S. F. Marshall(1), P. A. Milligan(1), D. J. Nichols(1) and M. O. Karlsson(2)
1) Pfizer Central Research, Sandwich, Kent, UK. 2) Division of Biopharmaceutics and Pharmacokinetics, University of Uppsala, Sweden.
For a drug or metabolite eliminated by renal mechanisms, impaired renal function (IRF) may alter its pharmacokinetics (PK) and pharamacodynamics (PD) to an extent that the dosage regimen needs to be changed. An IRF/PK/PD model can be proposed to characterise this relationship and allow potential future dosage algorithms to be assessed. This would optimally require that the following components of the model be determined:
1) Average CLer and CL/F relationship
2) Effect of renal function on non-renal clearance component
3) Effect of renal function on PD
4) PK/PD relationship
5) Intersubject variability in pharmacokinetics and pharmacodynamics
6) Distribution of renal function within the target population
Dofetilide is a selective class III antiarrhythmic agent, which is effective in the treatment of supra-ventricular cardiac arrhythmias. The inter and intra-subject variability in the pharmacokinetics is low and predictable across healthy volunteers and patients. Three analyses were undertaken to identify the effect of renal function on the pharmacokinetics of dofetilide:
1) Standard analysis of renal impairment study incorporating small groups of patients with moderate (n= 5) and severe renal impairment (n=6), and comparing them to data from ( healthy volunteers (n=18).
2) Population analysis ofearly dose ranging safety and efficacy trials (n=117)
3) Combined analysis of both These are presented and compared with respect to their ability to provide information on the components of the IRF/PK/PD model.
The discussion focuses on what needs to be known and should be known about the IRF/PK/PD model when predicting the dosing algorithm for Phase III and the utilisation of the recent FDA guidelinest in the optimisation of this process.
[1]. FDA Guidance on Pharmacokinetics and pharmacodynamics in patients with impaired renal function: Study design, data analysis, and impact on dosing and labelling, May 1997
Reference: PAGE 7 (1998) Abstr 674 [www.page-meeting.org/?abstract=674]
Poster: oral presentation