Switch from once-daily tacrolimus (Advagraf) to twice-daily immediate-release tacrolimus (Prograf) in liver transplantation: Case study

Mediterranean Journal of Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online www.medjpps.com ISSN: 2958-3101 print Fetati et al. Mediterr J Pharm Sci. 2025; 5(4): 78-82. 78 CASE REPORT article Switch from once-daily tacrolimus (Advagraf) to twice-daily immediate-release tacrolimus (Prograf) in liver transplantation: Case study Habiba Fetati * , Fatima Boudia , Fatima Z. Kouaidia , Nadjer FZ Mekaouchen Asmaa Memou Nihed Amara , and Houari Toumi Department of Pharmacovigilance, University Hospital Establishment 1st November 1954, BP N° 4166 Ibn Rochd 31000, and Pharmacy Department, Faculty of Medicine, University of Oran, 1 Ahmed Ben Bella, Research Laboratory in Pharmaceutical Development, B.P. 1510 El M'Naouer 31000, Oran, Algeria * Author to whom correspondence should be addressed Article number: 233, Received: 02-11-2025, Accepted: 11-12-2025, Published online: 13-12-2025 HOW TO CITE THIS Fetati et al. Switch from once-daily tacrolimus (Advagraf) to twice-daily immediate-release tacrolimus (Prograf) in liver transplantation: Case study. Mediterr J Pharm Sci. 2025; 5(4): 78-82. [Article number: 233]. https://doi.org/10.5281/zenodo.17916338 Keywords: Pharmacokinetic, tacrolimus, therapy individualizing, therapeutic drug monitoring Abstract: Tacroclimus is an immunosuppressive drug widely used for the prevention of rejection in organ transplants. It is marketed in two forms: Prograf administered twice a day, and Advagraf, which allows only one administration per day. Advagraf is often used in liver transplantation. Through this clinical case, we demonstrate the role of therapeutic drug monitoring in dosage optimization during the switch to tacrolimus from the Advagraf form to the Prograf form. This is a 60-year-old patient who underwent liver transplantation in 2014, treated with Advagraf 2.5 mg once in the morning. The residual CO concentration was 7.0 ng/ml. Due to the unavailability of Advagraf, this drug was switched to Prograf at the same dosage, 2.5 mg/d in two doses (1.5 mg in the morning and 1.0 mg in the evening). Co increased from 7.0 to 11.0 ng/ml, AUC was 194 ng.h/ml [120-150]. When substituting Advagraf for Prograf, C0 monitoring should be regular and close, and dosage adjustments should be made to ensure that a similar systemic exposure is maintained. Introduction Tacrolimus (Tac) and cyclosporine are immunosuppressive drugs (IS), calcineurin inhibitors (CNIs) which are widely used in solid organ transplantation, particularly in liver transplantation (LT). In LT, Tac is the first-line IS treatment for rejection prophylaxis. Compared to cyclosporine A, Tac reduces the incidence of acute rejection, graft loss and one-year mortality [1]. Tac was originally available as an Immediate Release Tac (IRTac) formulation (Prograf) given twice a day. To improve patient adherence to treatment and reduce interand intra-individual variability, an Extended-Release Tac (ER-Tac) formulation has been developed and administered once daily (Advagraf) [2]. There are no significant differences in terms of efficacy and toxicity between the two formulations [2]. However, Tac IR-TAC and ER-TAC are not bioequivalent and they should not be substituted without careful therapeutic drug monitoring [3]. The objective of this work is to demonstrate through a case report the role of the Therapeutic Drug Monitoring (TDM) in dosage optimization during the switch tacrolimus from the ER-TAC once-a-day dose to the IR-Tac twice-daily dose. Case report: On June 07th, 2020, a 60-year-old patient was admitted to the Pharmacovigilance Department of the Hospital and University Establishment of Oran (HUEO), in Algeria, for TDM of Tac. She underwent a Copyright© 2025. This open-access article is distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mediterranean Journal of Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online www.medjpps.com ISSN: 2958-3101 print Fetati et al. Mediterr J Pharm Sci. 2025; 5(4): 78-82. 