Pharmacokinetics of FK 506 in Transplant Patients
`.
`.
`R. Venkataramanan, A. Jain, V.S. Warty, K. Abu-Eimagd, M. Alessiani, J. Lever, A. Krajak, J. Flowers,
`S. Mehta, S. Zuckerman, J. Fung, S. Todo, and T.E. Starzl
`
`F K 506 has been in clinical use at the University of
`
`Pittsburgh Medical center since March 1989. Cur(cid:173)
`rently, it is used as the primary immunosuppressant in
`liver, kidney, and heart transplant patients. Use of FK 506
`has resulted in a significant reduction in the dose of steroid
`used and is associated with a lower incidence of hyperten(cid:173)
`sion in transplant patients. At the present time there are
`nearly 1,600 patients receiving FK 506 therapy at this
`institution. Various pharmacokinetic aspects and factors
`affecting the pharmacokinetics of FK 506 in transplant
`patients will be discussed here.
`
`DOSAGE FORMS OF FK 506
`FK 506 is available for clinical use as an IV formulation.
`Since the aqueous solubility of FK 506 is less than 100
`ng/mL, the IV formulation contains a nonionic surfactant
`to solubilize FK 506 in aqueous medium. The IV formula(cid:173)
`tion must be diluted with 5% (jextrose or normal saline and
`administered as an infusion to patients. FK 506 in 5%
`dextrose for injection is most stable and completely avail(cid:173)
`able from poly olefin bags or glass containers. 1 FK 506
`solution in normal saline is also completely stable and
`available from poly olefin bags or plastic syringes.
`Initially, FK 506 was administered at a dose of·O.I5
`mg/kg/d, as an IV infusion over 2 to 4 hours, twice a day.
`To minimize the potential side effects related to high peak
`concentrations of FK 506 at the end of a 2- or 4-hour
`infusion, it is administered as a continuous infusion over 24
`hours at the present time. The current practice is to
`administer a dose of 0.1 mg/kg/d as a continuous infusion
`over 24 hours, until the patient is able to tolerate oral
`intake. Patients normally receive an oral dose of0.3 mg/kg
`(as a solid dispersion of FK 506 in hard gelatin capsule) and
`further dosing adjustments are made based on the clinical
`status of the patient, the functional status of the liver and
`kidney, and the trough plasma FK 506 concentrations.
`
`ANALYTICAL METHODS
`The therapeutic plasma concentration of FK 506 appears
`to be approximately 0.5 to 2 ng/mL. At such low concen(cid:173)
`trations, FK 506 cannot be measured by high pressure
`liquid chromatography (HPLC) with ultraviolet (UV) de(cid:173)
`tection. Attempts to derivatize FK 506 to increase the
`detection limits have not been very successful. FK 506
`blood and plasma concentrations are currently measured
`by enzyme-linked immunoassay (ELISA), 2 which involves
`minor modifications of the assay method published by
`Tamura et al.J While the ELISA assay is specific enough
`not to cross-react with several other drugs coadministered
`
`to transplant patients, it appears to cross-react with some
`of the metabolites of FK 506. The relative concentrations
`of these metabolites in blood or plasma and the extent of
`cross-reactivity of these metabolites with FK 506 mono(cid:173)
`clonal antibody have not been completely characterized.
`
`PHARMACOKINETIC STUDIES
`Pharmacokinetic studies have been carried out after short
`IV infusion (2 to 4 hours), continuous IV infusion, or oral
`administration of FK 506. Multiple blood samples were
`collected over a 12- or 24-hour dosing interval. Blood
`samples were incubated at 37°C for 30 minutes to 1 hour
`and centrifuged at 37°C. Plasma samples were immediately
`frozen at -?o•c, until analyzed for FK 506 by ELISA. In
`certain studies whole blood samples kept frozen at -70"C
`were also assayed by a modified procedure. 2 In three
`patients receiving twice a week FK 506 dosing, blood
`samples were collected for up to 72 hours after IV infusion
`ofFK 506.
`Following IV infusion, peak plasma concentrations are
`reached at the end of infusion. The drug concentration
`declines rapidly immediately after the end of infusion
`indicating rapid distribution of the drug outside the plasma
`compartment. Once distribution equilibrium is reached,
`FK 506 concentrations decline at a slower rate correspond(cid:173)
`ing to the disposition of the drug (Fig 1).4-6 The behavior of
`the drug can be adequately described by a two compart(cid:173)
`ment model in most of the patients. The half life of FK 506
`based on plasma concentrations ranges from 3.5 to 40.5
`hours, while the clearance ranges from 7 to 103 mUminlkg
`(Table 1). In three patients who were studied for 72 hours,
`the half lives were 22, 34, anq 36 hours. The volume of
`distribution at steady state ranges from 5.6 to 65 L/kg.
