A model-based pharmacokinetic assessment of drug-drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19.

We experienced a patient with a remarkable and prolonged increase in tacrolimus blood concentrations when nirmatrelvir/ritonavir was concomitantly used. The inhibitory intensity and duration of nirmatrelvir/ritonavir on tacrolimus pharmacokinetics were examined using a model-based analysis. A renal transplant patient taking oral tacrolimus continuously was treated with nirmatrelvir/ritonavir for 5 days. The baseline tacrolimus trough blood concentration was 4.2 ng/mL. Tacrolimus was discontinued on Day 6 after the concomitant administration of nirmatrelvir/ritonavir, and the trough concentration increased to 96.4 ng/mL on Day 7. The model-based analysis showed that tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with before the coadministration. Therefore, nirmatrelvir/ritonavir drastically decreased both the apparent clearance and apparent volume of distribution. Simulated tacrolimus concentrations could be best fitted to the observed concentrations when the inhibitory effects of nirmatrelvir/ritonavir were modeled to disappear over about 10 days by first-order elimination. In conclusion, nirmatrelvir/ritonavir greatly increases tacrolimus concentrations by not only reducing clearance, but also increasing bioavailability. Interactions between nirmatrelvir/ritonavir and low-bioavailability drugs which are substrates for CYP3A and P-glycoprotein, such as tacrolimus, are harmful, and concomitant use of these medicines should be avoided.

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities.

Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middle-aged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stable KTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC6-12h /MPA-AUC0-12h , and MPA glucuronide (MPAG)-AUC0-12h /MPA-AUC0-12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC6-12h /MPA-AUC0-12h (p = 0.049) and increased MPAG-AUC0-12h /MPA-AUC0-12h (p = 0.036). MPA troughs (p = 0.045) were reduced in the elderly. TAC CL/BMI (p = 0.043) was reduced in the elderly. For therapeutic MPA AUC0-12h : 30-60 mg·h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC0-12h target: 100-190 ng·h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC0-12h for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age-related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age-adjusted individualization to optimize allograft function.

Tacrolimus Population Pharmacokinetic Model in Adult Chinese Patients with Nephrotic Syndrome and Dosing Regimen Identification Using Monte Carlo Simulations.

BACKGROUND: The study aimed to establish a population pharmacokinetic (PPK) model of tacrolimus for Chinese patients with nephrotic syndrome using the patient's genotype and Wuzhi capsule dosage as the main test factors. METHODS: Ninety-six adult patients with nephrotic syndrome, who were receiving tacrolimus treatment, were enrolled. A nonlinear mixed-effects model was used to determine the influencing factors of interindividual tacrolimus metabolism variation and establish a PPK model. To optimize the tacrolimus dosage, 10,000 Monte Carlo simulations were performed. RESULTS: The 1-chamber model of first-order absorption and elimination was the most suitable model for the data in this study. The typical population tacrolimus clearance (CL/F) value was 16.9 L/h. The percent relative standard error (RSE%) of CL/F was 12%. Increased Wuzhi capsule and albumin doses both decreased the tacrolimus CL/F. In CYP3A5 homozygous mutation carriers, the CL/F was 39% lower than that of carriers of the wild-type and heterozygous mutation. The tacrolimus CL/F in patients who were coadministered glucocorticoids was 1.23-fold higher than that of the control. According to the patient genotype and combined use of glucocorticoids, 26 combinations of Wuzhi capsule and tacrolimus doses were matched. The Monte Carlo simulation identified the most suitable combination scheme. CONCLUSIONS: An improved tacrolimus PPK model for patients with nephrotic syndrome was established, and the most suitable combination of Wuzhi capsule and tacrolimus doses was identified, thus, facilitating the selection of a more economical and safe administration regimen.

