J. Parke et Bg. Charles, Factors affecting oral cyclosporin disposition after heart transplantation: bootstrap validation of a population pharmacokinetic model, EUR J CL PH, 56(6-7), 2000, pp. 481-487
Objective: To determine factors affecting the population pharmacokinetics o
f oral cyclosporin (CsA) in cardiac allograft recipients during the first 3
; weeks after surgery.
Methods: Data were obtained from routine trough monitoring and from two ext
ra samples drawn during a dosing interval on a randomly selected day. Whole
blood CsA concentrations were assayed using highperformance liquid chromat
ography (HPLC). Approximately equal numbers of patients were prescribed San
dimmun (SAN) or Neoral (NEO) CsA formulations. Parameter values of a one-co
mpartment kinetic model with first-order absorption and elimination were so
ught together with the inter-patient and intra-patient variances using the
NONMEM program.
Results: Improved fits resulted from using the following expression in the
model to adjust apparent bioavailability as a function of post-operative da
y (POD): f = 0.2 + 10 x ABS (POD-5)/[(POD + 7) x 60]. The CsA clearance (CL
/f) was found to be influenced by current body weight (WT). There was an ab
sorption lag time of about 35 min with SAN, but zero lag time with NEO. Ora
l bioavailability (f) was increased by about 35% with concomitant diltiazem
and about 18% with NEO. The CL/f was 10% higher during the daytime than at
night. The final pharmacokinetic model was validated using 200 bootstrap s
amples of the original data.
Conclusions: Using a validated population modelling approach, it was found
that a number of factors influence the pharmacokinetics of CsA during the e
arly postoperative period in cardiac transplant patients. These influences
affecting oral bioavailability and clearance may need to be taken into acco
unt for maintaining appropriate: concentrations of CsA in the bloodstream.