Population Pharmacokinetic Estimation of Tacrolimus Apparent Clearance in Adult Liver Transplant Recipients

Zahir, Hamim; McLachlan, Andrew J.; Nelson, A. Christie; McCaughan, Geoffrey W.; Gleeson, M. H.; Akhlaghi, Fatemeh

doi:10.1097/01.ftd.0000170029.36573.a0

Cited by 56 publications

(45 citation statements)

References 25 publications

(39 reference statements)

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“…The dosing regimens of these drugs, which display broad interpatient variability in terms of clearance and a narrow therapeutic window, can be optimized using therapeutic drug monitoring (13,14,24). Such pharmacological management has been applied successfully to drug-drug interactions between anti-calcineurin inhibitors and azole antifungal agents or HIV1-protease inhibitors (8,19,22).…”

Section: Discussionmentioning

confidence: 99%

Practical Management of Boceprevir and Immunosuppressive Therapy in Liver Transplant Recipients with Hepatitis C Virus Recurrence

Coilly

Furlan

Roche

et al. 2012

Antimicrob Agents Chemother

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f Hepatitis C virus (HCV) recurrence is the most important complication in HCV liver transplant patients. Boceprevir with pegylated interferon and ribavirin (PegIFN/RBV) enabled improvement in sustained virological response rates of patients with genotype 1 HCV. Boceprevir interacts with immunosuppressive therapy (IT) by inhibiting the cytochrome P450 3A enzyme. Our aim was to study interactions and assess the safety of boceprevir in the context of HCV recurrence. Boceprevir (800 mg three times a day) initiated after a 4-week lead-in phase was associated with cyclosporine (three patients), tacrolimus (two patients), and everolimus (one patient) in five liver transplant patients with genotype 1 HCV infection who experienced HCV recurrence. The mean follow-up period after HCV therapy was 14.8 ؎ 3.1 weeks. Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anemia occurred in all patients, with a mean fall in hemoglobin levels between baseline and week 12 of 3.12 ؎ 2.27 g/dl. All patients required administration of ␤-erythropoietin (n ‫؍‬ 5), three needed ribavirin dose reduction, and one needed a blood transfusion. A virological response was observed in all patients (mean HCV viral load [HVL] decrease at week 12, 6.64 ؎ 0.35 log 10 IU/ml). These preliminary results in liver transplant patients with HCV recurrence demonstrate the feasibility and safety of coadministration of boceprevir and IT. E nd-stage liver disease due to hepatitis C virus (HCV) is still a common indication for liver transplantation (LT) (6). However, a recurrence of HCV infection is the most frequent cause of death and graft loss, accounting for two-thirds of graft failures. The natural history of HCV is accelerated after LT, leading to cirrhosis in 20 to 30% of patients 5 years post-LT (4). The decompensation rate is higher than 70% at 3 years in liver transplant recipients with established cirrhosis, versus less than 10% in immunocompetent patients (4). Progression from decompensation to death is also accelerated after LT, with a 3-year survival rate of Ͻ10% following the onset of HCV-related allograft failure (4). Few patients (Ͻ5%) experience cholestatic hepatitis, but their prognosis is the poorest (7). To prevent or to treat these occurrences, standard anti-HCV therapy, represented by pegylated interferon and ribavirin, can achieve a sustained virological response (SVR) in 30% of patients, who have a less severe outcome and lower mortality than nonresponders (21). Boceprevir is a novel peptidometic NS3 protease inhibitor that forms a covalent and reversible complex with the NS3 protease in vitro in the HCV replicon system. Recently, two phase III trials showed that combining boceprevir with pegylated interferon and ribavirin increased SVR rates in naive and previously treated nontransplant patients with genotype 1 HCV from 38% to 66% (SPRINT-2) and 21% to 66% (RESPOND-2), respectively (2, 20). The administration of such drugs in the context of HCV recurrence on the liver graft is one of the most...