`These obserVations indicate a large interindividual vari(cid:173)
`ability in the pharmacokinetics of FK 506 in transplant
`patients.
`Following oral administration, the drug is absorbed very
`rapidly in certain patients with peak plasma concentrations
`being reached within 0.5 hours after oral dose, while in
`other patients the drug appears to be absorbed continu(cid:173)
`ously over a prolonged time period yielding essentially a
`flat oral absorption profile (Fig 2). 5 While the reasons for
`
`From the Schools of Pharmacy and Medicine, University of
`Pittsburgh, Pittsburgh, Pennsylvania.
`Address reprint requests to A. Venkataramanan, PhD, 718 Salk
`·
`Hall, University of Pittsburgh, Pittsburgh, PA 15261.
`·
`© 1991 by Appleton & Lange
`0041-1345191/$3.00/+0
`
`2736
`
`Transplantation Proceedings, Vol 23, No 6 (December), 1991: pp 2736-2740
`
`BRK-EVR-0059398
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`
`PHARMACOKINETICS OF FK 506
`
`2737
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`
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`
`10
`
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`14
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`
`Fig 1. Plasma concentration time curve after IV administration of
`0.15 mglkg of FK 506 to one patient.
`
`Fig 2. Plasma concentration time curve after oral administration
`of 0.3 mg/kg to three different patients.
`
`such an observation are not completely understood, poor
`dissolution of FK 506 in gastric fluids due to low aqueous
`solubility and alterations in gastric motility in transplant
`patients are likely to be partially responsible for this
`observation. The oral bioavailability of FK 506 ranges
`from 5% to 67%, with a mean value of approximately 27%.
`FK 506 appears to be absorbed well from the transplanted
`small bowel. Small bowel transplant patients require FK
`506 oral maintenance doses similar to that used in liver
`transplant patients in order to maintain adequate immuno(cid:173)
`suppression. Adequate absorption of FK 506 by the trans(cid:173)
`planted gut has made small bowel transplantation more
`feasible with the use of oral FK 506 treatment.
`In blood, FK 506 is primarily associated with red bloo·d
`cells (RBCs). Intracellular contents appear to be responsi(cid:173)
`ble for the extensive binding of FK 506 to RBCs (unpub(cid:173)
`lished observations). It is possible that RBCs may contain
`large amounts ofFK binding protein (FKBP). The blood to
`plasma ratio of FK 506 in normal subjects at a total FK 506
`concentration of 10 nglmL is 12. The trough blood to
`plasma concentration ratio of FK 506 in transplant patients
`ranges from 3.6 to 39 with a mean of 10. In plasma, FK 506
`is primarily associated with al acid glycoprotein (unpub(cid:173)
`lished observations). This is in contrast to cyclosporine
`(CyA), which is primarily associated with lipoproteins in
`plasma. 7 Outside the vascular system, FK 506 appears to
`be distributed in the heart, lung, spleen, kidney, and
`pancreas. 4 No FK 506 can be detected in the cerebrospinal
`
`Table 1. Phannacoklnetlcs of FK 506
`Parameters•
`
`Time to peak concentrations (ng/mL)
`Extent of absorption(%}
`Half life (h)
`Total body clearance (mUmin/g)
`Renal clearance (mUmin)
`Volume of distribution (Ukg)
`
`0.5-4 h
`5-67 (mean 27)
`3.5-40.5
`7-103 (mean about 30)
`<1
`5·65 Ukg
`
`*Based on plasma concentrations analyzed by sond phase axlractlon and
`ELISA.
`
`fluid of patients with neurotoxicity, suspected to be related
`to FK 506 therapy. The concentration of FK 506 in
`placental tissue is greater than that in plasma indicating the
`potential transfer of FK 506 to the fetus (unpublished
`observations).
`FK 506 is primarily eliminated by metabolism.4
`•6 Most
`of the metabolites are excreted in the bile. We have
`isolated several metabolites of FK 506 from bile samples
`obtained from rats and humans. FK 506 metabolites have
`also been generated by incubation of FK 506 with rat liver
`microsomes (unpublished observations). FK 506 appears
`to undergo monodemethylation, didemethylation, hydrox(cid:173)
`ylation, and a combination of monodemethylation and
`hydroxylation. These metabolites are similar to the FK 506
`metabolites isolated from human small bowel and liver
`microsomes. 8 In addition, there is preliminary evidence to
`suggest the -presence of conjugates of FK 506 and its
`metabolites in human bile. However, less than 5% of the
`dose is excreted in the bile as FK 506 or its conjugates.
