Pharmacokinetics in children

In general, young children (neonates excluded) need 1,5 to 2 fold higher dosages compared to adults to reach similar blood concentrations.
In pediatric transplant patients total body clearance and volume of distribution appears to be two fold higher compared to healthy adults and adult transplant patients. A lower bioavailability of an extemporaneously prepared oral suspension compared to oral capsules was found in both pediatric liver and kidney transplant patients.[Reding 2002; Schijvens 2020] Clinicians should take this difference into account, especially when switching between formulations.

Reference	Population	F	Tmax (hours)	Vd Plasma (L/kg)	Vd whole blood (L/kg)	T½ (hours)	Cl plasma (L/hour/kg)	Cl whole blood (L/hour/kg)
Venkataramanan 1995	Adults: healthy; Ktx, Ltx, Small bowel tx. N=209	25%	2	30	1	12	1,8	0,06
Hebert 1999	Healthy adults. N=6	14,4%			1,4			0,036
Fay 1996	18-53years; SCT tx; N=27	32%	2		1,67	18,2		0,07
Wallemacq 2001	Adults Ltx N=unknown	22%	1,5		1,2	11,7		0,06
Wallemacq 1998	Child 0,7-13 years; Ltx n=16	25%	2,1  (oraal)		2,6	11,5  (IV); 12,4  (oraal)		0,14  (IV)
Webb 2002	Child mean 8,2 years (± 2,4 years) Ktx; n=12	18,6%	1,5			10,2		0,126
Shishido 2001	Child mean 9,3 years (± 3,7 years) Ktx; N=32	10%	2,8			11		0,126
Mehta 1999	Child 8-17 years SCTx, N=7							0,108  (1st Css); 0,097  (volledige duur IV behandeling)
Przepiorka 2000	Child median 9 years(6 months-18 years); SCTx; N=55							< 6 jaar: 0,0159 ; 6-12 jaar 0,109 ; > 12 jaar: 0,104
Wallin 2009	Child median 6 years (5 mnd-18 years); SCTx; N=22	15,7%			3,71			0,106 L/uur/kg0,75
Hao 2018	Child median 9,4 years (2,7-17,3 years); NS (relapse/remission unknown); N=28				4,7	9		0,69
Medeiros 2016	Child median 3,2 years (2,5-17,2 years) NS; N=7		Relapse: 1 ; Remission: 0,5			Relapse: 9,2 ; Remission: 8

KTx= kidney transplant; Ltx= liver transplant; SCTx=stemceltransplant; NS = nefrotic syndrome

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Prophylaxis for rejection of a transplanted liver

Oral Normal preparation (immediate release) 1 month up to 18 years [1] [7] [9] [26] Initial dose: 0.3 mg/kg/day in 2 doses. Maintenance dose: Based on the effect and determination of the level. Slow (modified or delayed) release 8 years up to 18 years [2] [8] Initial dose: (Advagraf) 0.3 mg/kg/day in 1 dose Maintenance dose: (Advagraf): based on the effect and determination of the concentration.. Intravenous 1 month up to 18 years [1] [6] 0.05 mg/kg/day, continuous infusion.

Prophylaxis for rejection of a transplanted kidney

Oral Normal preparation (immediate release) 1 month up to 18 years [1] [7] [9] [26] Initial dose: 0.3 mg/kg/day in 2 doses. Maintenance dose: Based on the effect and determination of the level. Slow (modified or delayed) release 8 years up to 18 years [2] [8] Initial dose: (Advagraf) 0.3 mg/kg/day in 1 dose Maintenance dose: (Advagraf): based on the effect and determination of the concentration.. Intravenous 1 month up to 18 years [1] [6] 0.075 - 0.1 mg/kg/day, continuous infusion.

Prophylaxis for rejection of heart transplant without antibody induction
Oral Normal preparation (immediate release) 1 month up to 18 years [1] [7] [9] [26] Initial dose 0.3 mg/kg/day in 2 doses. Maintenance dose: based on effect and serum concentrations. The first oral dose should be started 8 to 12 hours after stopping the intravenous therapy Intravenous 1 month up to 18 years [1] [6] 0.03 - 0.05 mg/kg/day, continuous infusion.