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Section: Discussionmentioning

confidence: 99%

Practical Management of Boceprevir and Immunosuppressive Therapy in Liver Transplant Recipients with Hepatitis C Virus Recurrence

Coilly

Furlan

Roche

et al. 2012

Antimicrob Agents Chemother

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“…This shows that genetic polymorphism is only one of the factors influencing tacrolimus pharmacokinetics, which, in fact, can be modified by many other variables (51,65,66). Thus, genotyping cannot substitute but only support the therapeutic monitoring of the immunosuppressor blood concentrations.…”

Section: Treated With Steroidsmentioning

confidence: 99%

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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Abstract. Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C 0 ) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5 For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C 0 levels were significantly lower in patients with one copy of the * 1 allele compared to those homozygous for the * 3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

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“…A few studies have compared oral and sublingual administration of TAC, [5][6][7] and their results showed achievement of acceptable TAC blood concentrations in patients who received sublingual TAC. Previous studies assessed the pharmacokinetics parameters of orally administered TAC; [8][9][10][11][12][13][14] however, there has not been any study that assesses the pharmacokinetics parameters of sublingual TAC in adult liver transplant recipients. This study sought to comparethe bioavailability and trough blood concentrations of orally and sublingually administered TAC in adult liver transplant recipients.…”

Section: Introductionmentioning

confidence: 99%

Clinical Pharmacokinetics of Oral Versus Sublingual Administration of Tacrolimus in Adult Liver Transplant Recipients

Nasiri-Toosi

Dashti‐Khavidaki²,

Nasiri-Toosi³

et al. 2012

Exp Clin Transplant

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Objectives: Oral tacrolimus administration is the common route of drug delivery. Recent studies suggest sublingual administration of tacrolimus as an alternative route may produce comparable drug trough levels with similar or even lower doses than the oral route, especially in lung transplant recipients; however, most of this research does not encompass intraindividual variations compared between the 2 routes. This study sought to compare the bioavailability and blood trough concentrations of orally and sublingually administered tacrolimus in adult liver transplant recipients by considering intraindividual variations in tacrolimus pharmacokinetics properties. Materials and Methods: Six adult liver transplant recipients received their tacrolimus either orally or sublingually within 2 consecutive days. Blood samples to determine tacrolimus concentrations were gathered at 0, 0.5, 1, 2, 4, 6, and 12 hours after oral and sublingual tacrolimus administration. Mean data values were used to calculate the pharmacokinetics parameters via the feathering or residual method, using the 1-compartment, firstorder elimination pharmacokinetics model. Compared pharmacokinetics parameters included drug bioavailability, maximum blood concentration (C max ), time to reach maximum blood level (T max ), and trough blood concentrations . Results: Trough whole blood levels, area under the concentration-time curve, T max , and C max after oral and sublingual administration of tacrolimus were not significantly different (10.4 ± 7.4 vs 11.2 ± 11.3 ng/mL for trough blood concentration, 181.5 ± 114.1 vs 160.8 ± 115.9 ng.h/mL for AUC, 1.9 ± 1.2 vs 1.4 ± 0.7 h for T max , and 19.9 ± 10.8 vs 17.2 ± 11.7 ng/mL for C max ). A double-peak phenomenon was observed in some concentrationtime profiles. Conclusions: Sublingual tacrolimus administration does provide therapeutic drug concentrations in adult liver transplant recipients. Therefore, sublingual tacrolimus may confidently be considered as an alternative route to oral administration in patients who are unable to swallow their drugs.

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Population Pharmacokinetic Estimation of Tacrolimus Apparent Clearance in Adult Liver Transplant Recipients

Cited by 56 publications

References 25 publications

Practical Management of Boceprevir and Immunosuppressive Therapy in Liver Transplant Recipients with Hepatitis C Virus Recurrence

Practical Management of Boceprevir and Immunosuppressive Therapy in Liver Transplant Recipients with Hepatitis C Virus Recurrence

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Clinical Pharmacokinetics of Oral Versus Sublingual Administration of Tacrolimus in Adult Liver Transplant Recipients

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