`Less than 1% of the IV dose is excreted in the urine as
`unchanged FK 506. Small amounts of FK 506 conjugates
`are also excreted in the urine.
`
`FACTORS AFFECTING FK 506
`PLASMA CONCENTRATIONS
`Several factors contribute to the observed inter and intra(cid:173)
`individual variability in FK 506 plasma concentrations in
`transplant patients. These include factors that alter the
`absorption, distribution, and elimination of FK 506.
`Studies in dogs indicate that the absorption of FK 506 is
`significantly increased in experimentally induced cholesta(cid:173)
`sis, presumably due to decreased presystemic metabo(cid:173)
`Iism.9 In addition, biliary diversion or addition of exoge(cid:173)
`nous bile salts in the presence or absence of endogenous
`bile did not significantly alter the extent of FK 506 absorp(cid:173)
`tion.9 These observations indicate that in contrast to CyA,
`the absorption of FK 506 is less dependent on the avail(cid:173)
`ability of bile. From a practical point of view, there is no
`need to decrease the dose of FK 506 when the t-tube is
`
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`

`
`2738
`
`5
`
`c
`
`o
`
`"
`
`c
`
`0 !1,~" c
`0 ° 0
`0 g Cb Efl 0~ c ~ c 8
`oc 0 Jl~A~"?'" Jlc
`"
`"
`" o 0 oBo
`0
`0~----.-----.-----r-----.---~~---,
`0.0
`0.1
`0.2
`0.3
`0.4
`0.5
`0.6
`FK 506 Dose (mg/kg)
`
`c
`
`0
`
`VENKATARAMANAN, JAIN, WARTY ET AL
`
`cantly increased in transplant patients when compared
`with normal subjects. 12
`FK 506 is primarily eliminated by metabolism. Several
`factors known to alter drug metabolism also alter the
`elimination ofFK 506. Following IV administration of0.15
`mg/kg/d, 24-hour trough plasma FK 506 concentrations are
`normally higher in patients with liver dysfunction when
`compared with patients with normal liver function. 10•13
`Correspondingly, patients with liver dysfunction tend to
`have.]onger half-lives and smaller clearance values. 10 With
`an improvement in liver function the half-life decreases to
`normal values. Cold ischemia and reperfusion injury to the
`liver may also alter the clearance of FK 506. Impairment in
`the elimination of FK 506 due to ischemic damage of the
`liver is expected to resolve with time.
`Increase in FK 506 concentrations is also seen when FK
`506 is coadministered with clotrimazole, ketoCOJlazole,
`erythromycin, fluconazole, diltiazam, and cimetidine in
`rats. Erythromycin, fluconazole, methylprednisolone, and
`clotrimazole-mediated increases in FK 506 concentration
`have also been observed in transplant patients. In patients
`who simultaneously receive hepatic drug metabolizing
`enzyme inducers or inhibitors, FK 506 should be used with
`caution. Another drug interaction that is of some impor(cid:173)
`tance is the interaction between FK 506 and cyclosporine
`(CyA). Combined use of these two agents results in
`synergistic immunosuppression 14 and increased nephro(cid:173)
`toxicity.15 FK 506 inhibits CyA metabolism in vitro. 16
`However, in liver transplant patients, short-term treatment
`with FK 506 does not appear to alter CyA clearance. 17
`Studies in dogs indicate that while FK 506 does not alter
`CyA clearance, it may increase FK 506 oral bioavailabil(cid:173)
`ity, presumably due to inhibition of presystemic metabo-
`
`Fig 3. Relationship between dose (mg/kg/d) and steady state
`plasma concentration (ng/mL) of FK 506 as measured by ELISA in
`clinically stable liver and kidney transplant patients.
`
`clamped in liver transplant patients.s· 10 Preliminary stud(cid:173)
`ies indicate that food does not alter the extent of absorp(cid:173)
`tion of FK 506 in liver transplant patients. In vitro studies
`indicate a significant loss of FK 506 from simulated gastric
`fluid in the presence of magnesium oxide and aluminum
`hydroxide gel. Until further in vivo data become available
`it is prudent to dose FK 506 and antacids separately. 1 1 The
`distribution of FK 506 within blood is influenced by
`hematocrit, FK 506 concentrations, temperature of the
`blood sample, and the concentration of plasma proteins.
