Abstract
Introduction: Tacrolimus is a macrolide immunosuppressant. It has a narrow therapeutic index and serious side effects which necessitate monitoring of tacrolimus blood concentration. The trough concentration of the drug may also differ based on the type of liver transplant. This study was conducted to investigate differences in pharmacokinetics between transplant types and to determine tacrolimus population pharmacokinetic in liver transplant recipients in Saudi Arabia.
 Method: Patients on tacrolimus, as the main immunosuppressant, who underwent liver transplant throughout2012-2014 were retrospectively studied. Demographic characteristic, tacrolimus blood trough concentrations, liver, renal, biochemistry, and hematology lab results were all collected. The pharmacokinetic parameters were estimated assuming one compartment model.
 Results: Tacrolimus pharmacokinetic parameters were found to be as following; elimination rate constant () 0.094 ± 0.0123, apparent volume of distribution () 112.48±63.033 L/hr, elimination half-life () 7.46± 1.01 hr and apparent total body clearance () 10.27± 5.69 L/hr (mean ± SD).
 Statistically significant difference was found between living-donor and deceased-donor liver transplant with respect to apparent clearance and apparent volume of distribution. Living-donor liver transplant recipients have apparent volume of distribution of 97.39±47.00 L (mean ± SD) and an apparent clearance of 8.89±4.24L/hr (mean± SD). On the other hand, deceased-donor liver transplant has an apparent clearance of 12.97±7.09L/hr (mean ± SD) and an apparent volume of distribution of 142.17± 78.65 L (mean ± SD).
 Conclusions: Tacrolimus pharmacokinetics parameters were accurately determined in liver transplant recipients in Saudi Arabia. The results of the present study can be clinically used in the therapeutic drug monitoring of tacrolimus in the individualization of drug dosage and taking the appropriate clinical decisions to prevent allograft rejection.
Highlights
Of absorption and absolute bioavailability in orally administered tacrolimusas [2] and the presence of some factors affecting its pharmacokinetic parameters [3] in addition of being a narrow therapeutic index drugs with a serious side effects [1,4,5,], Tacrolimus blood concentration should be monitored, and dose should be individualized based on patients-related factors to prevent rejection and serious side effects
Females’ mean height, weight, and ideal body weight (IBW) were 155.67 ± 6.71cm, 70.40 ± 19.33 kg, and 48.80 ± 6.04 kg, respectively, which are lower than the corresponding mean height, weight, and IBW for males (167.32 ± 8.66 cm, 74 ± 18.65 kg, and 63.80 ± 7.80 kg, respectively)
Tacrolimus trough levels for 184 adult liver transplant patients were extracted from the medical files of the studied patients, with other demographic characteristics, concurrent diseases, concomitant interacting drugs and important lab results
Summary
Rejection has been the most important issue after transplant but with the development of immunosuppressants, patients can overcome this problem. This study was conducted to identify the factors affecting pharmacokinetics of Tacrolimusas transplant type and to estimate pharmacokinetic parameters of Tacrolimus in Saudi liver transplant patients for better determination of the dose. The initial estimate for nonlinear regression were extracted from literature and confirmed by our preliminary calculations of pharmacokinetic parameters derived from our data. In this regard, the initial estimate of the elimination rate constant (kel) was assumed to be 0.1 hr-1, and the assumption of the apparent volume of distribution (Vd/F) was 200 L. BSA, using Mostellar [6] and Du Bois equations [7], IBW by Devine formula [8], and creatinine clearance by Cockcroft-Gault equations were all calculated for each patient [9]
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