Beneficial effects of Wuzhi Capsule on tacrolimus blood concentrations in liver transplant patients with different donor-recipient CYP3A5 genotypes.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Its metabolism mainly depends on the cytochrome P450 3A5 (CYP3A5), which has genetic polymorphisms. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A in animal studies in rats. To date, it remains unexplored whether WZC can be efficiently used to enhance the blood concentration of Tac in liver transplant patients with different donor-recipient CYP3A5 genotypes. METHODS: A total of 185 liver transplant patients were enrolled and two-way ANOVA was carried out, then they were divided into four groups according to the combinations of donor-recipient CYP3A5 phenotypes. WZC was given to patients when the dose of Tac was ≥4 mg, and the dose-adjusted C0 (C0 /D) of Tac measured twice in succession was ≤1 ng/ml/mg. The blood trough concentration of Tac (C0 ), C0 /D, and dose- and body weight-adjusted C0 (C0 /D/W) was analysed on days 7 and 14 after liver transplantation. RESULTS: The genotypes of donor and recipient or WZC had significant effects on C0, C0/D and C0/D/W. There were significant differences in the Tac blood concentrations between the groups. The recipient expression (*1)/donor expression (*1) (R+/D+) group had the lowest C0 , C0 /D and C0 /D/W among the four groups. Furthermore, a larger proportion of patients in the CYP3A5 expression groups required Tac dose adjustment to achieve a therapeutic effect and were given Tac with WZC. Notably, the use of WZC significantly increased the blood concentrations of Tac in the CYP3A5 expression groups and greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC in the CYP3A5 expression groups. What is more, WZC reduced the hospitalization cost of patients to a certain extent. WHAT IS NEW AND CONCLUSION: WZC significantly increased the C0 , C0 /D and C0 /D/W in the CYP3A5 expression groups and reduced the hospitalization expenses of patients to a certain extent. What is more, greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with ß-thalassemia major (ß-TM) undergoing HSCT are insufficient. OBJECTIVE: To establish a PPK model of tacrolimus in children with ß-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. METHODS: Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. RESULTS: A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. CONCLUSION AND RELEVANCE: A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.

Model-based assessment of pharmacokinetic changes of sunitinib, tacrolimus, and everolimus in a patient with metastatic renal cell carcinoma after renal transplantation.

The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.

Initial dosage optimization of tacrolimus in Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics.

BACKGROUND: The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics. METHODS: Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus. RESULTS: Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus in these patients. With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively. In addition, the initial dose for each condition is recommended. CONCLUSIONS: The initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the CYP3A5 genotype. In addition, lower initial doses are recommended with concurrent use of WZ.

Optimization of tacrolimus in kidney transplantation: New pharmacokinetic perspectives.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation (KT), but its use is complicated by a narrow therapeutic index and high inter- and intra-patient pharmacokinetic variability. There are three available oral formulations of tacrolimus: immediate-release tacrolimus (IR-Tac), extended-release tacrolimus (ER-Tac) and a MeltDose® (LCPT) formulation, the latter favoring a prolonged drug release and increased bioavailability. The time-concentration curves of these formulations are different. Compared with IR-Tac and ER-Tac, LCPT has a relatively flat pharmacokinetic profile with less fluctuation between trough and peak exposures, and a delayed peak concentration. This translates to a more stable delivery of tacrolimus and may alleviate the risk of underexposure and allograft rejection or overexposure and toxicity. The once-daily formulation of both ER-TAC and LCPT may also offer a potential advantage on patient adherence. Fast metabolizers of tacrolimus, the elderly, and human leukocyte antigen-sensitized patients are at risk of poorer outcomes after KT, possibly associated with a different exhibited pharmacokinetics of tacrolimus or different requirements in terms of exposure. Simple, practical strategies are needed to identify patients at risk of suboptimal KT outcomes and those who would benefit from a more proactively personalized approach to tacrolimus treatment. This review aims to increase awareness of the link between the pharmacokinetics of oral tacrolimus formulations and the clinical needs of patients after KT, particularly among those who have clinically significant pharmacokinetic variation of tacrolimus.

[Clinical Pharmacometrics for Rational Drug Treatment].

Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.

Population pharmacokinetics and dosage optimization of tacrolimus in pediatric patients with nephrotic syndrome
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OBJECTIVES: The aims of this study were to investigate the population pharmacokinetic (PPK) characteristics of tacrolimus in Chinese children with nephrotic syndrome and to apply it in clinical practice. MATERIALS AND METHODS: A total of 137 concentrations from 61 patients were collected from routine therapeutic drug monitoring data between 2011 and 2018. Population modeling was performed with the nonlinear mixed-effects model (NONMEM) program, using a one-compartment model with first-order absorption and elimination. The mean population estimate values of clearance (CL/F) and volume of distribution (V/F) were determined. Common demographic and clinical variables were tested for their influence on these parameters. External validation was conducted, and Monte Carlo simulation, based on the final model, was carried out to determine optimal dosage regimen. RESULTS: Age and body weight were the covariates that displayed a significant influence on CL/F and V/F according to the final regression model. Goodness-of-fit plots, bootstrap outcomes, and external validation confirmed the relatively good stability and prediction capability of the model. The interindividual variability of CL/F was 31.10%, and the residual variability was 0.91 ng/mL. Mean prediction error (MPE, %) and Mean absolute prediction error (MAPE, %) were 10.3% and 16.6%, respectively. Monte Carlo simulation based on the final model was carried out to determine optimal dosage regimen. CONCLUSION: A PPK model of tacrolimus in children with nephrotic syndrome was developed. Age and bodyweight could partly explain the interindividual variability in the CL/F and V/F of tacrolimus. The final model could be used to accurately predict tacrolimus individual pharmacokinetic parameters and assist in dosage optimization.
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Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas-kidney patients.