`Changes in one or more of these factors may contribute to
`the variability in the relative distribution of FK 506 in
`blood from transplant patients. It is well known ·that
`hematocrit increases with time after renal transplantation
`and that al acid glycoprotein concentrations are signifi-
`
`Condition
`
`Table 2. Comparison of Kinetics of FK 506 and CyA
`· FK 506
`
`CyA
`
`Absorption
`Rate
`Extent
`Bile
`Small bowel
`Transplant
`Distribution
`Blood: plasma
`Depends on
`
`Major binding protein in plasma
`Metabolism
`Metabolism
`Pathways
`
`Excretion
`Parent drug
`Metabolites
`Activity
`Parent drug
`Metabolites
`
`Variable
`5%·67%
`Less essential
`Good absorption
`
`Variable
`<5-89%
`Very essential
`Poor absorption
`
`>12; 4-39
`Hematocrit, temperature, drug concentration,
`plasma protein concentration
`a1 acid glycoprotein
`
`About 2
`Hematocrit, temperature, drug concentra·
`tion, plasma protein concentration
`Upoproteirr
`
`>98"k
`Hydroxylation, demethylation, conjugation
`
`>98%
`Hydroxylation, demethylation, conjugation
`
`<2% in urine
`Primarily in bile
`
`Most active
`A lot less active
`
`<2% in urine
`Primarily in bile
`
`Most active
`Less active
`
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`
`PHARMACOKINETICS OF FK 506
`
`Condition
`Switch from IV to oral therapy
`T-tube clamping
`Pediatric patients
`
`Liver dysfunction
`Renal dysfunction
`
`Dialysis
`Inhibitors of hepatic metE!bolism
`Inducers of hepatic metabolism
`
`2739
`
`Table 3. Dosing Recommendation fpr FK 506
`FK 506
`Threefold Increase in dose
`No cl'tange in dose
`About two times higher dose compared
`with adults
`Decrease IV dose; decrease oral dose
`Does not affect l<inetics
`Decrease dose to decrease levels if renal
`dysfunction Is related to the drug
`Not removed by dialysis
`Decrease dose
`Monitor drug level; increase dose
`
`CyA
`Threefold Increase in dose
`Decrease dose
`About two to three times higher dose com-
`pared with adults
`DecreaSe IV dose; increase oral dose
`Does not affect kinetics
`Deerease dose to decrease levels If renal dys-
`function is related to the drug
`Not removed by dialysis
`Decrease dose
`Monitor drug level; may need to increase dose
`
`lism. 18 This interaction is similar. to the reported interac(cid:173)
`in patients. 19
`tion between CyA and erythromycin
`Pediatric patients in general tolerate FK 506 better th~
`adults. This may be related to the higher clearance of FK
`506 from pediatric patients wheri compared with adult
`transplant patients (unpublished observations). Pediatric
`and adult patients appear to absorb FK 506 similarly. On
`an average, pediatric patients require nearly twice die FK
`506 dosage (mg/kg) given to adults in order to maintain
`similar therapeutic plasma co!1centrations. 20
`FK 506 is not dialyzable. This may be related to the
`extensive binding ofFK 506 to blood proteins and the large
`volume of distribution of this drug. Dialysis will be of
`limited use in FK 506 overdosing.
`
`THERAPEUTIC MONITORING
`FK 506 doses of 2 to 24 mg/d are required in order to
`maintain therapeutic plasma trough concentrations in the
`range of0.5 to 2 ng/mL in clinically stable liver and kidney
`transplant patients (Fig 3). This indicates that even in
`patients with normally functioning liver and kidney, there
`is wide variability in the kinetics ofFK 506. In addition, it
`has been shown that nephrotoxicity is the principal side
`effect of FK 506. It is therefore essentiat to monitor the
`blood or plasma concentration of FK 506 in patients to
`minimize incidence of the rejection and toxiCity. In adopt(cid:173)
`ing an analytical procedure for routine therapeutic mimi(cid:173)
`tonng, one should consider. the specificity' sensitivity'
`rapid turt)around time, and the precision of the method
`used. While immunologic monitoring is the ideal method
`for optimal immunosuppression, current status of this
`technology does not permit routine use of this procedure.
`Bioassay. as proposed recently is im attractive tool but its
`routine use is limited by the long time necessary for
`coniiucting this assay. 21 Studies are also currently under(cid:173)
`way to determine the right choic~ of biologic matrix (blood
`or plasma) that should be used for Fk 506 monitoring,
`based on ihe relationship between blood or plasma con(cid:173)
`centrations and toxicity or rejection episodes.
