Pharmacogenetics of Prograf and Advagraf

• Research type

  Research Study

• Full title

  The influence of CYP3A5 and ABCB1 genotype on the pharmacokinetics of Prograf and Advagraf

• IRAS ID

  15633

• Contact name

  Iain A M MacPhee

• Sponsor organisation

  St George's NHS Trust

• Eudract number

  2009-013461-25

• ISRCTN Number

  not issued

• Research summary

  The immunosuppressive drug tacrolimus is widely used to prevent rejection of kidney transplants. The twice daily preparation (Prograf) has been available for over 10 years with recent introduction of a once daily prolonged release formulation (Advagraf). Genetically determined differences in an active barrier to drug absorption in the gut result in differences between individuals in the proportion of tacrolimus absorbed into the blood. Depending on their genes, individuals either make the CYP3A5 enzyme (expressers) or they do not (non-expressers). CYP3A5 expressers require two fold higher doses of Prograf to achieve target blood tacrolimus concentrations than non-expressers. The ABCB1 genotype predicts whether individuals will have low or high levels of the protein P-glycoprotein on the surface of cells which flunces the absorption of tacrolimus. Expression of CYP3A5 decreases and expression of P-glycoprotein increases along the length of the intestine. Therefore, it cannot be assumed that genetic factors known to flunce the absorption of Prograf will apply to Advagraf, which is absorbed further along the intestine.The following hypotheses will be tested:1) The flunce of the CYP3A5 genotype on blood concentrations of tacrolimus will be less for Advagraf than for Prograf.2) The flunce of the ABCB1 genotype on blood concentrations of tacrolimus will be greater for Advagraf than for Prograf.Patients, at least 6 weeks after transplantation, on treatment with Prograf where treatment will be changed to Advagraf as part of routine clinical care will be invited to participate. Four groups will be studied comprising the permutations of individuals genetically predicted to be high or low-expressers of CYP3A5 and ABCB1. Series of blood samples to measure changes in tacrolimus concentrations in the blood over a 24 hour period will be collected on the current twice daily oral dose of Prograf and again two weeks after changing treatment to Advagraf.

• REC name

  London - West London & GTAC Research Ethics Committee

• REC reference

  09/H0707/91

• Date of REC Opinion

  9 Dec 2009

• REC opinion

  Further Information Favourable Opinion