INTRODUCTION: We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf). METHODS: In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work. RESULTS: Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study. CONCLUSIONS: It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients.

BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922.

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients.

OBJECTIVES: After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients. MATERIALS AND METHODS: This observational study inclu-ded 44 liver transplant patients (median age of 59 y; 63.6% men; median delay after transplant of 72.5 mo). Conversion was based on a 1:0.70 proportion. RESULTS: Mean dose of tacrolimus was 2.65 ± 1.24 mg/day before conversion and 2.09 ± 1.68 mg/day after conversion (P < .05), with ratio of 1:0.79. Mean serum tacrolimus trough level increased after conversion (4.92 ± 1.65 vs 5.60 ± 2.89 ng/mL; P < .05), with ratio of 1:1.14. Six months after conversion, mean dose of tacrolimus was 1.65 ± 0.93 mg/day (ratio of 1:0.62) and mean serum tacrolimus trough level was 4.82 ± 1.85 ng/mL, similar to the initial level before conversion. At the end of follow-up, 2 patients had returned to once-daily prolonged-release tacrolimus because of adverse effects (allergy, digestive trouble), which resolved thereafter. The mean cost of tacrolimus therapy was 5.54 ± 2.29 Euros/patient/day before conversion and 4.11 ± 2.32 Euros/patient/day after conversion (P < .05). CONCLUSIONS: Conversion from prolonged-release to extended-release tacrolimus in stable liver transplant patients is safe and cost-effective; however, initially, dose adaptations and careful monitoring are required.

Pharmacokinetics and Clinical Outcomes of Generic Tacrolimus (Hexal) Versus Branded Tacrolimus in De Novo Kidney Transplant Patients: A Multicenter, Randomized Trial.

BACKGROUND: Scrupulous comparison of the pharmacokinetic and clinical characteristics of generic tacrolimus formulations versus the reference drug (Prograf) is essential. The pharmacokinetics of the Tacrolimus Hexal (TacHexal) formulation is similar to Prograf in stable renal transplant patients, but data in de novo patients are lacking. METHODS: De novo kidney transplant patients were randomized to generic tacrolimus (TacHexal) or Prograf in a 6-month open-label study. RESULTS: The primary end point, the dose-normalized area under the curve0-12h at month 1 posttransplant, was similar with TacHexal or Prograf; back-transformed geometric means of adjusted log-transformed values (analysis of variance) were 18.99 ng·h·L (TacHexal) and 20.48 ng·h·L (Prograf) (ratio, 1.08; 90% confidence interval, 0.84-1.38; P = 0.605). The dose-normalized peak concentration geometric means at month 1 was also comparable between treatments (ratio, 1.16; 90% confidence interval, 0.88-1.54; P = 0.377). There were no relevant differences in other pharmacokinetic parameters at month 1 or in area under the curve0-4h and trough concentration when measured at months 3 and 6. The adjusted change in mean estimated glomerular filtration rate from baseline to month 6 (Nankivell) was noninferior for TacHexal versus Prograf using observed values (47.7 vs 38.6 mL/min per 1.73 m, P < 0.001) and was superior based on observed values (P = 0.044) but not using last observation-carried forward method. Rates of biopsy-proven acute rejection (5.7% vs 7.9%), adverse events, and serious adverse events were similar with TacHexal or Prograf. CONCLUSION: Tacrolimus pharmacokinetics is similar with TacHexal and Prograf early after kidney transplantation. Efficacy and safety in this limited data set were comparable, with at least equivalent graft function under TacHexal.

A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation.