Prophylaxis for rejection of heart transplant AFTER antibody induction
Oral Normal preparation (immediate release) 1 month up to 18 years [1] [7] [9] [26] Initial dose: 0.1 - 0.3 mg/kg/day in 2 doses. Maintenance dose: Based on the effect and determination of the level.

CAUTION:

Route of administration not applicable 0 years up to 18 years [10] [12] A lower bioavailability of an extemporaneously prepared oral suspension compared to oral capsules was found in both pediatric liver and kidney transplant patients.[1, 2] Clinicians should take this difference into account, especially when switching between formulations. Close TDM is advised. For conversion of patients from Prograf capsules or Advagraf to Envarsus, conversion on a 1:0.7 (mg:mg) total daily dose base is required

Steroid resistant nephrotic syndrome (SRNS); Frequently relapsing nephrotic syndrome (FRNS); Steroid dependent nephrotic syndrome (SDNS)
Oral Normal preparation (immediate release) 6 months up to 18 years [11] [27] [28] [29] [30] [31] [33] [36] [38] [39] Initial dose: 0.1 mg/kg/day in 2 doses. Maintenance dose: titrate based on bloodconcentration and effect.

Prophylaxis for Graft versus Host Disease after allogenic stemcel transplant

Oral Normal preparation (immediate release) 1 month up to 18 years [15] [32] [34] [37] [40] [41] Initial dose 0.2 mg/kg/day in 2 doses. Maintenance dose: titrate based on bloodconcentration and effect.. Intravenous 1 month up to 18 years [15] [32] [34] [35] [37] [40] [41] [42] [43] [44] Initial dose 0.04 mg/kg/day in 2 doses. Maintenance dose: titrate based on bloodconcentration and effect.. Intermittent dosing: every 12 hours by 2 hour infusion Alternatively: continuous infusion.

Renal impaiment in children > 3 months

• GFR ≥10 ml/min/1.73m2: no dose adjustment required
• GFR <10 ml/min/1.73m2:  no dose adjustment required

Note: owing to the nephrotoxic potential of tacrolimus careful monitoring of kidney function is recommended

 

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Ventricular or septal hypertrophy

• Reversible and mainly in children whose tacrolimus trough levels were well above the recommended maximum levels
• Other risk factors: existing heart disease, treatment with corticosteroids, high blood pressure, kidney or liver dysfunction, infections, fluid overload and edema

[SmPC Prograf]

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

The various preparations are not mutually interchangeable. Switching between preparations with and without controlled release can result in transplant rejection or additional side effects. When switching from a dosage of 2×/day (immediate release capsules) to a dosage of 1×/day (controlled-release tablet or capsule), the trough levels should be checked before conversion and within 2 weeks after (approx. 24 hours after the final dose, just before the next dose). Do not convert from the granulate to capsules/tablets with controlled release. When switching from Modigraf granulate to Prograft capsules, keep the total number of milligrams per day unchanged, or otherwise round the total daily dose of Prograft upwards and give the higher dose in the morning. On a transition from Prograft capsules to Modigraf granulate, keep the total number of milligrams per day unchanged, or otherwise round the total daily dose of Modigraf downwards and give the higher dose in the morning. Determine the trough levels before the conversion and again within one week after the switch. On switching from Prograft capsules to Advagraf, use a ratio of 1:1 (in mg) for the overall daily dose. On switching from Prograft capsules or Advagraf to Envasus, use a ratio of 1:0.7 (in mg) for the overall daily dose.

A lower bioavailability of an extemporaneously prepared oral suspension compared to oral capsules was found in both pediatric liver and kidney transplant patients.[1, 2] Clinicians should take this difference into account, especially when switching between formulations. Close TDM is advised.

Cardiomyopathies
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly patients should be monitored regularly before and during treatment.

