Tacrolimus (Page 11 of 17)

10 OVERDOSAGE

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in Adverse Reactions (6)(including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; and in adult rats, 16 times the recommended human IV dose (all based on body surface area corrections).

11 DESCRIPTION

Tacrolimus, previously known as FK506, is the active ingredient in tacrolimus capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3 S –[3 R *[ E (1 S *,3 S *,4 S *)],4 S *,5 R *,8 S *,9 E ,12 R *,14 R *,15 S *,16 R *,18 S *,19 S *,26a R *]]–5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a–hexadecahydro–5,19–dihydroxy–3–[2–(4–hydroxy–3–methoxycyclo–hexyl)–1–methylethenyl]–14,16–dimethoxy–4,10,12,18–tetramethyl–8–(2–propenyl)–15,19–epoxy–3H–pyrido[2,1– c ][1,4]oxaazacyclotricosine–1,7,20,21(4H,23H)–tetrone,monohydrate.

The chemical structure of tacrolimus is:

Tacrolimus Structural Formula

Tacrolimus has an empirical formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

Tacrolimus capsules, USP are available for oral administration containing 0.5 mg, 1 mg or 5 mg of tacrolimus. Inactive ingredients include lactose monohydrate, hypromellose E5, croscarmellose sodium, and magnesium stearate.

The 0.5 mg capsule shell contains gelatin, titanium dioxide, iron oxide yellow and sodium lauryl sulfate, the 1 mg capsule shell contains gelatin, titanium dioxide and sodium lauryl sulfate, and the 5 mg capsule shell contains gelatin, titanium dioxide, iron oxide red and sodium lauryl sulfate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

12.3 Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17).

Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients
*
not applicable
AUC 0-inf
not available
§
AUC 0-t
Determined after the first dose
#
Median [range]
Þ
AUC 0-12

Population

N

Route (Dose)

Parameters

C max (ng/mL)

T max

(hr)

AUC (ng•hr/mL)

t 1/2 (hr)

CL (L/hr/kg)

V (L/kg)

Healthy Volunteers

8

IV (0.025 mg/kg/4hr)

*

*

652 ± 156

34.2 ± 7.7

0.040 ± 0.009

1.91 ± 0.31

16

PO (5 mg) (granules)

35.6 ± 10.9

1.3 ± 0.5

320 ± 164

32.1 ± 5.9

PO (5 mg) (capsules)

28.8 ± 8.9

1.5 ± 0.7

266 ± 95

32.3 ± 8.8

IV (0.02 mg/kg/12 hr)

*

*

294 ± 262

18.8 ± 16.7

0.083 ± 0.050

1.41 ± 0.66

Kidney Transplant Patients

26

PO (0.2 mg/kg/day)

19.2 ± 10.3

3.0

203 ± 42

PO (0.3 mg/kg/day)

24.2 ± 15.8

1.5

288 ± 93

Liver Transplant Patients

17

IV (0.05 mg/kg/12 hr)

*

*

3300 ± 2130

11.7 ± 3.9

0.053 ± 0.017

0.85 ± 0.30

PO (0.3 mg/kg/day)

68.5 ± 30.0

2.3 ± 1.5

519 ± 179

11

IV (0.01 mg/kg/day as a continuous infusion)

*

*

954 § ± 334

23.6 ± 9.22

0.051 ± 0.015

Heart Transplant Patients

11

PO (0.075 g/kg/day)

14.7 ± 7.79

2.1 [0.5 to 6.0] #

82.7 Þ ± 63.2

*

14

PO (0.15 mg/kg/day)

24.5 ± 13.7

1.5 [0.4 to 4.0] #

142 Þ ± 116

*

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)] . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

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