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The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients
Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
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The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients Sayamon Sukkha a, Busba Chindavijak a, Wichit Nosoongnoen a, Bunyong Phakdeekitchareon b, c, Chagriya Kitiyakara b, c, Vasant Sumethkul b, c, * a
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand c Excellent Center for Organ Transplantation, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 July 2019 Received in revised form 16 September 2019 Accepted 16 October 2019 Available online xxx
Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TACOD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9e22). Blood samples were investigated for pharmacokinetic parameters before and 7e14 days after the conversion. Fifteen patients were included and provided AUC0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p ¼ 0.41). Mean trough blood concentration (Cmin) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p ¼ 0.01). Correlation coefficient (r) between Cmin and AUC0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of Cmin > 30% had a significant lower AUC0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of Cmin > 30% after conversion to TAC-OD will require additional dose adjustment.
Keywords: AUC0-24 Cmin de novo Early conversion Kidney transplant Once daily Pharmacokinetics Systemic exposure Tacrolimus Trough blood concentration
© 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
1. Introduction Tacrolimus is a keystone immunosuppressive agent after kidney transplantation. However, with a narrow therapeutic index and highly individual variation of tacrolimus, therapeutic drug monitoring (TDM) of conventional twice-daily tacrolimus (TAC-BID) is necessary to monitor tacrolimus clinical effects especially the
Abbreviations: AUC0-24, area under the blood concentration-time curve from 0 to 24 hours; Cmax, maximum blood concentration; Cmin, trough blood concentration; PK, pharmacokinetic; TAC-BID, twice-daily tacrolimus; TAC-OD, once-daily tacrolimus; Tmax, time to reach maximum blood concentration. * Corresponding author. Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajthevi District, Bangkok, 10400, Thailand. E-mail address: [email protected] (V. Sumethkul).
trough blood concentration (Cmin) and the correlation between Cmin and area under the blood concentration-time curve from 0 to 24 hours (AUC0-24) [1]. Once-daily tacrolimus (TAC-OD) was used in kidney transplant recipients effectively and safely comparing with TAC-BID [2]. However, the Cmin of TAC-OD in de novo and stable kidney transplant recipients was frequently found to be decreased after conversion from TAC-BID [3e7]. In addition, some de novo studies in Caucasians showed that TAC-OD provided AUC0-24 less than TACBID in approximately of 10e30%. Thus some patients required to increase dose equivalent of TAC-OD [3,4]. These have led to concern about inadequate tacrolimus exposure from TAC-OD in de novo initiation studies. Therefore, early conversion from TAC-BID to TACOD may offer the advantages in terms of reducing the risk of subtherapeutic tacrolimus concentration and also the risk of delaying time to achieve target tacrolimus concentration [8]. Up to now, the
https://doi.org/10.1016/j.dmpk.2019.10.004 1347-4367/© 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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S. Sukkha et al. / Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
target Cmin or systemic exposure of TAC-OD after early conversion has been unclear. Thus, this study aimed to investigate PK profiles at steady state condition of TAC-OD after early conversion from TAC-BID in order to propose an appropriate dose in de novo kidney transplant recipients. 2. Materials and methods This study was a single center, open-label, prospective and single arm conducted in de novo kidney transplant recipients during a six-month enrollment period. Eligible patients provided written informed consent. The study was approved by the Ethical Clearance Committee on Human Rights Related to Research Involving Human Subjects at the investigating hospital Ramathibodi Hospital. 2.1. Sample size estimation The sample size was estimated based on bioequivalence acceptance criteria using the difference between mean of AUC0-24 from a previous study [9]. The power of test was 80% with confidence level of 95%and the intra-subject variation of 20%. The bioequivalence sample size equation was created by Lui JP and Chow SC [10]. The estimated sample size was at least 12 subjects. 2.2. Study subjects The inclusion criteria were male or female kidney transplant recipients aged between 18 and 65 years old with a compatible ABO blood type; primary transplantation from deceased or living related/spouse donors; panel reactive antibody detected by Luminex (PRA Luminex) < 20%. Exclusion criteria were patients who a) received multi-organ transplantation; b) received a kidney allograft from expanded-criteria donor (ECD); c) had positive donor specific antibody (DSA); d) received a kidney allograft with a cold ischemic time more than 24 hours; e) had active infections; f) history or known hypersensitivity/contraindication to any of the immunosuppressive classes (tacrolimus, mycophenolic acid) or any excipients; g) history of drug or alcohol abuse; h) intake of the following concomitant medications that interfere with the metabolism of tacrolimus within 14 days of enrollment and during the PK study [anti-fungal agents (ketoconazole, fluconazole, itraconazole and voriconazole), antibiotics (erythromycin, clarithromycin), calcium channel antagonists (diltiazem, verapamil), phenytoin, phenobarbital and rifampin]; i) had hepatitis B or C infection and j) female patients who plan to have pregnancy during the study period. 2.3. Immunosuppressive regimen After transplantation, patients received the immunosuppressive regimen composed of tacrolimus, mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) using in the range of 1000e2000 mg/day in 2 divided doses and an intravenous bolus 1000 mg of methylprednisolone administered prior to reperfusion and then reduced to 500, 250, 125 mg at day 1, 2, 3 posttransplantations, respectively. An oral prednisolone was consequently started and adjusted to 15e20 mg/day during the first month. Some patients received basiliximab for induction therapy by using 20 mg intravenous infusion over 30 minutes at day 0 and day 4 after transplantation. All patients received co-trimoxazole (adjusted for renal function) and isoniazid prophylaxis as recommended in the practice protocol.
