Tacrolimus

Tacrolimus (TAC) or FK506 is a macrolide lactone derived from the bacteria Streptomyces tsukubaensis, extracted as one of three tautomeric forms of the molecule from bacterial fermentation. The chemical structure of TAC is depicted in Figure 1. As discussed previously, TAC is a calcineurin inhibitor similar in its effects to cyclosporin. It exhibits higher potency than cyclosporin, but it is similarly lipophilic and poorly water soluble (46). Selected physicochemical properties of this drug are shown in Table 1.

The commercial formulations of TAC include the Prograf capsules for oral administration (35) and the Protopic ointment for dermal application (36). Protopic ointment is a simple mixture of tacrolimus in a base of white petrolatum, mineral oil, paraffin, propylene carbonate, and white wax, and since the design of this formulation is not novel, it will not be discussed. Prograf capsules, however, are produced using a novel solid dispersion processing technique. The production of this solid dispersion formulation (SDF) is described by Yamashita et al. (47). TAC is dissolved in

Figure 11 Cyclosporin concentrations in lung tissue with respect to time following the first 24 h after administration of drug. Group A, aerosol cyclosporin 3 mg/kg; Group B, aerosol cyclosporin 5 mg/kg; Group C, intramuscular cyclosporin 5 mg/kg; Group D, intramuscular cyclosporin 15 mg/kg. Source: From Ref. 45.

Figure 11 Cyclosporin concentrations in lung tissue with respect to time following the first 24 h after administration of drug. Group A, aerosol cyclosporin 3 mg/kg; Group B, aerosol cyclosporin 5 mg/kg; Group C, intramuscular cyclosporin 5 mg/kg; Group D, intramuscular cyclosporin 15 mg/kg. Source: From Ref. 45.

ethanol and a stabilizing hydrophilic polymer is then added. After complete dissolution or swelling of the polymer, the ethanol is removed under reduced pressure and increased heat leading to formation of the SDF. Studies show that the SDF produced using this process contains tacrolimus in an amorphous state, which exhibits higher apparent solubility in dissolution media than does the corresponding crystalline form (47). The resulting SDF yields high supersaturation drug concentrations in vitro that are maintained for an extended period of time. The ability of these formulations to supersaturate the dissolution media highlights the possibility for increased bioavailability from an amorphous drug form. The meta-stable solubility of amorphous drug form may be as high as 100-times greater than its crystalline form (48). If the concentration of drug in solution is significantly increased, the higher chemical potential will lead to an increase in flux across an exposed membrane. This would lead to much higher blood levels for an amorphous drug form, compared to an identical crystalline formulation (49). The blood concentration of tacrolimus after oral administration of the SDF with hydroxypropyl methylcellulose (HPMC) to beagle dogs was measured against oral administration of the crystalline TAC powder (Fig. 13). The pharmacokinetic parameters derived from the analysis of blood concentration versus time curves are shown in Table 2. The AUC (0-8 h) of the SDF composition is almost 10-times higher than that of crystalline TAC, and the Cmax of the SDF composition shows similar 10-fold

Figure 12 Area under the concentration vs. time curve (AUC)/dose of cyclosporin (mg/kg) for each of the four study groups. Abbreviation: IM, intramuscular. Source: From Ref. 45.

increases in magnitude compared to the crystalline form (47). Honbo et al. compared tacrolimus SDF's with oily ethanol formulations (OEF) of TAC for efficacy against allograft rejection (50). A rat skin allograft transplantation study was conducted to determine the length of time the graft

Tacrolimus Area Under Curve Envarsus

Figure 13 Blood concentration of tacrolimus after oral administration of SDF with HPMC to beagle dogs. (O) tacrolimus crystalline powders; (•) SDF of tacrolimus with HPMC. Values are expressed as the mean with a vertical bar showing SE of six animals. Each dosage form was administered at the dose of 1 mg tacrolimus. Source: From Ref. 47.

Figure 13 Blood concentration of tacrolimus after oral administration of SDF with HPMC to beagle dogs. (O) tacrolimus crystalline powders; (•) SDF of tacrolimus with HPMC. Values are expressed as the mean with a vertical bar showing SE of six animals. Each dosage form was administered at the dose of 1 mg tacrolimus. Source: From Ref. 47.