Epstein-Barr virus
Very young (< 2 years), EBV-VCA-negative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with tacrolimus. During treatment, careful monitoring with EBV-PCR is recommended.

 

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Other immunosuppressants
	Azathioprine Related Medicines Menu">	L04AX01
	Methotrexate Related Medicines Menu">	L04AX03

Tumor necrosis factor alpha (TNF-alpha) inhibitors
	Adalimumab Related Medicines Menu">	L04AB04
	Etanercept Related Medicines Menu">	L04AB01
	Infliximab Related Medicines Menu">	L04AB02

Calcineurin inhibitors
	Ciclosporin Related Medicines Menu">	L04AD01

Mammalian target of rapamycin (mTOR) kinase inhibitors
	Everolimus Related Medicines Menu">	L04AH02

References

1. Astellas Pharma BV, SmPC Prograf (RVG 18107 / RVG 22236) 20-05-2022, www.geneesmiddeleninformatiebank.nl
2. Astellas Pharma BV, SPC Advagraf (EU/1/07/387/007) 13-4-2012 , www.geneesmiddeleninformatiebank.nl
3. Uptodate: UpToDate®, Pediatric Drug information: Tacrolimus Lexicomp® Version 217.0, accessed 11/18
4. Chiesi Farmaceutici S.p.A., SmPC Envarsus 0,75 / 1 / 4 mg Retardtabletten (EU/1/14/935/001, 04/16
5. Hexal AG, SmPC Crolimus 0,5 / 0,75 / 1 / 2 / 5 mg Hartkapseln (72819.00.00), 06/16
6. Astellas Pharma Europe B.V., SmPC Prograf 5 mg/ml concentrate for infusion (NL-RVG 18109) 20-05-2022, www.geneesmiddeleninformatiebank.nl
7. Astellas Pharma Europe B.V., SmPc Prograf 0,5 / 1 / 5 mg Hard capsules (DE 41954.00.00) , 05/18
8. Astellas Pharma Europe B.V., SmPC Advagraf 0,5 / 1 / 3 / 5 mg Hartkapseln, retardiert (EU/1/07/387/001), 05/18
9. Astellas Pharma Europe B.V., SmPC Modigraf 0,2 / 1 mg granulaat voor orale suspensie (EU/1/09/523/001) Rev 18,15-11-2022, www.geneesmiddeleninformatiebank.nl
10. Reding, R., et al., Efficacy and pharmacokinetics of tacrolimus oral suspension in pediatric liver transplant recipients, Pediatr Transplant, 2002, 6(2), 124-6.
11. Yang, E.M., et al., Tacrolimus for children with refractory nephrotic syndrome: a one-year prospective, multicenter, and open-label study of Tacrobell(R), a generic formula. , World J Pediatr,, 2016, 12(1), 60-5
12. Schijvens, A.M., et al.,, Low Bioavailability of Oral Tacrolimus Suspension in Pediatric Kidney Transplant Patients, Clin Pharmacokinet, 2020, 59(11), 1483-5
13. Venkataramanan, R., et al., Clinical pharmacokinetics of tacrolimus., Clin Pharmacokinet, 1995, 29(6), 404-30
14. Hebert, M.F., et al., Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers., J Clin Pharmacol, 1999, 39(1), 91-6
15. Osunkwo, I., et al., A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients, Biol Blood Marrow Transplant, 2004, 10(4), 246-58
16. Fay, J.W., et al., FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation., Blood, 1996, 87(8), 3514-9.
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18. Hao, G.X., et al., Population pharmacokinetics of tacrolimus in children with nephrotic syndrome., Br J Clin Pharmacol, , 2018, 84(8), 1748-56
19. Wallemacq, P.E., et al., Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients., Eur J Drug Metab Pharmacokinet, 1998, 23 (3), 367-70
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21. Wallin, J.E., et al., Population pharmacokinetics of tacrolimus in pediatric hematopoietic stem cell transplant recipients: new initial dosage suggestions and a model-based dosage adjustment tool., Ther Drug Monit, 2009, 31(4), 457-66
22. Medeiros, M., et al., Are Tacrolimus Pharmacokinetics Affected by Nephrotic Stage?, Ther Drug Monit, 2016, 38(3), 288-92