2.4. Tacrolimus conversion protocol Twice-daily tacrolimus (Prograf® Astellas Pharma; TAC-BID) was prescribed at the day of transplantation starting 2 hours before kidney transplantation with 0.10e0.15 mg/kg/dose and followed by twice-daily dosing according to standard practice in which the dose was individually adjusted based on clinical signs and Cmin. As the rate and extent of tacrolimus absorption were reduced when administered with food [11], tacrolimus was administered at a fixed time (07.00 a.m. and 07.00 p.m.) every day throughout the study. This is routinely managed for our de novo kidney transplant recipients. In addition, patients are allowed to have a meal on an empty stomach (at least 1 hour after a morning tacrolimus or 2e3 hours before an evening tacrolimus). The target Cmin of tacrolimus level for these patients was 5e8 ng/mL. After 7 days of transplantation, eligible patients were assessed for PK study if they met these two following criteria of 1) achieving steady state of tacrolimus concentration evaluated by reaching target Cmin for at least two times and 2) no clinical and/or pathological evidences of acute rejection and no requiring any antirejection therapy. Eligible patients were then enrolled to collect blood samples for 24-h PK study and recorded as PK1 study. After that, they were converted to the same daily dose of once-daily tacrolimus (Advagraf® Astellas Pharma; TAC-OD) by starting administration of the next dose at 7:00 a.m. of the following day. After 7e14 days of TAC-OD administration, blood samples were collected for 24-h PK study and labeled as PK2 study. Eligible patients who were modified tacrolimus dosing before study completion were excluded from the study. 2.5. Tacrolimus level measurement Whole blood samples were collected from the patients, who were required to fast from overnight to the next morning in order to determine the 24-h concentration-time profiles for TAC-BID and TAC-OD. The concentration-time profiles of TAC-BID were performed by collecting blood samples at time 0 (pre-dose), 1, 2, 3, 4, 6, 12, 13, 14, 15, 16, 18 and 24 hours. The concentrationetime profiles of TAC-OD were conducted by collecting blood samples at time 0 (pre-dose), 1, 3, 4, 5, 7, 12, 18 and 24 hours. Tacrolimus level measurement used a chemiluminescent microparticle immunoassay (CMIA) method (ARCHITECT i2000 system from ABBOTT laboratories, Abbott Park, IL, USA). The lower limit of quantification for the assay was 2 ng/mL and the upper limit of the measurement was 30 ng/mL [12]. 2.6. Outcome measurement The primary outcome was AUC0-24 comparison between TACBID and TAC-OD administrations calculated by the trapezoidal rule method. The secondary outcomes were other pharmacokinetic parameters. Cmin values were determined using the whole blood tacrolimus concentration value at the 24-h time point (C24). The maximum blood concentration (Cmax) and time to reach maximum blood concentration (Tmax) were determined after the morning dose of both TAC-BID and TAC-OD. Average blood concentration (Cavg) was calculated by the AUC0-24 divided by the dosing interval. The percentage of fluctuation was analyzed both TAC-BID and TACOD by the calculation of (Cmax e Cmin)/Cavg x 100 [13]. The correlation coefficient (r) between Cmin and AUC0-24 was also investigated from both tacrolimus formulations. Safety outcomes were investigated by clinical symptoms and laboratory findings especially the renal function estimated from
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
S. Sukkha et al. / Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
glomerular filtration rate (eGFR) using CKD-EPI equation during the conversion study. 2.7. Statistical and pharmacokinetic analysis The baseline characteristics were summarized and presented as mean and standard deviation. The pharmacokinetic parameters were analyzed by Phoenix WinNonlin version 6.4 (Centara USA, Inc. Princeton, USA) and assessed for statistically significant difference with confidence level of 95% by one-way ANOVA or paired sample t - test as appropriated. The SPSS Statistics 18.0 software was used. The correlation coefficient between the Cmin and AUC0-24 was assessed by a simple linear regression model.
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dosing at the time of conversion was 4.3 ± 1.7 mg/day (0.08 ± 0.04 mg/kg/day) and the mean ± SD of the time to reach steady state for PK1 study was 5.0 ± 1.9 (range 4e10) days after taking a same dose of TAC-BID. At PK1 study, 8 patients were on the same tacrolimus dose between the morning and the evening dose. Whereas 4 patients and 3 patients were on a higher and a lower tacrolimus dose in the morning compared with the evening dose, respectively. After converting to TAC-OD with one to one ratio, the mean ± SD of the time to reach steady state for PK2 study was 9.1 ± 2.4 (range 6e14) days after taking a same dose of TAC-OD. At 6th week after transplantation, the mean ± SD of MMF dose was 1464.3 ± 307.9 mg/day (in the range of 1000 to 2000 mg/day) and the mean ± SD of prednisolone dose was 19.7 ± 1.3 mg/day (in the range of 15e20 mg/day).