`
`DOSING REGIMEN DESIGN FOR FK 506
`Studies in renal transplant patients indicate that at a
`plasma FK 506 concentration of 0.8 ng/IilL or greater,
`more than 90% of the lymphocytes are inhibited iil an in
`vitro test system. 22 Censidering 0.8 ng/mL to be the
`desired steady state concentration, one can calculate the
`average and maximum infusion rate requirect based on
`average and maximum plasma clearanc~ of FK 506 . in
`tn!JlSplant patients. The average and maximum infusion
`rate required will be 0.04 and 0.093 mg/kg/d, respectively.
`The maximum infusion rate derived from this formu!a is
`close to the current infusion regimen (0.1 mg/kg/d) used at
`our institution. Based on an oral bioavailability of 27%, the
`mean and maximal oral dose required should be 0.15 and
`0.35 mglkgld, respectively. Further adjustment in closing
`regimen should be made based on liver function, kidney
`fu.nction, use of other immunosuppressants, and other
`drugs known to interact with FK 506. Table 2 summarizes
`the dosing recommendation for FK 506 as compared with
`.
`CyA.
`In summary, F~ 506 is similar to CyA in terms of tHe
`extent of absorption and metabolism (,fable 3) .. Howev.er,
`they differ in the requirement of bile for absorption aild in
`their distribution within blood. Liver disease also appears
`to alter FK 506 kinetics differently as compared with Cy A.
`Improved understanding of the pharmacokinetics, phar(cid:173)
`macodynamics, and various factors affecting i:he phamia(cid:173)
`cokinetics and pharmacodynamics of FK 506 using spe(cid:173)
`cific assay methods will help us to optimize therapy with
`this novel and potent immunosuppressant
`ACKNOWLEDGMENTS
`The authors gratefully acknowledge the contributions of the staff
`of the University of Pittsburgh Medical Center Pharmacy FK S06
`production laboratory, FK 506 analysis Laooratory, and the
`Clinical Pharmacokinetics Laboratory.
`REFERENCES
`1. Taormina D. Abdall$ HY, Venkataramanan R, et al: Am J
`Hasp Pharm (in press)
`2. Warty VS, Venkataramanari R, Zendehrough P, et al: Clin
`Chern (in press)
`
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`
`2740
`
`3. Tamura K, Kobayashi M, Hashimato K, et al: Transplant
`Proc 19:23, 1987
`4. Venkataramanan R, Warty VS, Zemaitis MA, et al: Trans-·
`plant Proc 19:30, 1987 (suppl 6)
`5. Venkataramanan R, Jain A, Warty VS, et al: Transplant
`Proc 23:931, 1991
`6. Venkataramanan R, Jain AB, Cadoff E, et al: Transplant
`Proc 22:52, 1990 (suppl 1)
`7. Warty VS, Venkataramanan R, Zendehrouh P, et al: Trans(cid:173)
`plant Proc 23:954, 1991
`8. Christians U, Kruse C, Kownatzki R, et al: Transplant Proc
`23:940, 1991
`9. Furukawa H, Imventarza 0, Venkataramanan R, et al:
`Transplantation (in press)
`10. Jain AB, Venkataramanan ·R, Cadoff E, et al: Transplant
`Proc 22:55, 1990 (suppl I)
`11. Steeves M, Abdallah HY, Venkataramanan R, et al: J
`Pharm Pharmacol43:547, 1991
`12. Huang M-L, Venkataramanan R, Burckart GJ, et al: J Clin
`Pharmacal 28:505, 1988
`
`VENKATARAMANAN, JAIN, WARTY ET AL
`
`13. Abu-Elmagd K, Fung JJ, Alessiani M, et al: Transplanta(cid:173)
`tion (in press)
`14. Zeevi A, Duquesnoy R, Eiras G, et al: Transplant Proc
`19:40, 1987
`15 .. McCauley J, Takaya S, Fung JJ, et al: Transplant Proc
`23:1444, 1991
`16. Omar G, Shah A, Thompson AW, et al: Transplant Proc
`23:934, 1991
`17. Jain AB, Venkataramanan R, Fung J, et al: Transplant Proc
`23:(thls issue), 1991
`18. Wu YM, Venkataramanan R, Suzuki M, et al: Transplant
`Proc 23:(this issue), 1991
`19. Gupta SK, Bakran A, Johnson RWG, et al: Br J Clin
`Pharmacol27:475, 1989
`20. Jain A, Fung J, Tzakis A, et al: Transplant Proc (in press)
`21. Zeevi A, Venkataramanan R, Eiras G, et al: Transplant
`Proc 23:(this issue), 1991
`22. Karlix J, Burckart G, Ptachcinski RJ, et al: J Clin Pharma(cid:173)
`col (submitted for publication)
`
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