CASE REPORTS

Pharmacokinetics of Tacrolimus andCyclosporine in Short-Bowel SyndromeJames Thielke,* Jill Martin,* Fredrick L. Weber Jr,† Timothy J. Schroeder,†‡Sharon Goretsky,§ and Douglas W. Hanto§

P atient variability in the absorption of cyclospo-rine and tacrolimus has been well docu-

mented.1-8 This problem is magnified in patientswith short-bowel syndrome (SBS),9 but there are nocomparative data on the bioavailability of differentimmunosuppressants in the same patient. We pre-sent a patient with SBS and liver failure secondaryto total parenteral nutrition (TPN) who was evalu-ated pretransplantation for the absorption of tacro-limus (Prograf, Fujisawa USA, Deerfield, IL) andtwo formulations of cyclosporine (Sandimmuneand Neoral, Novartis Pharmaceuticals, E. Hanover,NJ).

Case ReportA 39-year-old white woman with Crohn’s disease under-went multiple small-bowel resections, leaving approxi-mately 2 feet of small intestine. She developed SBS, andTPN was initiated in 1991. In January 1994, a liverbiopsy showed findings consistent with TPN-inducedcholestasis. By May 1994, her bilirubin level had in-creased to 23 mg/dL, and the patient was evaluated forliver transplantation. An endoscopic retrograde cholan-giopancreatography (ERCP) 1 month earlier docu-mented a normal biliary system. To guide the choice ofposttransplant immunosuppression and to evaluate thepotential need for a concurrent small-bowel transplant, asingle-dose pharmacokinetic study was performed withthe two formulations of cyclosporine (Sandimmune andNeoral), as well as tacrolimus (Prograf), during herpretransplant evaluation.

The laboratory studies at the time the pharmacoki-netic studies were performed 6 months after the ERCPshowed the following values: sodium, 138 mmol/L;potassium, 4.1 mmol/L; chloride, 99 mmol/L; carbon

dioxide, 18 mmol/L; blood urea nitrogen, 24 mg/dL;serum creatinine, 0.8 mg/dL; aspartate aminotransferase,102 U/L; alanine aminotransferase, 67 U/L; alkalinephosphatase, 208 U/L; gamma-glutamyl transferase(GGT), 76 U/L; total bilirubin, 7.3 mg/dL; albumin, 3.2g/dL; prothrombin time, 13.4 seconds; partial thrombo-plastin time, 37.7 seconds; and cholesterol, 146 mg/dL.

The patient was 52 kg and 5859 at the time of thestudy. She was administered 250 mg (5 mg/kg) ofSandimmune and 5 mg (0.1 mg/kg) of tacrolimus orallyon separate occasions, 1 week apart. A 250-mg dose ofNeoral was administered approximately 7 months laterwhen the product became available. At that time, herliver function values included aspartate aminotransfer-ase, 119 U/L; alkaline phosphatase, 131 U/L; totalbilirubin, 24.7 mg/dL; and albumin 2.6 g/dL. Serial bloodsamples were drawn at approximately 0, 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, 5, 6, 7, and 8 hours after the dose wasadministered.

After the administration of Sandimmune, all levelswere less than 25 ng/mL (undetectable by this assay; Fig.1). The area under the curve (AUC) and maximum bloodconcentration (Cmax) after both Neoral and tacrolimusadministration in this patient were reduced comparedwith healthy volunteers.10,11 However, therapeutic levelsappear to be achievable in this patient.

Discussion

Limited information is available regarding theabsorption of immunosuppressants in patients withSBS. The only two previous case reports evaluatedSandimmune. These yielded undetectable cyclospo-rine blood concentrations in 1 patient, despite veryhigh doses, and only 3% bioavailability in theother.9 Similarly, our patient had negligible absorp-tion of Sandimmune, and it was obviously not atherapeutic option in this patient.

There have been no previous reports evaluatingthe absorption of the new microemulsion formula-tion of cyclosporine (Neoral) in SBS. Pharmacoki-netic evaluations of a single 180-mg dose in healthyvolunteers resulted in an AUC of 3407 6 692h · ng/mL10 and, in liver transplant recipients, a7.5-mg/kg dose resulted in an AUC of 2846 6 498µg/h · L and Cmax of 493 6 61 µg/L (T-tube open).12

From the Departments of *Pharmacy, †Internal Medicine,‡Pathology and Laboratory Medicine, and §Surgery, UniversityHospital, Inc, Cincinnati, OH.

Address reprint requests to Jill Martin, PharmD, Department ofPharmacy Services, University Hospital, Inc, 234 Goodman St,Cincinnati, OH 45267-0740.

Copyright r 1998 by the American Association for the Study ofLiver Diseases

1074-3022/98/0405-0013$3.00/0

Liver Transplantation and Surgery, Vol 4, No 5 (September), 1998: pp 432-434432

In our patient, absorption of Neoral was less thanthat found in healthy volunteers (Table 1). How-ever, proportionately, it was similar to that of theliver transplant recipients, which should be suffi-cient to obtain therapeutic levels with appropriateadjustments of the dose.