3. Results 3.3. Pharmacokinetic results 3.1. Study population A total of sixty-two patients underwent de novo kidney transplantation at Ramathibodi hospital during study period. Thirtyseven patients received tacrolimus as calcineurin inhibitor (CNI). Nineteen patients were excluded from the analysis. Three patients could not complete the post-conversion study due to Cmin after conversion being less than 3 ng/mL and excluded from PK2 study. Finally, fifteen patients completed for PK comparisons. All eligible patients received TAC-BID and converted to TAC-OD after approximately fourteen days of transplantation (range of 9e22 days). The mean ± SD of serum creatinine at the time of conversion was 0.98 ± 0.32 mg/dL. Patient characteristics are shown in Table 1. 3.2. Drug administration and exposure These patients received TAC-BID starting with 0.10e0.15 mg/kg/ day on the day of transplantation. The mean ± SD of tacrolimus Table 1 Characteristics of all studied patients. Patient characteristics
Number of patients (n ¼ 15)
Age, mean ± SD, years Gender, n (%) Male Female Weight, mean ± SD, kg Height, mean ± SD, cm Body mass index, mean ± SD, kg/m2 Duration of dialysis before kidney transplantation, mean (range), years Number of HLA mismatch ± SD Type of kidney transplantation, n (%) Living-related kidney transplantation Deceased-donor kidney transplantation Cause of ESRD, n (%) Diabetic nephropathy Hypertensive nephropathy IgA nephropathy Others Unknown Immunosuppressive medications other than Tacrolimus Basiliximab, n (%) MMF/MPA, n (%) Prednisolone, n (%) Pre-conversion eGFR (TAC-BID), mean ± SD (range), mL/min/1.73 m2 Post-conversion eGFR (TAC-OD), mean ± SD (range), mL/min/1.73 m2 (p ¼ 0.10 compared with the pre-conversion eGFR)
40 ± 11
The mean ± SD of whole blood tacrolimus concentration - time profiles in de novo kidney transplant recipients are illustrated in Fig. 1. The PK parameters between two formulations showed that the systemic exposure considered from AUC0-24 was insignificant difference. The mean ± SD of AUC0-24 of TAC-BID and TAC-OD was 202.9 ± 44.4 ng h/mL and 193.0 ± 63.4 ng h/mL, respectively (p ¼ 0.41). The mean ratio of TAC-OD/TAC-BID exposure calculated using ln-transformed of AUC0-24 was 0.95 and 90% confidence interval (90% CI) was in the range of 82.47e104.97 complied with the bioequivalence criteria. The intra-subject variation was 18.42 and the power of test was 92.22%. However, Cmin and Cmax of TAC-OD were significantly lower than those of TAC-BID. The Tmax of TACOD was longer than that of TAC-BID. Data are shown in Table 2. TAC-OD provided the relationship between Cmin and AUC0-24 with correlation coefficient (r) of 0.875 (p ¼ 0.01) whereas TAC-BID provided a smaller correlation with r equal to 0.620 (p ¼ 0.01) (Fig. 2). The percent of mean variation of AUC0-24 calculated from the real observation and the linear regression equation of TAC-BID (y ¼ 19.145 x þ 80.550) and of TAC-OD (y ¼ 34.355 x þ 23.063) was 12.60% and 11.11%, respectively. Fisher's Z transformation test was used to compare the value of correlation coefficient (r) of the linear regression equation of TAC-BID and TAC-OD. This showed that the Z value was 1.531 (p ¼ 0.125) and suggested that correlation
8 (53) 7 (47) 56.2 ± 13.5 164.0 ± 8.0 20.7 ± 3.8 4 (1e8) 2.2 ± 1.3 9 (60) 6 (40) 2 2 2 1 8
(13) (13) (13) (7) (53)
4 (27) 14/1 (93/7) 15 (100) 88.40 ± 24.70 (48.00e120.00) 81.27 ± 25.68 (47.40e117.10)
Fig. 1. Tacrolimus concentration-time profiles in de novo kidney transplant recipients after TAC-BID (circle) and TAC-OD (triangle) administrations. Each point and bar represent the mean ± SD (TAC-BID ¼ twice-daily tacrolimus, TAC-OD ¼ once-daily tacrolimus).
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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S. Sukkha et al. / Drug Metabolism and Pharmacokinetics xxx (xxxx) xxx
Table 2 Results of pharmacokinetic parameters before conversion (TAC-BID) and after conversion (TAC-OD) in de novo kidney transplant recipients (n ¼ 15). Pharmacokinetic parameters
TAC-BID
TAC-OD
p-value
AUC0-24 (ng h/mL) Cmin (ng/mL) Cmax (ng/mL) Tmax (h) Half-life (h) CL/F (L/h) Fluctuation (%)
202.9 ± 44.4 6.4 ± 1.4 18.4 ± 5.7 2.0 (0.9e5.9) 9.5 ± 3.2 0.0122 ± 0.0061 139.1 ± 52.2
193.0 ± 63.4 4.9 ± 1.6 15.1 ± 5.2 3.0 (1.0e7.0) 18.8 ± 4.3 0.0140 ± 0.0064 126.9 ± 41.4
0.41 0.01 <0.01 0.73 <0.01 0.10 0.41
The data are presented as means and standard deviations for all parameters except Tmax presented as medians and ranges. Cmin values were determined at the 24-h time point (C24) both TAC-BID and TAC-OD. Cmax and Tmax values were determined after the morning dose of both TAC-BID and TAC-OD.
Fig. 2. The linear correlation between trough blood concentration (Cmin) and systemic exposure (AUC0-24) for TAC-BID ( ) and TAC-OD ( ).
