 matched HVs received 50 microg/kg/day rhGH (subcutaneous (s.c.) injection) for 8 or 7 days, respectively. Blood samples were drawn every 30 min for 24h 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 Michaëlis-Menten absorption and elimination. The following estimates were obtained: maximum absorption rate (VMA) - 11.3 microg/kg/h (both groups); amount of drug corresponding to half-maximum absorption rate (KMA) - 1.06 and 18.8 microg/kg (ESRD patients and HVs, respectively; P<0.001); maximum elimination rate (VM) - 9.37 and 13.0 microg/kg/h (ESRD patients and HVs, respectively; P<0.001); amount of drug corresponding to half-maximum elimination rate - 18.9 microg/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 20-22h 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.
Klitgaard
Thomas
T
Department of Biomodelling, Novo Nordisk A/S, Building 9ES.20, Krogshøjvej 53A, 2880 Bagsvaerd, Denmark. tkt@novonordisk.com
Nielsen
Jakob N
JN
Skettrup
Mia P
MP
Harper
Angela
A
Lange
Martin
M
D000042:Absorption; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D005260:Female; D019382:Human Growth Hormone / Q000097:blood* / Q000493:pharmacokinetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000097:blood* / Q000493:pharmacokinetics*; D006435:Renal Dialysis / Q000379:methods*; D013997:Time Factors; D016896:Treatment Outcome
D011994:Recombinant Proteins; D019382:Human Growth Hormone