BACKGROUND: Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI). METHODS: We sought to determine whether safety, efficacy, and pharmacokinetic data obtained from the medical literature through a comprehensive literature search could be used to estimate the TI of cyclosporine, tacrolimus, and sirolimus. In this analysis, we considered TI ≤2 as a criterion to define a drug as having an NTI. RESULTS: Published literature indicates that cyclosporine has a TI of 2-3, which falls just short of our criteria to be classified as having an NTI. We found sirolimus and tacrolimus to have a therapeutic range of 5-12 ng/mL and of 5-20 ng/mL, respectively, but were unable to calculate the TI. CONCLUSIONS: Although the current literature does not provide a clear indication that these drugs have an NTI, the routine use of therapeutic drug monitoring in clinical practice suggests that more stringent testing of their pharmacokinetic and pharmacodynamic properties should be performed before the approval of generic formulations.

Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients.

There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.

[Effects of multiple-trough sampling design and algorithm on the estimation of population and individual pharmacokinetic parameters].

The purpose of this study is to investigate the effects of multiple-trough sampling design and nonlinear mixed effect modeling (NONMEM) algorithm on the estimation of population and individual pharmacokinetic parameters. Oxcarbazepine and tacrolimus were used as one-compartment and two-compartment model drugs, respectively. Seven sampling designs were investigated using various number of trough concentrations per individual ranging from 1-4. Monte Carlo simulations were performed to produce state-steady trough concentrations. One-compartment model was used to fit simulated data from oxcarbazepine and tacrolimus. The accuracy and precision of the estimated parameters were evaluated using the median prediction error (PE), the median absolute PE and boxplot. The results indicated that trough concentrations could yield reliable estimates of apparent clearance (CL/F). For oxcarbazepine, as the number of trough concentrations per subject increased, the accuracy and precision of CL/F, between-subject variability (BSV) of CL/F and residual variability (RUV) tended to be improved. For tacrolimus, however, although no improvement were observed in the accuracy of CL/F and BSV of CL/F, the PE distribution ranges were significantly narrowed and the RUV estimates were less bias and imprecise. In terms of algorithm, Monte Carlo importance sampling (IMP) and IMP assisted by mode a posteriori estimation (IMPMAP) were consistently better than other methods. Additionally, the sampling design had no significant effects on the individual parameter estimates, which were only depended on the interaction between BSV and RUV in various algorithms. Decreased in BSV and RUV levels can improve the accuracy and precision of the estimation for both population and individual pharmacokinetic parameter estimates.

Co-administration of Wuzhi capsules and tacrolimus in patients with idiopathic membranous nephropathy: clinical efficacy and pharmacoeconomics.

PURPOSE: Tacrolimus is an effective (but relatively expensive) immunosuppressant that is used widely in patients with membranous nephropathy. To reduce the tacrolimus dose while maintaining an equivalent therapeutic effect, we studied the clinical efficacy and pharmacoeconomic impact of co-administration of Wuzhi capsules (WZC that protects against damage to liver cells) and tacrolimus. METHODS: Sixty patients with membranous nephropathy were divided randomly into two groups: experimental (tacrolimus + WZC + corticosteroids) and control (tacrolimus + corticosteroids). Each group received treatments continuously for >6 months. Liver function; renal function; and whole-blood concentrations of tacrolimus, sugars, lipids, as well as 24-h urinary protein levels were used in the clinical evaluation. The cost of drugs was calculated, and the pharmacoeconomic cost-effectiveness analyses were carried out to compare indices between the two groups. RESULTS: Doses and costs of tacrolimus differed significantly between experimental and control groups (p < 0.01 or p < 0.05). Costs in the experimental group were 13,702.62 ± 1,458.6 CNY (2,194.10 ± 233.56 USD) and those in the control group were 17,796.87 ± 2,469.27 CNY (2,849.69 ± 395.39 USD), with clinical efficacy of 93.3 and 90.0 %, respectively. The cost-effectiveness ratios were 146.86 ± 15.63 and 197.73 ± 27.44, respectively. Compared with the experimental group, the control group showed an incremental cost-effectiveness ratio of 1,240.68 ± 306.25 CNY (198.66 ± 49.04 USD), whereas remission between the two groups was similar. CONCLUSION: Co-administration of WZCs and tacrolimus can reduce the dose of tacrolimus and decrease the costs incurred by patients within the same therapeutic window to that seen for treatment with tacrolimus alone.

Assessment of tacrolimus absorption from the human intestinal tract: open-label, randomized, 4-way crossover study.

BACKGROUND: Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract. OBJECTIVE: To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon. METHODS: The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters Cmax, Tmax after the capsule activation, AUC0-24, and mean residence time were determined from the concentration-time profiles. RESULTS: Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC0-24 values revealed some site-specific absorption tendencies, the mean AUC0-24 values obtained were similar regardless of the location of tacrolimus release from the capsule. CONCLUSIONS: Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC0-24, possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.