between the Cmin and AUC0-24 was not significantly different across the two groups. All patients had a decrease of Cmin value of TAC-OD after switching from TAC-BID. An additional analysis revealed that the percentage of patients having a Cmin value within the target range (5e8 ng/mL) were 7/15 (46.6%) and the remaining patients had a Cmin value < 5 ng/mL. The proportion of patients with <10%, 10e20%, 20e30% and >30% lowering of Cmin after converting to TAC-OD were 3/15 (20%), 2/15 (13%), 2/15 (13%), and 8/15 (53%), respectively. When correlated with systemic exposure (AUC0-24), patients with a value of Cmin decreased more than 30 %had a significant lower AUC0-24 when compared with the pre-conversion value (202.7 ± 19.1 VS 174.4 ± 17.7 ng h/mL) (p ¼ 0.03, Wilcoxson signed rank test). 3.4. Renal function and safety outcomes For safety concern, renal function of all patients at the time of pre-conversion showed eGFR of 88.40 ± 24.70 mL/min/1.73 m2 and at week 6th after conversion showed eGFR of 81.27 ± 25.68 mL/ min/1.73 m2 (p ¼ 0.10). In addition, there was no episode of serum creatinine rising more than 25%. The renal function was similar
between two tacrolimus formulations. Moreover, patients who received TAC-OD presented well tolerated and mild adverse effect profiles consistently with TAC-BID. The most frequent adverse event of these two formulations was tremor. Incidences of new onset diabetes after transplantation (NODAT), hypertension and hyperlipidemia were also similar between two formulations. In addition, patients were not affected from biopsy-proven acute rejection (BPAR), lost graft or death during study period. 4. Discussion Our study showed a comparable AUC0-24 after 1:1 conversion with a significantly lower Cmin of TAC-OD after early conversion from TAC-BID in de novo kidney transplant recipients. Only patients with a decreased in Cmin more than 30% will be significantly associated with a reduced AUC0-24 after early conversion. This application is that only particular patients with a high drop in Cmin should be concerned about a possibility of low tacrolimus exposure. The physicians may make a decision to measure AUC0-24 or slightly increase the dose of TAC-OD after conversion. The difference between our study and other de novo initiation studies is that all subjects in our study are ensured to have a dose of tacrolimus within therapeutic range before converting to TAC-OD. On the contrary, patients in de novo initiation studies are at risk of a 10e30% lower tacrolimus AUC0-24 of TAC-OD when compared with that from patients starting TAC-BID [3,4]. The explanation of a lower Cmin and/or AUC0-24 of TAC-OD after conversion is still unclear. Of note, CYP3A5 polymorphism plays an important factor in tacrolimus pharmacokinetics. There has been evidence that CYP3A5 is expressed both in the jejunum and ileum resulting in a higher metabolism of a prolonged-release characteristics TAC-OD, which is typically released further the gastrointestinal tract [14]. As a result, patients taking TAC-OD is likely to have a lower Cmin and/or AUC0-24 of tacrolimus compared with those taking TAC-BID. This notion was supported by the evidence that AUC0-24 of TAC-OD (post-conversion) after switching from TAC-BID (pre-conversion) was significantly reduced in stable kidney transplant patients presenting CYP3A5 expresser [15,16]. In addition, a previous pharmacogenetic study from our group of Asian population found that 50% of our subjects were CYP3A5 expressers (CYP3A5 *1/*1 or CYP3A5 *1/*3) [17]. It is thus possible that a significant proportion of patients in our study may carry CYP3A5 expresser gene that can be associated with a lower Cmin and/or tacrolimus exposure when they were switched to TAC-OD. In this regard, the impact of genetic polymorphism of other additional genes should also be further investigated. TAC-OD was gradually released and slowly absorbed presenting a delay Tmax. The Cmax was unable to be directly compared between TAC-BID and TAC-OD as a result of unequal dosing in the morning tacrolimus administration. As for TAC-BID, the Cmax and AUC of tacrolimus after the morning dose were clearly higher than those after the evening dose regardless of a slightly smaller dose (0.5 mg) in the morning which was found in three patients. We designed to control factors affecting tacrolimus pharmacokinetics (such as a similar time to collect blood samples between tacrolimus dosing, time of food delivery, as well as drug administration on an empty stomach). A circadian effect on tacrolimus disposition may be a possible explanation for day and night differences observed in our finding. Previous literature reported that tacrolimus Cmax and AUC0-24 after the morning dose were significantly larger than those after the evening dose [18e20]. The half-life of tacrolimus is generally long and variable which has been reported in the range of 8.7e37.9 hours [11]. As for the impact on tacrolimus formulation, both immediate release and prolonged release formulation was believed to have a similar half-life. The difference
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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in dosing frequency between TAC-BID and TAC-OD has been reported to result from a rapid versus slower absorption pattern [21]. The finding from our study that the half-life of TAC-OD is significantly longer than TAC-BID is thus an interesting observation. As the time to achieve steady state is approximately 3e5 times of half-life, we have found that TAC-OD required a longer time (at least 3e4 days) than TAC-BID to ensure a sustainable tacrolimus level to adjust the new dose properly. The narrow fluctuation suggested that TAC-OD generated more constant blood concentration during 24 hours which supported the benefit of reducing dose-related toxicity including hyperglycemia, hyperlipidemia and nephrotoxicity [22,23]. Renal function as well as adverse effects in patients taking TAC-OD were similar to TACBID during the early conversion period. These clinical parameters need to be followed up throughout TAC-OD prescription. The strengths of our study included the prospective full AUC024 study design. As the first AUC0-24 of TAC-BID was performed at 14.5 ± 4.1 days after kidney transplantation, we could limit the effect of changing corticosteroid dosing/gastrointestinal motility which has a great impact on tacrolimus exposure during the first operative week. The similarity in apparent total body clearance (CL/F) between TAC-BID and TAC-OD also proved that factors associated with tacrolimus clearance such as hemoglobin level, albumin level, or drugs interfering with tacrolimus level could not affect our main results [19]. Tacrolimus level was analyzed by chemiluminescent microparticle immunoassay (CMIA) which presented a high correlation coefficient compared with the gold standard LC/MS/MS [12]. However, further studies investigating patients with high risk of rejection are still required for the early conversion protocol. In summary, the early conversion to TAC-OD approximately fourteen days after kidney transplantation is associated with a similar systemic exposure despite a significantly lower Cmin when compared with TAC-BID. For the application, we would like to propose that patients who are planned to receive early conversion from TAC-BID to TAC-OD should keep a high normal level of Cmin before conversion to assure that Cmin remains mostly within the target range after conversion. A dose of 1:1 conversion is suggested. Patients who have a decrease of Cmin > 30% should be planned to receive a small increase in prescribed dose of TACOD. This is aimed to achieve good efficacy and safety clinical outcomes. Authors contribution SS participate in study design, data collection, analysis of data, writing of the manuscript. BC participate in study design, analysis of data and writing of the manuscript. WN participate in study design, analysis of data and writing of the manuscript. BP participate in study design and data collection. CK participate in study design and data collection. VS participate in study design, data collection, writing of the manuscript, research summary and recommendation. All authors approved the submission of the manuscript. Declaration of Competing Interest The authors report no conflict of interest. Acknowledgements The pharmacokinetic program software (Phoenix WinNonlin version 6.4) was supported by Aroonrut Lucksiri, Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University.