Information regarding the absorption of tacro-limus in SBS has also not been available. In healthyvolunteers administered a dose of 0.07 mg/kg, theAUC was 271 6 122 ng/mL/h, and the Cmax was28.6 6 8.6 ng/mL.11 The absorption of tacrolimushas been evaluated in small-bowel transplant recipi-ents (SBTRs). The mean tacrolimus bioavailabilitywas 19% and 24.5% in adult and pediatric SBTRs,

respectively,13 which were similar to results fromliver and kidney transplant recipients.5-7 Tacro-limus has been used in SBTRs because of both itspotency and more predictable absorption com-pared with cyclosporine. Based on the absorptionof Neoral in our patient, this may be a suitablealternative for patients who are intolerant of tacro-limus.

Our data suggest that either tacrolimus or Neoralmay be suitable for the treatment of patients withSBS who require immunosuppression. There arelimitations to this single-patient report. The timeframe over which the pharmacokinetic studieswere performed was extended, and the patient’s

Figure 1. All Sandim-mune values are less thanthe assay quantitationlimits (25 ng/mL). CSA,cyclosporine A.

Table 1. Pharmacokinetics of Tacrolimus and Cyclosporine in SBS Healthy Volunteers and Transplant Recipients

Drug Dose (mg/kg) Dose (mg) Cmax (ng/mL)* Tmax (h)* AUC0.4 (h·ng/mL)*

Current caseSandimmune† 5 250 ,25 — —Neoral† 5 250 367 1 1993Prograf‡ 0.1 5 30 2.5 106

Reference valuesNeoral§ 10 180 1010 6 163 1.49 6 .41 3407 6 692Neoral\ 12 7.5 493 6 61 3 6 3.1 2846 6 498Prograf11 0.07 5 28.6 6 8.6 1.4 6 .62 271 6 122

*Values expressed as mean 6 standard deviation.†TDX whole blood assay (Abbott Diagnostics, North Chicago, IL).‡IMX whole-blood assay (Abbott Diagnostics, North Chicago, IL).§Healthy volunteers.\Liver transplant recipients with T-tube open.

Tacrolimus and Cyclosporine in SBS 433

condition did change during this period, althoughnot to the degree that would make the outcomedisputable. It should also be noted that resultscould change once a patient undergoes transplanta-tion, because the cirrhosis in this patient mayinfluence the elimination of these agents. A truerevaluation of bioavailability may have been per-formed by also using an intravenous formulation ofeach drug. However, it was believed to be unneces-sary to expose this patient to the toxicities of theseforms. Further studies comparing the absorption ofthese drugs in patients with SBS are warranted.

References

1. Kahan BD. Drug therapy: Cyclosporine. N Engl J Med1989;321:1725-1738.

2. Naoumov NV, Tredger JM, Steward CM, O’Grady JG,Grevel J, Niven A, et al. Cyclosporine A pharmacokinet-ics in liver transplant recipients in relation to biliaryT-tube clamping and liver dysfunction. Gut 1989;30:391-396.

3. Grevel J. Absorption of cyclosporine A after dosing.Transplant Proc 1986;18(suppl 5):9-15.

4. Grevel J. Optimisation of immunosuppressive therapyusing pharmacokinetic principles. Clin Pharmacokinet1992;23:380-390.

5. Hebert MF, Roberts JP. Focus on tacrolimus: A new

macrolide immunosuppressive agent for liver transplantrecipients. Hosp Formul 1994;29:447-453.

6. Jusko WJ, Thompson AW, Fung J, McMaster P, WongSH, Zylber-Katz E, et al. Consensus document: Thera-peutic monitoring of tacrolimus (FK-506). Ther DrugMonit 1995;17:606-614.

7. Peters DH, Fitton A, Plosker GL, Faulds D. Tacrolimus:A review of its pharmacology, and therapeutic potentialin hepatic and renal transplantation. Drugs 1993;46:746-794.

8. Baumgardner GL, Roberts JP. New immunosuppres-sive agents. Gastroenterol Clin North Am 1993;22:421-449.

9. Roberts R, Sketris IS, Abraham I, Givner ML, MacDon-ald AS. Cyclosporine absorption in two patients withshort-bowel syndrome. Drug Intell Clin Pharm 1988;22:570-572.

10. Kovarik JM, Mueller EA, vanBree JB, Tetzloff W, Katz K,et al. Reduced inter- and intraindividual variability incyclosporine pharmacokinetics from a microemulsionformulation. J Pharm Sci 1994;83:444-446.

11. Fujisawa USA, Inc. Prograf Product Information. Deer-field, IL. August, 1995.

12. Levy G, Rochon J, Freeman D, Wong PY, Banks L,Roach C, et al. Cyclosporine (Neoral) in liver transplantrecipients. Transplant Proc 1994;26:2949-2952.

13. Jain AB, Venkataramanan R, Lever J, Warty V, Aby-Elmayd K, Kurukawa H. FK 506 in small-bowel trans-plant recipients: Pharmacokinetics and dosing. Trans-plant Proc 1994;26:1609-1610.

Thielke et al434