Dose Prediction of Tacrolimus in de novo Kidney Transplant

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					                                           Dose Prediction of Tacrolimus in de novo Kidney Transplant
                                           Patients with Population Pharmacokinetic Modelling Including
                                           Genetic Polymorphisms.
                                           R.R. Press1, B.A. Ploeger2,3, J. den Hartigh1, R.J.H.M. van der Straaten1, J. van Pelt1, M. Danhof2,3, J.W. de Fijter1, and H.J.
                                           1Departments of Clinical Pharmacy and Toxicology, Nephrology and Clinical Chemistry, Leiden University Medical Center, The Netherlands.

                                           2Leiden Amsterdam Center for Drug Research (LACDR), Leiden, The Netherlands.

                                           3LAP&P Consultants BV, Leiden, The Netherlands.

Introduction                                                          Methods                                                                                                                                                                                                                               The pharmacokinetic data were analysed using NON-linear
                                                                                                                                                                                                                                                                                                            Mixed Effect Modelling (NONMEM, version V).
                                                                      De novo kidney transplant patients (n = 33) were treated with                                                                                                                                                                         A 2 compartment model with first order absorption and
The immunosuppressive drug tacrolimus belongs to the group
                                                                      basiliximab, mycophenolate mofetil (fixed dose), prednisolone                                                                                                                                                                         elimination from the central compartment was used to describe
of calcineurin inhibitors together with cyclosporin A.
                                                                      and tacrolimus. Patients received oral tacrolimus either once or                                                                                                                                                                      the data. Random effects for interindividual variability on CL
Tacrolimus is responsible for liver toxicity as well as acute and
                                                                      twice daily. Tacrolimus dose was adjusted according to a                                                                                                                                                                              and Vc and interoccassion variability on F were identified
chronic nephrotoxicity. Other complications of (chronic)
                                                                      preset target AUC [2]. PK samples were collected up to 12                                                                                                                                                                             assuming a log-normal distribution. The effects of the potential
therapy are cardiovascular- and neurotoxicity, diabetes and
                                                                      hours after administration on week 2, 4, 6, 8, 10, 12, 17, 21,                                                                                                                                                                        covariates hematocrit, albumin, age, weight, prednisolon dose
several other clinical disorders [1]. A number of complications
                                                                      26, 39 and 52 post transplantation. Whole blood                                                                                                                                                                                       and genetic polymorphisms in CYP3A4, CYP3A5,
are related to the blood concentration of tacrolimus.
                                                                      concentrations were measured with microparticle enzyme                                                                                                                                                                                P-glycoprotein (P-gp, ABCB1) and the nuclear hormone
Tacrolimus has a narrow therapeutic index and its
                                                                      immunoassay (MEIA) on an IMx-analyzer.                                                                                                                                                                                                receptor Pregnane-X-receptor on tacrolimus pharmacokinetics
pharmacokinetics shows considerable inter- and intra-
                                                                                                                                                                                                                                                                                                            were studied [1, 3, 4].
individual variability, therefore therapeutic drug monitoring
(TDM) in kidney transplant patients is mandatory. The
empirical target was established as the area under the curve
(AUC) of the whole blood concentration time curve of                                                                                                                            9

tacrolimus [2]. Individual dose adjustments are made to

                                                                                                                                                                                                                                                                                                                                               Goodness of Fit
achieve target exposure within days after start of the body           Results                                                                                                   3


                                                                                                                                                           Observed (mcg/L)

weight based regimen. However, frequent dose adjustments                                                                                                                      101

are often required which is still attended with under or
                                                                                                                                                                                7                                                                                                                           5

overexposure for a considerable amount of time. As this could


result in either lack of efficacy or toxicity it is important to                                                                                                                2

                                                                                                                                                                                                                                                                                       Observed (mcg/L)
                                                                                                                                                                                    3   4    5   6   7   8    9                    2         3   4   5   6
                                                                                                                                                                                                             Individual Prediction (mcg/L)                                                                  2
reduce the frequency of dose adjustments by selecting an
individualized optimal starting dose. This requires insight into      In the present investigation TRL pharmacokinetics as well as
factors (i.e. covariates) that explain the variability in the         the interindividual variability relevant to individualised dosing                                                                                                                                                                     8

pharmacokinetics of tacrolimus.                                       is adequately described (Figure 1).                                                                                                                                                                                                   7

                                                                      As expected bodyweight does not correlate with tacrolimus                                                                                                                                                                             3

                                                                      clearance in the way this is demonstrated for cyclosporin A. In
Aim                                                                   addition, a clear relationship is observed between bodyweight
                                                                                                                                                                                                                                                                                                                3          4   5   6    7    8 9
                                                                                                                                                                                                                                                                                                                                                  101                  2    3        4   5

                                                                      and the difference between the observed and target AUC in the                                                                                                                                                                                                         Population Prediction (mcg/L)

Selecting an optimal individualised starting dose by                  first 2 weeks post transplantation (Figure 2), showing that this
identifying mechanistically plausible and clinically relevant         difference increases when the difference from the median body                                                                                                                             Figure 1: Population and individual prediction vs. observed concentrations.

covariates that explain observed variability in the                   weight increases (weight range: 43-119 kg, median 75 kg).                                                                                                                                 Figure 2: Difference from target exposure (CYP3A5*3*3 only).
pharmacokinetics of tacrolimus.                                       Hence, subjects with a body weight below the median body
                                                                      weight are under-exposed, potentially resulting in lack of                                                                                                                                                                                    DIFFERENCE FROM TARGET EXPOSURE ON WEEK 2 POST Tx
                                                                                                                                                                                                                                                                                                                                                  0.2 mg/kg/day regimen
                                                                      efficacy (i.e. rejection). On the other hand, heavier subjects are
                                                                      overdosed thereby increasing the risk for adverse events.