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The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients Sayamon Sukkha a, Busba Chindavijak a, Wichit Nosoongnoen a, Bunyong Phakdeekitchareon b, c, Chagriya Kitiyakara b, c, Vasant Sumethkul b, c, * a
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand c Excellent Center for Organ Transplantation, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 July 2019 Received in revised form 16 September 2019 Accepted 16 October 2019 Available online xxx
Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TACOD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9e22). Blood samples were investigated for pharmacokinetic parameters before and 7e14 days after the conversion. Fifteen patients were included and provided AUC0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p ¼ 0.41). Mean trough blood concentration (Cmin) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p ¼ 0.01). Correlation coefficient (r) between Cmin and AUC0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of Cmin > 30% had a significant lower AUC0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of Cmin > 30% after conversion to TAC-OD will require additional dose adjustment.
Keywords: AUC0-24 Cmin de novo Early conversion Kidney transplant Once daily Pharmacokinetics Systemic exposure Tacrolimus Trough blood concentration
© 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
1. Introduction Tacrolimus is a keystone immunosuppressive agent after kidney transplantation. However, with a narrow therapeutic index and highly individual variation of tacrolimus, therapeutic drug monitoring (TDM) of conventional twice-daily tacrolimus (TAC-BID) is necessary to monitor tacrolimus clinical effects especially the
Abbreviations: AUC0-24, area under the blood concentration-time curve from 0 to 24 hours; Cmax, maximum blood concentration; Cmin, trough blood concentration; PK, pharmacokinetic; TAC-BID, twice-daily tacrolimus; TAC-OD, once-daily tacrolimus; Tmax, time to reach maximum blood concentration. * Corresponding author. Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajthevi District, Bangkok, 10400, Thailand. E-mail address: [email protected] (V. Sumethkul).
trough blood concentration (Cmin) and the correlation between Cmin and area under the blood concentration-time curve from 0 to 24 hours (AUC0-24) [1]. Once-daily tacrolimus (TAC-OD) was used in kidney transplant recipients effectively and safely comparing with TAC-BID [2]. However, the Cmin of TAC-OD in de novo and stable kidney transplant recipients was frequently found to be decreased after conversion from TAC-BID [3e7]. In addition, some de novo studies in Caucasians showed that TAC-OD provided AUC0-24 less than TACBID in approximately of 10e30%. Thus some patients required to increase dose equivalent of TAC-OD [3,4]. These have led to concern about inadequate tacrolimus exposure from TAC-OD in de novo initiation studies. Therefore, early conversion from TAC-BID to TACOD may offer the advantages in terms of reducing the risk of subtherapeutic tacrolimus concentration and also the risk of delaying time to achieve target tacrolimus concentration [8]. Up to now, the
https://doi.org/10.1016/j.dmpk.2019.10.004 1347-4367/© 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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target Cmin or systemic exposure of TAC-OD after early conversion has been unclear. Thus, this study aimed to investigate PK profiles at steady state condition of TAC-OD after early conversion from TAC-BID in order to propose an appropriate dose in de novo kidney transplant recipients. 2. Materials and methods This study was a single center, open-label, prospective and single arm conducted in de novo kidney transplant recipients during a six-month enrollment period. Eligible patients provided written informed consent. The study was approved by the Ethical Clearance Committee on Human Rights Related to Research Involving Human Subjects at the investigating hospital Ramathibodi Hospital. 2.1. Sample size estimation The sample size was estimated based on bioequivalence acceptance criteria using the difference between mean of AUC0-24 from a previous study [9]. The power of test was 80% with confidence level of 95%and the intra-subject variation of 20%. The bioequivalence sample size equation was created by Lui JP and Chow SC [10]. The estimated sample size was at least 12 subjects. 2.2. Study subjects The inclusion criteria were male or female kidney transplant recipients aged between 18 and 65 years old with a compatible ABO blood type; primary transplantation from deceased or living related/spouse donors; panel reactive antibody detected by Luminex (PRA Luminex) < 20%. Exclusion criteria were patients who a) received multi-organ transplantation; b) received a kidney allograft from expanded-criteria donor (ECD); c) had positive donor specific antibody (DSA); d) received a kidney allograft with a cold ischemic time more than 24 hours; e) had active infections; f) history or known hypersensitivity/contraindication to any of the immunosuppressive classes (tacrolimus, mycophenolic acid) or any excipients; g) history of drug or alcohol abuse; h) intake of the following concomitant medications that interfere with the metabolism of tacrolimus within 14 days of enrollment and during the PK study [anti-fungal agents (ketoconazole, fluconazole, itraconazole and voriconazole), antibiotics (erythromycin, clarithromycin), calcium channel antagonists (diltiazem, verapamil), phenytoin, phenobarbital and rifampin]; i) had hepatitis B or C infection and j) female patients who plan to have pregnancy during the study period. 2.3. Immunosuppressive regimen After transplantation, patients received the immunosuppressive regimen composed of tacrolimus, mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) using in the range of 1000e2000 mg/day in 2 divided doses and an intravenous bolus 1000 mg of methylprednisolone administered prior to reperfusion and then reduced to 500, 250, 125 mg at day 1, 2, 3 posttransplantations, respectively. An oral prednisolone was consequently started and adjusted to 15e20 mg/day during the first month. Some patients received basiliximab for induction therapy by using 20 mg intravenous infusion over 30 minutes at day 0 and day 4 after transplantation. All patients received co-trimoxazole (adjusted for renal function) and isoniazid prophylaxis as recommended in the practice protocol.
