Explaining Variability in Tacrolimus Pharmacokinetics to Optimize Early Exposure in Adult Kidney Transplant Recipients.
Press, Rogier R PharmD *+; Ploeger, Bart A PharmD, PhD ++[S]; Hartigh, Jan den PharmD, PhD *; Straaten, Tahar van der PhD *; Pelt, Johannes van PhD [P]; Danhof, Meindert PharmD, PhD ++[S]; Fijter, Johan W de MD, PhD +; Guchelaar, Henk-Jan PharmD, PhD *
Therapeutic Drug Monitoring.
31(2):187-197, April 2009.
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To prevent acute rejection episodes, it is important to reach adequate tacrolimus (TRL) exposure early after kidney transplantation. With a better understanding of the high variability in the pharmacokinetics of TRL, the starting dose can be individualized, resulting in a reduction in dose adjustments to obtain the target exposure. A population pharmacokinetic analysis was performed to estimate the effects of demographic factors, hematocrit, serum albumin concentration, prednisolone dose, TRL dose interval, polymorphisms in genes coding for ABCB1, CYP3A5, CYP3A4, and the pregnane X receptor on TRL pharmacokinetics. Pharmacokinetic data were prospectively obtained in 31 de novo kidney transplant patients randomized to receive TRL once or twice daily, and subsequently, the data were analyzed by means of nonlinear mixed-effects modeling. TRL clearance was 1.5-fold higher for patients with the CYP3A5*1/*3 genotype compared with the CYP3A5*3/*3 genotype (5.5 /- 0.5 L/h versus 3.7 /- 0.3 L/h, respectively). This factor explained 30% of the interindividual variability in apparent clearance (exposure). Also, a relationship between the pregnane X receptor A 7635G genotype and TRL clearance was identified with a clearance of 3.9 /- 0.3 L/h in the A allele carriers versus 5.4 /- 0.6 L/h in the GG genotype. Finally, a concomitant prednisolone dose of more than 10 mg/d increased the TRL apparent clearance by 15%. In contrast, body weight was not related to TRL clearance in this population. Because patients are typically dosed per kilogram body weight, this might result in underexposure and overexposure in patients, with a low and high body weight, respectively. This integrated analysis shows that adult renal transplant recipients with the CYP3A5*1/*3 genotype require a 1.5 times higher, fixed, starting dose compared with CYP3A5*3/*3 to reach the predefined target exposure early after transplantation.
(C) 2009 Lippincott Williams & Wilkins, Inc.