Thomas Klitgaard

Publications (2)5.52 Total impact

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

  Thomas Klitgaard, Jakob N Nielsen, Mia P Skettrup, Angela Harper, Martin Lange
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  ABSTRACT: 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. 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. 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. A population PK model was established, which showed acceptable performance for trial-simulation purposes.
  Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 03/2009; 19(6):463-70. · 2.35 Impact Factor
• Source

  Available from: PubMed Central

  Article: Pharmacokinetics and pharmacodynamics of growth hormone in patients on chronic haemodialysis compared with matched healthy subjects: an open, nonrandomized, parallel-group trial.

  Irene H Langbakke, Jakob N Nielsen, Mia P Skettrup, Angela Harper, Thomas Klitgaard, Angelika Weil, Eva Engelhardt, Martin Lange
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  ABSTRACT: GH may be beneficial in treating patients with end-stage renal disease (ESRD). However, the efficacy and safety of GH could be compromised by the potential for accumulation in the circulation. The objective was to investigate the pharmacokinetics and safety of GH treatment in ESRD patients. This was an open, nonrandomized, single-centre parallel-group study lasting 8-9 days. Eleven adult ESRD patients and 10 matched healthy individuals received recombinant human GH (50 microg/kg/day for 7 days) by subcutaneous injection; there were two dose reductions (25%) from Day 5/7. ESRD patients underwent dialysis four times. Serum concentrations of GH, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-I (IGFBP-I), IGFBP-III and GHBP were measured. The primary end-point was GH exposure [area-under-the-curve (AUC) calculated from the 24-h profile] on Days 7-8. GH AUC(0-24 h) was greater for patients (387.91 +/- 134.13 microg h/l) than healthy subjects (225.35 +/- 59.63 microg h/l) and the 90% confidence interval (CI) for the estimated patient : healthy subject ratio (1.40-2.07) was not within the acceptance interval (0.67-1.50). GH AUC(18-24 h) for patients and healthy subjects (3.03 +/- 2.71 microg h/l and 6.37 +/- 4.21 microg h/l) returned approximately to baseline (2.86 +/- 3.91 microg h/l and 1.09 +/- 1.43 microg h/l); terminal half-life (t(1/2,z)) was shorter for patients (2.28 +/- 00.43 h vs. 3.23 +/- 00.75 h). No major safety issues were identified. Results demonstrate a difference between patients and healthy subjects regarding GH AUC(0-24 h). However, GH concentrations for both groups were comparable to baseline by 20-22 h, thus GH was not retained in the circulation of ESRD patients.
  Clinical Endocrinology 12/2007; 67(5):776-83. · 3.17 Impact Factor