Quantitation of Tacrolimus in Human Whole Blood Samples Using the MITRA Microsampling Device.

BACKGROUND: The calcineurin inhibitor tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dose on the basis of systemic exposure. MITRA microsampling offers a minimally invasive approach for the collection of capillary blood samples from a fingerprick as an alternative to conventional venous blood sampling for quantitation of tacrolimus concentrations. METHODS: A bioanalytical method for the quantitation of tacrolimus in human whole blood samples collected on MITRA tips was developed, using liquid-liquid extraction followed by liquid chromatography with tandem mass spectrometry detection. Validation experiments were performed according to the current Food and Drug Administration and European Medicines Agency guidelines on validation of bioanalytical methods. Validation criteria included assay specificity and sensitivity, interference, carryover, accuracy, precision, dilution integrity, matrix effect, extraction recovery, effect of hematocrit and hyperlipidemia, and stability. RESULTS: All assay validation results were within the required acceptance criteria, indicating a precise and accurate tacrolimus quantitation method. The validated assay range was 1.00-50.0 ng/mL. No interference, carryover or matrix effect was observed. Extraction recovery was acceptable across the assay range. Samples were stable for up to 96 days at -20°C and 20°C, and 28 days at 40°C. Hematocrit, hyperlipidemia, and lot-to-lot differences in the nominal absorption volume of the 10-µL MITRA tips were shown not to influence tacrolimus quantitation by this assay method. CONCLUSIONS: The bioanalytical method validated in this study is appropriate and practical for the quantitation of tacrolimus in human whole blood samples collected using the MITRA microsampling device.

Validation of a Capillary Dry Blood Sample MITRA-Based Assay for the Quantitative Determination of Systemic Tacrolimus Concentrations in Transplant Recipients.

BACKGROUND: Tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dosing based on systemic exposure. MITRA microsampling offers a convenient, minimally invasive approach for the collection of capillary blood samples from a finger prick versus conventional venous blood sampling for quantitation of tacrolimus blood concentrations. However, the suitability of MITRA microsampling for the determination of tacrolimus concentrations requires assessment in clinical settings. METHODS: Paired venous (2 mL) and capillary (10 µL) blood samples were collected pre-tacrolimus dose and 1 and 3 hours postdose during routine outpatient visits from stable adult liver or kidney transplant patients receiving prolonged-release tacrolimus. Tacrolimus concentrations were determined by liquid chromatography-tandem mass spectrometry, and the concentrations obtained by the 2 sampling methods were compared by linear regression and Bland-Altman agreement analyses. RESULTS: Samples were available for 82 transplant recipients (kidney, n = 41; liver, n = 41). A high correlation was observed between tacrolimus concentrations in capillary and venous blood samples (Pearson correlation coefficient, 0.97; Lin concordance coefficient, 0.87; slope of the fitted line, >1.0). Tacrolimus concentrations in capillary samples were 22.5% higher on average than in the corresponding venous blood samples (95% limits of agreement, 0.5%-44.6%). Similar results were observed in both transplant subgroups. CONCLUSIONS: MITRA finger prick sampling provides a convenient alternative to venipuncture for therapeutic drug monitoring in transplant recipients maintained on prolonged-release tacrolimus. When using the finger prick MITRA method, the positive bias in tacrolimus concentrations observed with this technique, when compared with venipuncture, needs to be taken into consideration.

Intermittent micafungin for prophylaxis in a rat model of chronic Candida albicans gut colonization.

BACKGROUND: During antifungal prophylaxis, micafungin is generally infused IV once daily over 1 h. In practice, less-frequent dosing could improve the quality of life in patients requiring long-term treatment or prophylaxis. The feasibility of this approach was assessed using humanized doses of daily or infrequent micafungin regimens. OBJECTIVES: To evaluate the effectiveness of intermittent high-dose micafungin, simulating human exposure, for prophylaxis of invasive candidiasis in a rat model of chronic Candida albicans gastrointestinal colonization and systemic dissemination. METHODS: Two weeks post-infection with an oral challenge of C. albicans, Sprague-Dawley rats were immunocompromised with a cytotoxic drug and a steroid. Rats received IV infusions of: daily vehicle control; daily subcutaneous micafungin (20 mg/kg SC); high-dose micafungin (20 mg/kg bolus SC + 80 mg/kg infusion/72 h, to simulate intermittent human dosing of 300 mg/72 h); or daily fluconazole by mouth (10 mg/kg PO). The effects of antifungal prophylaxis on faecal fungal burden and systemic C. albicans dissemination were evaluated. RESULTS: A rat model of chronic C. albicans gastrointestinal colonization and systemic dissemination was established, characterized by a sustained microbiological burden over 29 days and fungal recovery from normally sterile tissues. Using this model, intermittent high-dose micafungin (delivered via iPrecio pumps) to simulate humanized doses of 300 mg/72 h was significantly more effective than vehicle control, as effective as once-daily micafungin and similar to daily fluconazole at reducing faecal burden and preventing systemic dissemination. CONCLUSIONS: These data indicate that intermittent high-dose micafungin can be as effective as daily therapy, supporting clinical assessment in high-risk patients requiring long-term antifungal prophylaxis.