2.4. Tacrolimus conversion protocol Twice-daily tacrolimus (Prograf® Astellas Pharma; TAC-BID) was prescribed at the day of transplantation starting 2 hours before kidney transplantation with 0.10e0.15 mg/kg/dose and followed by twice-daily dosing according to standard practice in which the dose was individually adjusted based on clinical signs and Cmin. As the rate and extent of tacrolimus absorption were reduced when administered with food [11], tacrolimus was administered at a fixed time (07.00 a.m. and 07.00 p.m.) every day throughout the study. This is routinely managed for our de novo kidney transplant recipients. In addition, patients are allowed to have a meal on an empty stomach (at least 1 hour after a morning tacrolimus or 2e3 hours before an evening tacrolimus). The target Cmin of tacrolimus level for these patients was 5e8 ng/mL. After 7 days of transplantation, eligible patients were assessed for PK study if they met these two following criteria of 1) achieving steady state of tacrolimus concentration evaluated by reaching target Cmin for at least two times and 2) no clinical and/or pathological evidences of acute rejection and no requiring any antirejection therapy. Eligible patients were then enrolled to collect blood samples for 24-h PK study and recorded as PK1 study. After that, they were converted to the same daily dose of once-daily tacrolimus (Advagraf® Astellas Pharma; TAC-OD) by starting administration of the next dose at 7:00 a.m. of the following day. After 7e14 days of TAC-OD administration, blood samples were collected for 24-h PK study and labeled as PK2 study. Eligible patients who were modified tacrolimus dosing before study completion were excluded from the study. 2.5. Tacrolimus level measurement Whole blood samples were collected from the patients, who were required to fast from overnight to the next morning in order to determine the 24-h concentration-time profiles for TAC-BID and TAC-OD. The concentration-time profiles of TAC-BID were performed by collecting blood samples at time 0 (pre-dose), 1, 2, 3, 4, 6, 12, 13, 14, 15, 16, 18 and 24 hours. The concentrationetime profiles of TAC-OD were conducted by collecting blood samples at time 0 (pre-dose), 1, 3, 4, 5, 7, 12, 18 and 24 hours. Tacrolimus level measurement used a chemiluminescent microparticle immunoassay (CMIA) method (ARCHITECT i2000 system from ABBOTT laboratories, Abbott Park, IL, USA). The lower limit of quantification for the assay was 2 ng/mL and the upper limit of the measurement was 30 ng/mL [12]. 2.6. Outcome measurement The primary outcome was AUC0-24 comparison between TACBID and TAC-OD administrations calculated by the trapezoidal rule method. The secondary outcomes were other pharmacokinetic parameters. Cmin values were determined using the whole blood tacrolimus concentration value at the 24-h time point (C24). The maximum blood concentration (Cmax) and time to reach maximum blood concentration (Tmax) were determined after the morning dose of both TAC-BID and TAC-OD. Average blood concentration (Cavg) was calculated by the AUC0-24 divided by the dosing interval. The percentage of fluctuation was analyzed both TAC-BID and TACOD by the calculation of (Cmax e Cmin)/Cavg x 100 [13]. The correlation coefficient (r) between Cmin and AUC0-24 was also investigated from both tacrolimus formulations. Safety outcomes were investigated by clinical symptoms and laboratory findings especially the renal function estimated from
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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glomerular filtration rate (eGFR) using CKD-EPI equation during the conversion study. 2.7. Statistical and pharmacokinetic analysis The baseline characteristics were summarized and presented as mean and standard deviation. The pharmacokinetic parameters were analyzed by Phoenix WinNonlin version 6.4 (Centara USA, Inc. Princeton, USA) and assessed for statistically significant difference with confidence level of 95% by one-way ANOVA or paired sample t - test as appropriated. The SPSS Statistics 18.0 software was used. The correlation coefficient between the Cmin and AUC0-24 was assessed by a simple linear regression model.
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dosing at the time of conversion was 4.3 ± 1.7 mg/day (0.08 ± 0.04 mg/kg/day) and the mean ± SD of the time to reach steady state for PK1 study was 5.0 ± 1.9 (range 4e10) days after taking a same dose of TAC-BID. At PK1 study, 8 patients were on the same tacrolimus dose between the morning and the evening dose. Whereas 4 patients and 3 patients were on a higher and a lower tacrolimus dose in the morning compared with the evening dose, respectively. After converting to TAC-OD with one to one ratio, the mean ± SD of the time to reach steady state for PK2 study was 9.1 ± 2.4 (range 6e14) days after taking a same dose of TAC-OD. At 6th week after transplantation, the mean ± SD of MMF dose was 1464.3 ± 307.9 mg/day (in the range of 1000 to 2000 mg/day) and the mean ± SD of prednisolone dose was 19.7 ± 1.3 mg/day (in the range of 15e20 mg/day).