79 cadaveric liver transplant on May 03th, 2014. Her medical history was asthma, open-angle glaucoma, anemia, and HIV positive. After LT, she developed high blood pressure and insulin-dependent type 2 diabetes. Its immunosuppressive treatment was ER-Tac 2.5 mg once daily combined with mycophenolate mofetil (MMF) and corticosteroids. In addition to this IS treatment, she had a triple therapy of antiretrovirals (Rilpivirine, Lamivudine, and Raltegravir), a bronchodilator (Salbutamol), an antihypertensive calcium channel blocker (Amlodipine), rapid and slow insulin therapy and vitamin supplementation (Table 1). The blood dosing of Tac at the Department of Pharmacovigilance shown a residual concentration (CO) at 7.0 ng/ml, the therapeutic range of Tac when it is combined with MMF is 5.0-8.0 ng/ml [4]. Her previous COs for the same dosage were 6.1, 6.4, and 7.4 ng/ml, respectively (All in therapeutic range, Figure 1). On June 15th, 2020, due to the lack of availability of the prolonged formulation (ER-Tac once a day) of tacrolimus (Advagraf) at the hospital. Her physician has replaced him with an IR-Tac twice a day dose formulation at an equivalent dosage (1: 1) of 2.5 mg/day (1.5 mg in the morning and 1.0 mg in the evening) (Figure 1). Once the steady-state was attained, another check was carried out on June 24th, 2020, who showed a C0 at 11 ng/ml. One week later, the C0 remained supratherapeutic at 12.7 ng/ml. The evolution of the C0 as a function of time is shown (Figure 1). This increase in Tac concentration (Co) coincided with a disturbance of the biological parameters: Blood creatinine, triglycerides and a decrease in renal creatinine clearance (Table 2). It should be noted that there was no drug interaction or any pathological condition that could increase Tac concentrations and hepatic function (elimination pathway and metabolization of Tac) was correct (Table 2). In order to effectively optimize the dosage, an AUC0 → 12.0 hrs. calculated by the Bayesian method on the platform ABIS et sites pour l’individualisation thérapeutique en transplantation CHU of Limoge was performed on June 30th, 2020, showing an overdose: AUC0 → 12h=194 ng.h/ml, therapeutic range [120-150] ng.h/ml. A dosage of 1.0 mg twice a day determined on the basis of AUC has been proposed. Subsequently, the C0 became in the therapeutic range (C0=7.3 ng/ml) (Figure 1). An ethical approval was obtained from our institute. Table 1: Medication list Specialty/dosage International common denomination Dosage Advagraf (ER-Tac) tacrolimus 2,5 mg once daily in the morning Cellcept 250 mg tablet MMF Twice daily Aspegic 100 mg Acetylsalicylic acid Once daily Amlor 5 mg tablet Amlodipine Once dialy Tardyferon B9 Sulfate ferreux-acide folique Twice daily Sterogyl H Ergocalciférol One every 6 months Vitamin B12 Cobalamin One injection IM per month Calciforte 500: Gluconate de calcium Once daily Edurant 25 mg table Rilpivirine Once daily Lamivudine Mylan 300 mg Lamivudine Once daily Isentress : 400 mg Raltégravir Twice daily Ganfort Bimatoprost-timolol a drople in the evening during 6 months Vitamin A: ophthalmic ointment Rétinol – lanoline One application in the evening Ventolin aero 200 Salbutamol 2 puffs in case of crisis Inovaire Beclomethasone-formoterol Two tablets per day in the morning Doliprane 500 mg Paracetamol 03 tablets/day Efferaglagan codéine Paracetamol –codeine 01 tablets*2/day Movicol Macrogol 03 tablets/day Stilnox 10 mg Zolpidem 01 Tablet in the evening Levimir Insulin detemir 10 IU in the evening Actrapid Insulin human 10 IU twice a day Mediterranean Journal of Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online www.medjpps.com ISSN: 2958-3101 print Fetati et al. Mediterr J Pharm Sci. 2025; 5(4): 78-82. 80 Figure 1: TDM of Tac results: C0 evolution as a function of time Results and discussion Tacrolimus, a calcineurin inhibitor, remains a mainstay of the treatment for rejection prophylaxis post liver transplantation. To improve adherence and reduce intraand inter-individual variability, the TAC Extended Release (Advagraf) a once-a-day formulation, is the most widely used in LT [5, 6]. In the literature, several conversion studies from IR-Tac twice a day formulation to ER-Tac once a day formulation have been documented in adult stable kidney [7] and liver [8] transplants and in stable pediatric liver transplant recipients [9] who were converted on an mg: mg basis from twice daily TAC to a single morning dose of the ER-Tac formulation. All these studies have shown that the conversion to the ER-Tac one dose is safe and effective. However, to the best of our knowledge, there is no clinical data about the conversion from the ER-Tac once daily dose to the IR-Tac twice daily dose. In this patient, the conversion of the form the ER-Tac once a day to the IR-Tac twice a day (1.0 mg: 1.0 mg) resulted in an overdose of tacrolimus (C0 to 11.0 and 12.7 ng/ml). Since the latter is nephrotoxic [10] and can cause hypertriglyceridemia [11], this dosage could be responsible for the slight increase in creatinine; therefore, a decrease in renal clearance and an increase in triglycerides were observed (Table 2). To prevent the risk of Tac toxicity, to quickly and efficiently optimize the dosage and possibly to correct the observed biological disturbances, we suggested that the patient perform an AUC0 → 12.0 hrs. calculated by Bayesian methods on the platform ABIS et sites pour l’individualisation thérapeutique en transplantation CHU of Limoge by taking three samples: C0, CI, and C3. The results have also shown a supratherapeutic AUC at AUC0 → 12 hrs.