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Efficacy and safety of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate- or prolonged-release tacrolimus.

BACKGROUND AND AIMS: This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein. MATERIALS AND METHODS: Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout. RESULTS: The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7). CONCLUSIONS: In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation.

Efficacy and safety of prolonged-release tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus - a Phase 2, open-label, single-arm, one-way crossover study.

There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

Pharmacokinetics of tacrolimus granules in pediatric de novo liver, kidney, and heart transplantation: The OPTION study.

Tacrolimus granules were developed for patients who are unable to swallow capsules. Therapeutic drug monitoring (TDM) is required to optimize efficacy and safety, which is based on Ctrough for tacrolimus capsules. Pharmacokinetic (PK) data for tacrolimus granules are required to establish the basis for TDM in those who are unable to swallow capsules. In this phase IV study (NCT01371331) of children undergoing liver, kidney, or heart transplantation, patients received tacrolimus granules 0.15 mg/kg twice daily; first dose was administered within 24 hours of reperfusion. PK analysis samples were collected after reperfusion, after first dose of tacrolimus (Day 1), and at steady state (Day 7; >4 days stable dose). Of the 52 transplant recipients enrolled, 38 had two evaluable PK profiles. Mean AUCtau after first dose of tacrolimus was 211, 97, and 224 hour*ng/mL in liver, kidney, and heart transplant recipients, respectively; corresponding mean AUCtau at steady state was 195, 208, and 165 hour*ng/mL. Ctrough and AUCtau were positively correlated after first dose of tacrolimus and at steady state (Pearson's coefficients: r = 0.81 and r = 0.87, respectively). This study demonstrated that Ctrough is a reliable marker for TDM in pediatric transplant recipients treated with tacrolimus granules, consistent with TDM for other tacrolimus formulations.

Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus to prolonged-release tacrolimus formulation.

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days -30 to -1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration-time curve over 24 hours (AUC24 ); secondary end-points were maximum concentration Cmax and concentration at 24 hours C24 . The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC24 , max , and C24 , and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24 , and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method.

Comparative pharmacokinetics of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate- or prolonged-release tacrolimus.

Phase 2, parallel-group, multicenter, open-label, 4-week study, comparing PK of PR-T vs IR-T in de novo pediatric patients undergoing primary kidney, liver, or heart transplantation. Patients randomized 1:1 to receive once daily, PR-T-, or twice-daily, IR-T-based regimens; dose adjustments permitted after Day 1. Twenty-four-hour PK profiles collected on Days 1, 7, and 28. Primary endpoint: tacrolimus AUC24 . Secondary end points included tacrolimus C24 and Cmax . Endpoints compared between PR-T and IR-T on Days 1, 7, and 28. Predefined similarity interval for CIs of LSM ratios: 80%-125%. PK analysis set comprised 33 patients (PR-T, n = 15; IR-T, n = 18). Overall, AUC24 and Cmax were lower on Day 1 vs 7 and 28. Geometric LSM ratios of PR-T:IR-T on Days 1, 7, and 28 were 66.3%, 92.5%, 99.9%, respectively, for AUC24 ; 66.3%, 82.2%, 90.9% for C24 ; and 77.3%, 120.3%, 92.2% for Cmax . AUC24 90% CI within predefined similarity interval on Day 28; other 90% CIs fell outside. Linear relationship was similar between AUC24 and C24 , and between tacrolimus formulations, suggesting that the same therapeutic drug monitoring method can be used with both formulations in de novo pediatric allograft recipients.

Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy.

BACKGROUND: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses. METHODS: This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant. RESULTS: Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC0-24 ) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0-24 (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0-24 and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations. CONCLUSIONS: Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials.gov number: NCT00189826).

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus.

Effect of Breakfast on the Exposure of the Once-Daily Tacrolimus Formulation in Stable Kidney Transplant Recipients.

BACKGROUND: The once-daily Tacrolimus formulation (Tac ONCE-DAILY) has to be taken on an empty stomach. This is inconvenient for patients and may hamper compliance. The influence of food intake on the exposure of Tac ONCE-DAILY is unknown in transplant recipients. We compared the pharmacokinetics (PKs) of Tac ONCE-DAILY in stable kidney transplant recipients under fasted and fed conditions. METHODS: In an open-label, single-center, cross-over PK study, 27 stable kidney white transplant recipients (17 male, 10 female) treated with Tac ONCE-DAILY under fasted conditions were enrolled. Two 10-point 24-hour blood concentration time profiles [area under the blood concentration time curve from time 0 to 24 hours (AUC0-24)] were collected under steady state conditions. The primary objective was to investigate the effect of food on the PKs and relative bioavailability of Tac ONCE-DAILY. RESULTS: Twenty-seven stable renal transplant patients provided 1 AUC0-24 under fasted and fed conditions, respectively. AUC0-24, C24, and Cmax, were lower in the fed state and Tmax was 1 hour postponed. The 90% confidence interval ratio (fed: fasted) for AUC0-24 was 0.81-0.91 and for C24 0.82-0.92 (both P < 0.001). The majority (60%) had no significant change, but the change in AUC0-24 ranged from -38% to +29%. One trough level was below the target range after fed intake. CONCLUSIONS: When Tac ONCE-DAILY is ingested with standard continental breakfast, AUC0-24 and C24 decrease overall, with C24 in the therapeutic range in almost all patients. The convenient fed intake could promote therapy adherence. Given the possible significant change in exposure, we advise monitoring of the tacrolimus trough level 1 week after fed ingestion of Tac ONCE-DAILY.

Pharmacokinetic profile of micafungin when co-administered with amphotericin B in healthy male subjects.

OBJECTIVE: Micafungin and amphotericin B are antifungal agents with potent activity against a broad spectrum of fungal spp., including Candida and Aspergillus. The objective of this study was to evaluate the potential pharmacokinetic (PK) interaction of the two drugs in healthy subjects. METHODS: PK were evaluated in healthy adults in an open-label, phase I clinical trial, following separate treatments with micafungin (200 mg; days 1 - 5) and conventional amphotericin B (0.25 mg/kg; days 8 - 13) alone, and following co-administration of both drugs (days 14 - 18). RESULTS: In 20 male subjects, systemic exposure to micafungin (measured using peak plasma micafungin concentration (Cmax) and area under the plasma micafungin concentration-time curve (AUC0-τ)) were similar following coadministration of micafungin and amphotericin B (day 18; Cmax 19.1 µg/mL, AUC0-τ 232 µg×h/mL) compared with administration of micafungin alone (day 5; Cmax 18.7 µg/mL, AUC0-τ 236 µg×h/mL), suggesting that administration of amphotericin B does not affect the PK of micafungin. The exposure to amphotericin B was ~ 30% greater following co-administration of both drugs (day 18; Cmax 704 µg/mL, AUC0-τ 9157 µg×h/mL) than after administration of amphotericin B alone (day 13; Cmax 621 µg/mL, AUC0-τ 7023 µg×h/mL). Concurrent treatment with micafungin and amphotericin B was less well tolerated than when either agent was administered alone. CONCLUSIONS: PK and safety-related observations during co-administration of micafungin and amphotericin B were considered to be a consequence of accumulation of amphotericin B to a steady state, indicating that co-administration of the two drugs does not affect the PK of micafungin.

γ-Cyclodextrin hydrogel for the sustained release of josamycin for potential ocular application.

Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current clinical practice, application of the drug, Mitomycin C, prevents or delays fibrosis, but can lead to additional side effects, such as bleb leakage and hypotony. Previous in silico drug screening and in vitro testing has identified the known antibiotic, josamycin, as a possible alternative antifibrotic medication with potentially fewer side effects. However, a suitable ocular delivery mechanism for the hydrophobic drug to the surgical site does not yet exist. Therefore, the focus of this paper is the development of an implantable drug delivery system for sustained delivery of josamycin after glaucoma surgery based on crosslinked γ-cyclodextrin. γ-Cyclodextrin is a commonly used solubilizer which was shown to complex with josamycin, drastically increasing the drug's solubility in aqueous solutions. A simple γ-cyclodextrin crosslinking method produced biocompatible hydrogels well-suited for implantation. The crosslinked γ - cyclodextrin retained the ability to form complexes with josamycin, resulting in a 4-fold higher drug loading efficiency when compared to linear dextran hydrogels, and prolonged drug release over 4 days.

Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study.

Although prolonged-release tacrolimus (PR-T) is widely approved for posttransplantation immunosuppression in kidney recipients, large-scale studies are required to assess long-term outcomes. We present follow-up data from the Advagraf-based Immunosuppression Regimen Examining New Onset Diabetes Mellitus in Kidney Transplant Recipients (ADVANCE) trial, in which kidney transplant patients (KTPs) received corticosteroid minimization with PR-T. Methods: ADVANCE was a 24-wk, randomized, open-label, phase-4 study. De novo KTPs received PR-T with basiliximab and mycophenolate mofetil and were randomized to receive an intraoperative corticosteroid bolus plus tapered corticosteroids until day 10 (arm 1) or an intraoperative corticosteroid bolus (arm 2). In this 5-y, noninterventional follow-up, patients received maintenance immunosuppression according to standard practice. The primary endpoint was graft survival (Kaplan-Meier). Secondary endpoints included patient survival, biopsy-confirmed acute rejection-free survival, and estimated glomerular filtration rate (4-variable modification of diet in renal disease). Results: Follow-up study included 1125 patients. Overall graft survival at 1 and 5 y posttransplantation was 93.8% and 88.1%, respectively, and was similar between treatment arms. At 1 and 5 y, patient survival was 97.8% and 94.4%, respectively. Five-year graft and patient survival rates in KTPs who remained on PR-T were 91.5% and 98.2%, respectively. Cox proportional hazards analysis demonstrated similar risk of graft loss and death between treatment arms. Five-year biopsy-confirmed acute rejection-free survival was 84.1%. Mean ± standard deviation values of estimated glomerular filtration rate were 52.7 ± 19.5 and 51.1 ± 22.4 mL/min/1.73 m2 at 1 and 5 y, respectively. Fifty adverse drug reactions were recorded, probably tacrolimus-related in 12 patients (1.5%). Conclusions: Graft survival and patient survival (overall and for KTPs who remained on PR-T) were numerically high and similar between treatment arms at 5 y posttransplantation.

Tacrolimus pharmacokinetics of once- versus twice-daily formulations in de novo kidney transplantation: a substudy of a randomized phase III trial.

BACKGROUND: Tacrolimus is a well-established immunosuppressive agent for the treatment and prevention of solid organ graft rejection. It is available as an immediate-release, twice-daily formulation (Tacrolimus BID) and a prolonged-release, once-daily formulation (Tacrolimus QD). In a previous study of the pharmacokinetics (PK) of these formulations, mean systemic exposure [area under the curve from 0 to 24 hours (AUC0-24)] of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than for Tacrolimus BID; by day 14, systemic exposure was similar; however, the mean dose of Tacrolimus QD was higher to achieve similar systemic exposure as Tacrolimus BID. METHODS: To further compare the PK of the tacrolimus formulations during the first 2 weeks posttransplant, a substudy was performed in a subset of patients enrolled into a phase III trial in de novo kidney transplant recipients comparing Tacrolimus QD and Tacrolimus BID. To minimize the difference in exposure observed in the earlier study, tacrolimus therapy was initiated before transplant. The PK analysis set comprised 34 patients (17 patients per treatment group) who had 4 complete PK profiles and no major PK-related protocol violations. RESULTS: Mean AUC0-24 of tacrolimus on day 1 was approximately 16% lower for Tacrolimus QD than for Tacrolimus BID, although by day 3 onward, the exposure was similar between treatment groups. Analysis of dose-normalized AUC0-24 (dose normalized to 0.1 mg/kg) showed a similar pattern. There was a good correlation between AUC0-24 and concentration of tacrolimus at 24 hours postdose for both formulations (Tacrolimus QD, r = 0.87; Tacrolimus BID, r = 0.92), and the slope of the line of best fit was similar. CONCLUSIONS: These results suggest that initiating tacrolimus therapy before transplant reduces the difference in exposure between Tacrolimus QD and Tacrolimus BID.

Pharmacokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations.

BACKGROUND: A prolonged-release formulation of tacrolimus for once-daily administration (Tacrolimus QD) has been developed to offer potential improvements in patient adherence. This study compared the pharmacokinetics (PK) of tacrolimus in stable kidney transplant recipients before and after conversion from twice-daily tacrolimus (Tacrolimus BID) to Tacrolimus QD. METHODS: This was an open-label, multicenter replicate design study in stable adult kidney transplant recipients (≥6 months posttransplantation) maintained on Tacrolimus BID. Patients underwent four sequential 14-day treatment periods of alternating Tacrolimus BID and QD (mg:mg conversion). Four 24-hour PK profiles were collected, one on the last day of each treatment period. Adverse events were also reported. RESULTS: A total of 60 of 69 patients completed all 4 PK profiles. Steady-state tacrolimus area under the curve from 0 to 24 hours and Cmin were comparable for both formulations, with treatment ratio means (90% confidence intervals) of 92.9% (89.8%-96.0%) and 90.9% (87.3%-94.6%), respectively (acceptance interval: 80%-125%). Both formulations were well tolerated, with renal function remaining stable over the 8-week period. There was a good correlation between area under the curve from 0 to 24 hours and Cmin for Tacrolimus QD and BID (r = 0.88 and 0.82, respectively). The relationship between these two parameters was also similar. CONCLUSIONS: The results of this study provide evidence for safe conversion from Tacrolimus BID to QD with appropriate trough concentration monitoring.

Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng · h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng · h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.

Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study.

BACKGROUND: Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). METHODS: DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). RESULTS: Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. CONCLUSIONS: In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.

Pharmacokinetic modeling and development of Bayesian estimators in kidney transplant patients receiving the tacrolimus once-daily formulation.

BACKGROUND: The once-daily formulation of tacrolimus has been reported to exhibit the same efficacy and safety profile as compared with the immediate-release form administered twice daily. However, as a result of differences in their pharmacokinetic (PK) profile, the PK models or Bayesian estimators (MAP-BE) previously developed for the immediate-release formulation cannot be used for the new once-daily formulation. Using the PK information obtained from a Phase II trial, the aim of this study was to explore the feasibility of developing a PK model and a MAP-BE able to estimate, on the basis of a routinely applicable limited sampling strategy, tacrolimus individual PK parameters and AUC0-24h in de novo renal transplant patients given the once-daily formulation. METHODS: Twelve de novo kidney transplant recipients receiving once-daily tacrolimus as part of their immunosuppressive regimen provided full PK profiles (17 concentration time points over 24 hours) on Days 14 and 42 posttransplantation. On the basis of a one-compartment open model with absorption described as following a double gamma distribution, a classic iterative two-stage method was applied to develop MAP-BEs. All the limited sampling strategies with a maximum of three sampling times within 4 hours postdose were tested for Bayesian forecasting with the aim of accurately estimating the AUC0-24h. RESULTS: Once-daily tacrolimus exhibited a high interpatient PK variability with coefficients of variation of 34.3% and 36.2% for AUC0-24h/dose (mg/kg) on Days 14 and 42, respectively. Regression analysis between C0 and AUC0-24h yielded r = 0.68 and 0.76 at these two periods, respectively. The iterative two-stage approach led to the development of a different MAP-BE for each posttransplantation period, which allowed estimation of once-daily tacrolimus pharmacokinetics and AUC0-24h on the basis of a C0-C1h-C3h sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 4.2% +/- 6.1% (range, -11.8% to +11.2%; root mean square error = 7.1%) on Day 14 and 0.2% +/- 7.9% (range, -12.9% to +14.1%; root mean square error = 7.8%) on Day 42. CONCLUSION: A PK model and Bayesian estimators allowing estimation of tacrolimus AUC0-24h based on a routinely applicable limited sampling strategy were developed for once-daily tacrolimus in renal transplantation. Further validation in independent groups of patients is required to confirm their applicability for optimizing the monitoring of once-daily tacrolimus in routine clinical practice or to conduct observational or comparative therapeutic drug monitoring clinical trials.