3. Results 3.3. Pharmacokinetic results 3.1. Study population A total of sixty-two patients underwent de novo kidney transplantation at Ramathibodi hospital during study period. Thirtyseven patients received tacrolimus as calcineurin inhibitor (CNI). Nineteen patients were excluded from the analysis. Three patients could not complete the post-conversion study due to Cmin after conversion being less than 3 ng/mL and excluded from PK2 study. Finally, fifteen patients completed for PK comparisons. All eligible patients received TAC-BID and converted to TAC-OD after approximately fourteen days of transplantation (range of 9e22 days). The mean ± SD of serum creatinine at the time of conversion was 0.98 ± 0.32 mg/dL. Patient characteristics are shown in Table 1. 3.2. Drug administration and exposure These patients received TAC-BID starting with 0.10e0.15 mg/kg/ day on the day of transplantation. The mean ± SD of tacrolimus Table 1 Characteristics of all studied patients. Patient characteristics
Number of patients (n ¼ 15)
Age, mean ± SD, years Gender, n (%) Male Female Weight, mean ± SD, kg Height, mean ± SD, cm Body mass index, mean ± SD, kg/m2 Duration of dialysis before kidney transplantation, mean (range), years Number of HLA mismatch ± SD Type of kidney transplantation, n (%) Living-related kidney transplantation Deceased-donor kidney transplantation Cause of ESRD, n (%) Diabetic nephropathy Hypertensive nephropathy IgA nephropathy Others Unknown Immunosuppressive medications other than Tacrolimus Basiliximab, n (%) MMF/MPA, n (%) Prednisolone, n (%) Pre-conversion eGFR (TAC-BID), mean ± SD (range), mL/min/1.73 m2 Post-conversion eGFR (TAC-OD), mean ± SD (range), mL/min/1.73 m2 (p ¼ 0.10 compared with the pre-conversion eGFR)
40 ± 11
The mean ± SD of whole blood tacrolimus concentration - time profiles in de novo kidney transplant recipients are illustrated in Fig. 1. The PK parameters between two formulations showed that the systemic exposure considered from AUC0-24 was insignificant difference. The mean ± SD of AUC0-24 of TAC-BID and TAC-OD was 202.9 ± 44.4 ng h/mL and 193.0 ± 63.4 ng h/mL, respectively (p ¼ 0.41). The mean ratio of TAC-OD/TAC-BID exposure calculated using ln-transformed of AUC0-24 was 0.95 and 90% confidence interval (90% CI) was in the range of 82.47e104.97 complied with the bioequivalence criteria. The intra-subject variation was 18.42 and the power of test was 92.22%. However, Cmin and Cmax of TAC-OD were significantly lower than those of TAC-BID. The Tmax of TACOD was longer than that of TAC-BID. Data are shown in Table 2. TAC-OD provided the relationship between Cmin and AUC0-24 with correlation coefficient (r) of 0.875 (p ¼ 0.01) whereas TAC-BID provided a smaller correlation with r equal to 0.620 (p ¼ 0.01) (Fig. 2). The percent of mean variation of AUC0-24 calculated from the real observation and the linear regression equation of TAC-BID (y ¼ 19.145 x þ 80.550) and of TAC-OD (y ¼ 34.355 x þ 23.063) was 12.60% and 11.11%, respectively. Fisher's Z transformation test was used to compare the value of correlation coefficient (r) of the linear regression equation of TAC-BID and TAC-OD. This showed that the Z value was 1.531 (p ¼ 0.125) and suggested that correlation
8 (53) 7 (47) 56.2 ± 13.5 164.0 ± 8.0 20.7 ± 3.8 4 (1e8) 2.2 ± 1.3 9 (60) 6 (40) 2 2 2 1 8
(13) (13) (13) (7) (53)
4 (27) 14/1 (93/7) 15 (100) 88.40 ± 24.70 (48.00e120.00) 81.27 ± 25.68 (47.40e117.10)
Fig. 1. Tacrolimus concentration-time profiles in de novo kidney transplant recipients after TAC-BID (circle) and TAC-OD (triangle) administrations. Each point and bar represent the mean ± SD (TAC-BID ¼ twice-daily tacrolimus, TAC-OD ¼ once-daily tacrolimus).
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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Table 2 Results of pharmacokinetic parameters before conversion (TAC-BID) and after conversion (TAC-OD) in de novo kidney transplant recipients (n ¼ 15). Pharmacokinetic parameters
TAC-BID
TAC-OD
p-value
AUC0-24 (ng h/mL) Cmin (ng/mL) Cmax (ng/mL) Tmax (h) Half-life (h) CL/F (L/h) Fluctuation (%)
202.9 ± 44.4 6.4 ± 1.4 18.4 ± 5.7 2.0 (0.9e5.9) 9.5 ± 3.2 0.0122 ± 0.0061 139.1 ± 52.2
193.0 ± 63.4 4.9 ± 1.6 15.1 ± 5.2 3.0 (1.0e7.0) 18.8 ± 4.3 0.0140 ± 0.0064 126.9 ± 41.4
0.41 0.01 <0.01 0.73 <0.01 0.10 0.41
The data are presented as means and standard deviations for all parameters except Tmax presented as medians and ranges. Cmin values were determined at the 24-h time point (C24) both TAC-BID and TAC-OD. Cmax and Tmax values were determined after the morning dose of both TAC-BID and TAC-OD.
Fig. 2. The linear correlation between trough blood concentration (Cmin) and systemic exposure (AUC0-24) for TAC-BID ( ) and TAC-OD ( ).