Table 2 Pharmacokinetic Parameters of Tacrolimus after its Oral Administration to Dogs as Crystalline Powders or SDF of Tacrolimus with HPMC

Sample AUC0-8 h (ng h/mL)

Cmax (ng/mL)

Tmax (h)

MRT (h)

Crystalline powder 1.1 -1.4 SDF with HPMC 10.9 - 6.1a

0.4 - 0.3 4.0 - 1.2a

3.1 -3.0 0.6 - 0.2

3.3 - 0.9 2.7 - 0.1

Note: Each value represents the mean + SE of six animals. Each dosage form was administered at the dose of 1 mg as tacrolimus.

a = P<0.05, compared to the corresponding parameter of crystalline powder. Source: From Ref. 47.

Note: Each value represents the mean + SE of six animals. Each dosage form was administered at the dose of 1 mg as tacrolimus.

a = P<0.05, compared to the corresponding parameter of crystalline powder. Source: From Ref. 47.

could remain viable when administered doses of oral TAC of 0, 1, 3.2, 10, and 32mg/kg/day. At 1 and 3.2mg/kg/day TAC, the animals in both OEF and SDF groups survived for over 30 days. The mean survival time was 14.4 days in the SDF-treated group and 11.2 days in the OEF treated group (50). Survival graphs are shown in Figure 14.

For oral absorption, the major site of absorption for TAC was identified to be the upper small intestine (35). Following administration, TAC has a high volume of distribution and binds extensively into red blood cells and blood proteins. Clearance occurs mainly through the biliary route. Prograf is rapidly absorbed in some patients, with tmax occurring within 0.5-3 h, while in other patients, a relatively flat absorption profile was observed, indicating continuous and prolonged absorption. The poor dissolution of TAC in gastric fluids, its low aqueous solubility, and variable

Figure 14 Results of (A) SDF-tacrolimus and (B) OEF-tacrolimus in the secondary rat skin allograph transplantation study. Dose 0, 1, 3.2, 10, and 32mg/kg/day; dosage period, once daily for 30 days; number of animals, 5. * - died with living graft. Source: From Ref. 50.

gastric motility is thought to be responsible for this observation. For kidney transplant patients, single oral doses of 0.1, 0.15, and 0.2mg/kg resulted in Cmax of 19.2, 24.2, and 47.9ng/mL, respectively. The tmax for these measurements varied from 0.7 to 6 h. The mean bioavailability of Prograf capsules was 21.8% for liver transplant patients, 20.1% for kidney transplant patients, and 14.4-17.4% for healthy subjects. Oral bioavail-ability was reduced when co-administered with a fatty meal. Decreases in AUC (—35% in whole blood) and Cmax (—57% in whole blood) and increases in tmax (173% in whole blood) were observed, showing that both rate and extent of absorption is affected by food (35). Oral absorption of TAC in Prograf, therefore, is incomplete and highly variable, indicating problems with the commercial dosage form.

In addition to its primary use in inhibiting organ transplant rejection, TAC has been used for treatment in a variety of other disorders where reduction of an inflammatory/immune response is critical. Targeted delivery of TAC to the large intestine was investigated by Lamprecht et al. with sustained local release of TAC for treatment of ulcerative colitis (51-53). Microspheres, manufactured using Eudragit P-4135F, show pH-dependent release in the colon using an emulsification/solvent extraction method. In vitro release studies showed the TAC microspheres limited drug release at pH 6.8 and below (less than 10% release over 6 hours) and rapid release (100% within 30 min) at pH > 7.4 (51). Myeloperoxidase activity in the rat animal model was used to indicate the severity of colitis, with decreasing activity showing less colonic inflammation. TAC microspheres were shown to be as effective in mitigation of colitis induced inflammation when administered subcutaneously, and they are more effective than when administered orally as a solution. The TAC subcutaneous group, however, showed increased levels of adverse effects, including kidney impairment indicated by lower creatinine clearance, than the tacrolimus microsphere formulation. This was mainly due to the higher bioavailability of the TAC, due to the avoidance of the PGP efflux and CYP 3A4 effects seen with the oral administration of TAC (53).

Was this article helpful?

0 0
Dealing With Asthma Naturally

Dealing With Asthma Naturally

Do You Suffer From ASTHMA Chronic asthma is a paralyzing, suffocating and socially isolating condition that can cause anxiety that can trigger even more attacks. Before you know it you are caught in a vicious cycle Put an end to the dependence on inhalers, buying expensive prescription drugs and avoidance of allergenic situations and animals. Get control of your life again and Deal With Asthma Naturally

Get My Free Ebook


Post a comment