=194 ng.h/ml. Dosage adjustment according to AUC0 → 12 hrs. allowed the residual concentration to be located within the therapeutic range (Co=7.3 ng/ml). Conclusion: Through this case report, we have demonstrated the role of therapeutic drug monitoring in securing and managing the conversion from extended-release once-day dose formulation (Advagraf) to immediate-release twice-day dose Tac formulation (Prograf). When substituting Advagraf with Prograf, C0 monitoring should be regular and close, and dosage adjustments should be made to ensure that a similar systemic exposure is maintained. Mediterranean Journal of Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online www.medjpps.com ISSN: 2958-3101 print Fetati et al. Mediterr J Pharm Sci. 2025; 5(4): 78-82. 81 Table 2: Biological parameters Parameters (unit) Results June 09th, 2020 Results June 20th, 2020 Norms Glycemia (mmol/L) 7.3 08.67 3.8-5.8 Hb A1c (%) - 08,10 4-6 blood creatinine (mg/l) 14,36 6-12 Total bilirubin/conjugate (µmol/l) 09/04 05,3/2,57 <17/<06 ASAT/ALAT (U/l) 22/14 22,8/16,4 <35 GGT(U/l) 24 22,9 <36 PAL (U/l) 148 126 56-152 Total cholesterol (g/l) - 1.92 <2.00 Triglycerides (g/l) - 2.36 <1.50 Creatinine clearance (ml/min) 50.68 HbA1c: A hemoglobin A1C; ASAT: aspartate aminotransferase; ALAT: alanine aminotransferase; GGT: gamma-glutamyltransferase; PAL: phosphatase alkaline. References 1. Tasdogan BE, Ma M, Simsek C, Saberi B, Gurakar A. Update on immunosuppression in liver transplantation. Euroasian Journal of Hepato-Gastroenterology. 2019; 9(2): 96-101. doi: 10.5005/jp-journals10018-1301 2. Ma TK-W, Chow KM, Cheng PM-S, Kwan BC-H, Leung CB, Li PK, Szeto CC. Pharmacokinetic study of oncedaily formulation of tacrolimus (Advagraf) in stable Chinese kidney transplant recipients. Hong Kong Journal of Nephrology. 2016; 19: 1-6. doi: 10.1016/j.hkjn.2016.03.002 3. Clinical Guidelines For Transplant Medications 2019. CMV guideline update (cardiac) AMB.03.007 Rev11 Eff 4. Brunet M, van Gelder T, Åsberg A, Haufroid V, Hesselink DA, Langman L, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy: Second consensus report. Therapeutic Drug Monitoring. 2019; 41(3): 261307. doi: 10.1097/FTD.0000000000000640 5. Beckebaum S, Iacob S, Sweid D, Sotiropoulos GC, Saner F, Kaiser G, Radtke A, Klein CG, Erim Y, de Geest S, Paul A, Gerken G, Cicinnati VR. Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation. Transplant International. 2011; 24(7): 666-675. doi: 10.1111/j.1432-2277.2011.01254.x 6. 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Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients. American Journal of Transplantation. 2007; 7(6): 1609-1615. doi: 10.1111/j.1600-6143.2007.01803.x 10. Moini M, Schilsky ML, Tichy EM. Review on immunosuppression in liver transplantation. World Journal of Hepatology. 2015; 7(10): 1355-1368. doi: 10.4254/wjh.v7.i10.1355 11. Trana Hussaini, Siegfried Erb, Eric M. Yoshida. Immunosuppressive pharmacotherapy in liver transplantation. AME Medical Journal. 2018; 3(1): 18. doi: 10.21037/amj.2018.01.07 Mediterranean Journal of Pharmacy & Pharmaceutical Sciences ISSN: 2789-1895 online www.medjpps.com ISSN: 2958-3101 print Fetati et al. Mediterr J Pharm Sci. 2025; 5(4): 78-82. 82 Acknowledgements: We express our gratitude to patients who contribute indirectly to research, to clinicians for their collaboration to promote health, to the biologists' agents (Samar Leila, Amiar Amina, Sayah Lila, Zinasni Djamila, Zouaoui Yasmine) for the analytical measure. Authors’ contribution: HF & FB conceived and designed the study. FB, FZK & NFZK collected data. AM, NA & HT contributed to data analysis. All authors drafted, reviewed and approved the final version of the manuscript. Conflict of interest: The authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethical issues: The authors completely observed ethical issues, including plagiarism, informed consent, data fabrication or falsification, and double publication or submission. Data availability statement: The raw data that support the findings of this article are available from the corresponding author upon reasonable request. Author declarations: The authors confirm that they have followed all relevant ethical guidelines and obtained any necessary IRB and/or ethics committee approvals. Generative AI disclosure: No Generative AI was used in the preparation of this manuscript.