between the Cmin and AUC0-24 was not significantly different across the two groups. All patients had a decrease of Cmin value of TAC-OD after switching from TAC-BID. An additional analysis revealed that the percentage of patients having a Cmin value within the target range (5e8 ng/mL) were 7/15 (46.6%) and the remaining patients had a Cmin value < 5 ng/mL. The proportion of patients with <10%, 10e20%, 20e30% and >30% lowering of Cmin after converting to TAC-OD were 3/15 (20%), 2/15 (13%), 2/15 (13%), and 8/15 (53%), respectively. When correlated with systemic exposure (AUC0-24), patients with a value of Cmin decreased more than 30 %had a significant lower AUC0-24 when compared with the pre-conversion value (202.7 ± 19.1 VS 174.4 ± 17.7 ng h/mL) (p ¼ 0.03, Wilcoxson signed rank test). 3.4. Renal function and safety outcomes For safety concern, renal function of all patients at the time of pre-conversion showed eGFR of 88.40 ± 24.70 mL/min/1.73 m2 and at week 6th after conversion showed eGFR of 81.27 ± 25.68 mL/ min/1.73 m2 (p ¼ 0.10). In addition, there was no episode of serum creatinine rising more than 25%. The renal function was similar
between two tacrolimus formulations. Moreover, patients who received TAC-OD presented well tolerated and mild adverse effect profiles consistently with TAC-BID. The most frequent adverse event of these two formulations was tremor. Incidences of new onset diabetes after transplantation (NODAT), hypertension and hyperlipidemia were also similar between two formulations. In addition, patients were not affected from biopsy-proven acute rejection (BPAR), lost graft or death during study period. 4. Discussion Our study showed a comparable AUC0-24 after 1:1 conversion with a significantly lower Cmin of TAC-OD after early conversion from TAC-BID in de novo kidney transplant recipients. Only patients with a decreased in Cmin more than 30% will be significantly associated with a reduced AUC0-24 after early conversion. This application is that only particular patients with a high drop in Cmin should be concerned about a possibility of low tacrolimus exposure. The physicians may make a decision to measure AUC0-24 or slightly increase the dose of TAC-OD after conversion. The difference between our study and other de novo initiation studies is that all subjects in our study are ensured to have a dose of tacrolimus within therapeutic range before converting to TAC-OD. On the contrary, patients in de novo initiation studies are at risk of a 10e30% lower tacrolimus AUC0-24 of TAC-OD when compared with that from patients starting TAC-BID [3,4]. The explanation of a lower Cmin and/or AUC0-24 of TAC-OD after conversion is still unclear. Of note, CYP3A5 polymorphism plays an important factor in tacrolimus pharmacokinetics. There has been evidence that CYP3A5 is expressed both in the jejunum and ileum resulting in a higher metabolism of a prolonged-release characteristics TAC-OD, which is typically released further the gastrointestinal tract [14]. As a result, patients taking TAC-OD is likely to have a lower Cmin and/or AUC0-24 of tacrolimus compared with those taking TAC-BID. This notion was supported by the evidence that AUC0-24 of TAC-OD (post-conversion) after switching from TAC-BID (pre-conversion) was significantly reduced in stable kidney transplant patients presenting CYP3A5 expresser [15,16]. In addition, a previous pharmacogenetic study from our group of Asian population found that 50% of our subjects were CYP3A5 expressers (CYP3A5 *1/*1 or CYP3A5 *1/*3) [17]. It is thus possible that a significant proportion of patients in our study may carry CYP3A5 expresser gene that can be associated with a lower Cmin and/or tacrolimus exposure when they were switched to TAC-OD. In this regard, the impact of genetic polymorphism of other additional genes should also be further investigated. TAC-OD was gradually released and slowly absorbed presenting a delay Tmax. The Cmax was unable to be directly compared between TAC-BID and TAC-OD as a result of unequal dosing in the morning tacrolimus administration. As for TAC-BID, the Cmax and AUC of tacrolimus after the morning dose were clearly higher than those after the evening dose regardless of a slightly smaller dose (0.5 mg) in the morning which was found in three patients. We designed to control factors affecting tacrolimus pharmacokinetics (such as a similar time to collect blood samples between tacrolimus dosing, time of food delivery, as well as drug administration on an empty stomach). A circadian effect on tacrolimus disposition may be a possible explanation for day and night differences observed in our finding. Previous literature reported that tacrolimus Cmax and AUC0-24 after the morning dose were significantly larger than those after the evening dose [18e20]. The half-life of tacrolimus is generally long and variable which has been reported in the range of 8.7e37.9 hours [11]. As for the impact on tacrolimus formulation, both immediate release and prolonged release formulation was believed to have a similar half-life. The difference
Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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in dosing frequency between TAC-BID and TAC-OD has been reported to result from a rapid versus slower absorption pattern [21]. The finding from our study that the half-life of TAC-OD is significantly longer than TAC-BID is thus an interesting observation. As the time to achieve steady state is approximately 3e5 times of half-life, we have found that TAC-OD required a longer time (at least 3e4 days) than TAC-BID to ensure a sustainable tacrolimus level to adjust the new dose properly. The narrow fluctuation suggested that TAC-OD generated more constant blood concentration during 24 hours which supported the benefit of reducing dose-related toxicity including hyperglycemia, hyperlipidemia and nephrotoxicity [22,23]. Renal function as well as adverse effects in patients taking TAC-OD were similar to TACBID during the early conversion period. These clinical parameters need to be followed up throughout TAC-OD prescription. The strengths of our study included the prospective full AUC024 study design. As the first AUC0-24 of TAC-BID was performed at 14.5 ± 4.1 days after kidney transplantation, we could limit the effect of changing corticosteroid dosing/gastrointestinal motility which has a great impact on tacrolimus exposure during the first operative week. The similarity in apparent total body clearance (CL/F) between TAC-BID and TAC-OD also proved that factors associated with tacrolimus clearance such as hemoglobin level, albumin level, or drugs interfering with tacrolimus level could not affect our main results [19]. Tacrolimus level was analyzed by chemiluminescent microparticle immunoassay (CMIA) which presented a high correlation coefficient compared with the gold standard LC/MS/MS [12]. However, further studies investigating patients with high risk of rejection are still required for the early conversion protocol. In summary, the early conversion to TAC-OD approximately fourteen days after kidney transplantation is associated with a similar systemic exposure despite a significantly lower Cmin when compared with TAC-BID. For the application, we would like to propose that patients who are planned to receive early conversion from TAC-BID to TAC-OD should keep a high normal level of Cmin before conversion to assure that Cmin remains mostly within the target range after conversion. A dose of 1:1 conversion is suggested. Patients who have a decrease of Cmin > 30% should be planned to receive a small increase in prescribed dose of TACOD. This is aimed to achieve good efficacy and safety clinical outcomes. Authors contribution SS participate in study design, data collection, analysis of data, writing of the manuscript. BC participate in study design, analysis of data and writing of the manuscript. WN participate in study design, analysis of data and writing of the manuscript. BP participate in study design and data collection. CK participate in study design and data collection. VS participate in study design, data collection, writing of the manuscript, research summary and recommendation. All authors approved the submission of the manuscript. Declaration of Competing Interest The authors report no conflict of interest. Acknowledgements The pharmacokinetic program software (Phoenix WinNonlin version 6.4) was supported by Aroonrut Lucksiri, Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University.
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Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004
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Please cite this article as: Sukkha S et al., The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.10.004