                                                                                                                                                                                                                                                                 AUC observed - target AUC (mcg*h/l)

                                                                                                              GENETIC POLYMORPHISMS IN TACROLIMUS PHARMACOKINETICS
Tacrolimus dosing can be individualised by using biomarkers
such as SNPs in CYP3A5 and PXR or hematocrit. A SNP in
CYP3A5 necessitates a 1.5 fold higher dose than the wild-type                                             5
                                                                       tacrolimus clearance (L/h)

Target exposure based on whole blood measurements can
potentially be reached earlier after transplantation in adult
renal transplant patients within the studied bodyweight range                                                                                                                                                                                                                                                         50               60              70              80       90
(weight range: 43-119 kg, median 75 kg) when the bodyweight                                                                                                                                                                                                                                                                                      BODY WEIGHT (kg)

based regimen will be replaced by a dose based on the                                                     2

presently identified effects of genotype and hematocrit.                                                                       *3*3 (GG)                  *1*3 (GA)
                                                                                                                                                                                                                                                             A relationship between dose and CL/F was observed, which could at
                                                                                                                                             CYP3A5                                                                                                          least partly be attributed to TDM. Patients are selected on basis of their
                                                                                                                                                                                                                                                             blood levels, as patients with high blood levels (i.e. low clearance) are
                                                                                                                                                                                                                                                             titrated to receive lower doses and vice versa [5].

                                                                                                                                                                                                                                                             Two populations with different values for tacrolimus clearance were
                                                                             tacrolimus clearance (L/h)

                                                                                                                                                                                                                                                             identified. This bimodal distribution could be related to genetic
                                                                                                                                                                                                                                                             polymorphisms. Pharmacogenetic differences (Figure 3) were found
Pregnane-X-receptor (PXR)                                                                                                                                                                                                                                    between these populations with genetic polymorphisms (SNPs) in
                                                                                                                                                                                                                                                             CYP3A5*3 (CL= 3.4 ± 0.5 vs. 5.3 ± 0.8 L/h) and PXR (CL=3.5 ± 0.7
PXR is a nuclear hormone receptor. It acts as a transcription                                                                                                                                                                                                vs. 4.9 ± 1.0 L/h). SNPs in these proteins are responsible for higher TRL
factor and plays a role in regulation of gene expression for                                              2                                                                                                                                                  clearance compared to the wild type.
genes involved in drug metabolism and disposition. PXR is a                                                                                                                                                                                                  Moreover, an association between the presence of promotor SNPs
                                                                                                                          CC                   CT                                       TT
low affinity, high capacity receptor for glucocorticoids and                                                                               PXR genotype                                                                                                      CYP3A4*1B (SNP responsible for increased CL) and ABCB T-129C
could potentially increase tissue specific gene expression of P-                                                                                                                                                                                             (P-gp, SNP responsible for decreased CL) and tacrolimus clearance was
                                                                      Figure 3. Genetic polymorphisms in CYP3A5 and PXR.
gp and CYP enzymes. Glucocorticoids are substrate for the                                                                                                                                                                                                    observed.
                                                                      Relationship between genotype and tacrolimus clearance.
glucocorticoid receptor at physiological concentrations [4].
When (high dose) prednisolone is administrated, or high
glucocorticoid levels exist in the body due to for instance           References
stress, this low capacity receptor will be saturated and the
glucocorticoid will induce its own metabolism through binding         [1] Staatz, C.E. et al. Clinical Pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004: 43 (10): 623-53.
to PXR which increases transcription of CYP and other                 [2] Scholten, E.M. eta la. AUC guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant patients. Kidney Int. 2005; 67: 2440-47.
relevant enzymes. Interestingly this could potentially affect the     [3] Hesselink et al. Genetic polymorphisms of the CYP3A4, CYP3A5 and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus.
metabolism of other compounds, such as tacrolimus.                                                        Clin. Pharmacol. Ther. 2003; 74:245-54.
                                                                      [4] Lambda, J. et al. Genetic variants of PXR and CAR and their implication in drug metabolism and pharmacogenetics. Curr. Drug Metab.2005;6: 369-383.
                                                                      [5] Ahn, J.E. et al. Inherent correlation between dose and clearance in therapeutic drug monitoring settings: possible misinterpretation in population pharmacokinetic analyses.
                                                                                                          J PKPD 2005; 32 (5-6): 703-18.