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. 2015 Sep;80(3):548-59.
doi: 10.1111/bcp.12703. Epub 2015 Aug 3.

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit

Hylke de Jonge  1 , Thomas Vanhove  1 , Henriëtte de Loor  2 , Kristin Verbeke  3 , Dirk R J Kuypers  1
Affiliations

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit

Hylke de Jonge et al. Br J Clin Pharmacol. 2015 Sep.

Abstract

Aims: The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.

Methods: Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.

Results: Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h(-1) at day 7; 17 ± 9.1 l h(-1) at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min(-1) at day 7 vs. 730 ± 344 ml min(-1) at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min(-1) for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.

Conclusions: The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.

Keywords: CYP3A4; CYP3A5; CYP3A5*1; cyclosporine; kidney transplantation; tacrolimus.

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Figures

Figure 1
Figure 1
Systemic (A) and apparent oral midazolam (MDZ) (B) clearance over time. Evolution of systemic and apparent oral midazolam clearance over time in all patients (black bars) and in tacrolimus (Tac)- (dark grey bars) and cyclosporine (CsA)- (light gray bars) treated patients, respectively. Systemic and apparent oral midazolam clearance are expressed as mean ± standard deviation. D, day; M, month
Figure 2
Figure 2
The first three panels show (weight-corrected) tacrolimus (Tac) dose requirements (A), dose-corrected Tac tacrolimus predose trough level (C0) and dose-interval area under the concentration–time curve (AUC0–12) (B) and (weight-corrected) Tac steady-state clearance (CLss) over time (C). The final three panels show the evolution of (weight-corrected) Tac dose requirements (D), dose-corrected Tac C0 and AUC0–12 (E) and (weight-corrected) Tac CLss over time (F) in all Tac-treated patients. The various Tac pharmacokinetic parameters are expressed as mean ± standard deviation
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