23. Shishido, S., et al.,, Pharmacokinetics of tacrolimus in pediatric renal transplant recipients., Transplant Proc, 2001, 33(1-2), 1066-8
24. Mehta, P., et al., Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation., Bone Marrow Transplant,, 1999, 24(12), 1323-7
25. Przepiorka, D., et al., Tacrolimus clearance is age-dependent within the pediatric population. , Bone Marrow Transplant, 2000, 26(6), 601-5
26. Sandoz B.V, SmPC Adport capsules (RVG 102902) 14-07-2022, www.geneesmiddeleninformatiebank.nl
27. McCauley, J., et al., Pilot trial of FK 506 in the management of steroid-resistant nephrotic syndrome., Nephrol Dial Transplant, 1993, 8(11), 1286-90
28. Choudhry, S., et al., Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial., Am J Kidney Di, 2009, 53(5), 760-9
29. Wang, J., et al., Evaluation of mycophenolate mofetil or tacrolimus in children with steroid sensitive but frequently relapsing or steroid-dependent nephrotic syndrome., Nephrology (Carlton), 2016, 21(1), 21-7
30. Gulati, A., et al., Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome., Kidney Int,, 2012, 82(10), 1130-5
31. Sinha, A., et al., Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome., Kidney Int,, 2017, 92(1), 248-57
32. Przepiorka, D., et al., Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated donor cord blood transplantation, Bone Marrow Transplant, 1999, 23(12), 1291-5
33. Li, S., et al., Efficacy and safety of immunosuppressive medications for steroid-resistant nephrotic syndrome in children: a systematic review and network meta-analysi, Oncotarget,, 2017, 8(42), 73050-62
34. Yanik, G., et al., Tacrolimus (FK506) and methotrexate as prophylaxis for acute graft-versus-host disease in pediatric allogeneic stem cell transplantation, Bone Marrow Transplant, 2000, 26(2), 161-7
35. Sabapathy, C., et al., Tacrolimus with mini-methotrexate as prophylaxis for graft-versus-host disease in pediatric patients after allogeneic peripheral blood stem cell transplant or bone marrow transplant, J Pediatr Hematol Oncol, 2008, 30(12), 945-9
36. Liu, I.D., et al., Cochrane Database Syst Rev, , Interventions for idiopathic steroid-resistant nephrotic syndrome in children. , 20019, (11), CD003594.
37. Offer, K., et al., Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation, Biol Blood Marrow Transplant, 2015, 21(3), 496-502
38. Basu, B., et al., Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial, JAMA Pediatr, 2018, 172(8), 757-764
39. Delbet, J.D., et al., Infrequent tacrolimus-induced nephrotoxicity in French patients with steroid-dependent nephrotic syndrome, Pediatr Nephrol,, 2019, 34(12), 2605-8
40. Kanamitsu, K., et al., Clinical Factors Affecting the Dose Conversion Ratio from Intravenous to Oral Tacrolimus Formulation among Pediatric Hematopoietic Stem Cell Transplantation Recipients, Ther Drug Monit, 2020, 42(6), 803-10
41. Militano, O., et al., Mycophenolate mofetil administered every 8 hours in combination with tacrolimus is efficacious in the prophylaxis of acute graft versus host disease in childhood, adolescent, and young adult allogeneic stem cell transplantation recipients., Pediatr Blood Cancer, 2018, 65(8), e27091
42. Skeens, M., et al., Twice daily i.v. bolus tacrolimus infusion for GVHD prophylaxis in children undergoing stem cell transplantation, Bone Marrow Transplant, 2012, 47(11), 1415-8
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45. University Medical Centre Groningen , Expert Opinion use of tacrolimus in pediatric liver transplant, Dec 6, 2022

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