Burckart, GJ

Esquivel, C

Iwatsuki, S

Ptachcinski, RJ

Starzl, TE

Van Thiel, DH

Venkataramanan, R

English

D-Scholarship@Pitt

Cyclosporine Trough Concentration Monitoring in Liver Transplant Patients G.J. Burckart, R.J. Ptachcinski, R. Venkataramanan, S. Iwatsuki, C. Esquivel, D.H. Van Thiel, and T.E. Starzl CYCLOSPORINE A (esA) monitoring of blood or plasma concentration measure-ments is recognized as an important part of the care of a transplant patient receiving the drug. The quantitation of CsA in biological fluids is essential for several reasons: (I) wide variability in the amount of CsA absorbed and the clearance rate of esA have been observed, particularly in orthotopic liver transplant (OLT) patients l ; (2) low CsA concentrations in blood or plasma secondary to poor drug absorption or rapid CsA elimination can be detected and adjusted; these situations are common in OL T patients due to diversion of bile through a T-tube and due to the occa-sional need for anticonvulsant administration; (3) high blood or plasma concentrations of CsA can be avoided through routine monitor-ing programs; these high levels may occur in OLT patients secondary to time-dependent increases in CsA absorption or to clamping of the T-tube; drugs that inhibit CsA metabo-lism such as erythromycin2 also can compli-cate therapy in OLT patients; (4) blood or plasma concentration monitoring aids adjust-ment of CsA dosage during the transition from intravenous (IV) to oral therapy and from a high initial oral dose to a lower long-term maintenance CsA dose; and (5) patient 'compliance with the medication regimen can From the Schools of Pharmacy and Medicine. Univer-sity of Pittsburgh. Pittsburgh. PA. Supported in part by Grant 5ROIAM34475. National Institute of Arthritis, Diabetes. Digestive, and Kidney Diseases. and by Sandoz Pharmaceuticals, East Han-over. NJ. Address reprint request to Dr G.J. Burckart, Univer-sity of Pittsburgh. Clinical Pharmacokinetics Labora-tory. 807 Salk Hall. Pittsburgh. PA 15261. c 1986 by Grune & Stratton, Inc. 004J-J 345/86/1806-5026S03.00/0 be followed by blood or plasma esA measure. ment. CsA can be measured in whole blood or in plasma and serum samples. Important ditTer. ences exist among the sample matrices and have been discussed previously.! The interpre. tation of assay results from the two analytical methodologies available, high-performance liquid chromatography (HPLC) and the: radioimmunoassay (RIA), is particularly crit. ical in OLT patients. This article therefore discusses the appropriate timing of a trough sample and outlines those factors that affect the RIA and HPLC results in OL T patients. SAMPLE TIMING The trough concentrations of CsA should be that time at which the blood or plasma concentration is lowest. A delay in the rise of CsA concentrations following oral ingestion occurs because of delayed gastric emptying, but concentrations in blood or plasma increase by I hour following an oral dose. In most institutions, trough levels are obtained for drug concentration determination within I hour prior to the drug dose. The dosing interval may determine how critical the timing of a trough CsA concentra-tion should be. With terminal elimination half-lives ranging from 10.7 hours in renal transplant patients4 to 20.4 hours in patient~ with hepatic cirrhosis,5 small differences in sample timing will have little effect on the trough concentration if CsA absorption and distribution are complete. Therefore, no clini-cally significant difference will occur in trough samples obtained I to 2 hours prior to a dose when the patient receives CsA as a once-daily dose. However, shorter dosing intervals of 8 or 12 hours may require more precise timing of trough esA samples. esA 188 Transplantation Proceedings, Vol XVIII, No 6. Suppl5 IDecember), 1986: pp 188-19' r I t , I I : I ~ • J (;SA TROUGH CONCENTRATION IN LIVER TX concentrations in blood or plasma may not peak until eight hours after an oral dose,s and the absorption and distribution processes are frequ('ntly prolonged for up to 12 hours. The change in CsA concentrations in blood or plasma during the interval of 6 to 12 hours following an oral dose is rapid in comparison wilh the slow elimination half-life of the drug. Altering the timing of the trough sample by I to 2 hours in a patient on an 8- to 12-hour CsA dosing schedule can result in significantly different blood or plasma concentrations. For example, Fig 1 presents the blood concentra-tions of CsA measured by RIA and HPLC following an oral dose in a transplant patient. The CsA blood concentrations measured by HPLC at eight hours (544 ng/mL) fall rap-idly to the 12-hour concentration (127 ng/ mL). The blood concentrations in this same patient measured by RIA decreased from 1,512 ng/mL to only 1,244 ng/mL, resulting in a significant change in the ratio of RIA:HPLC. Imprecise sampling of blood dur-ing the CsA absorptive and distributive phases of this patient could result in differing trough concentrations and their interpretation. Be-cause changes in gastrointestinal (G I) func-lion, dose administered, or concurrent drug therapy influence the absorptive pattern of CsA, precise trough sampling timing in patients on 8- or 12-hour dosing schedules should improve the reproducibility and clini-_ 1600 ~ 1400 r·~·" '" c - 1200 w z "-~ ii 1000 0 B;aoo 0 ...J 600 ~ /x"-.. x/"-.. u 0 400 0 ~x~-x-x 0 200 ...J m 0 2 4 6 8 10 12 14 16 18 TIME( hr) Fig 1. Blood cyclosporine concentrations vtime in a transplant patient following en orel drug dOle. Measure-mentl are by HPlC (x) and RIA (0). 189 cal utility of blood or plasma monitoring for CsA. Transplant patients on multiple daily doses of CsA should have their trough blood or plasma concentration sampled at the same time each day. CsA clearance rates have a diurnal variation with a more rapid clearance rate during the nighttime hours.6 Predose trough concentrations increased 38% and 72% when eveninglmples were collected in com-parison with morning samples in two OL T patients.' Individual patient and transplant center sample times should be standardized so that the center can develop its own consistent guidelines for acceptable desired CsA concen-trations. Differences in the sampling time and the CsA dosing interval used may account for the minor variations in the desired CsA range noted between transplant centers (see Table 1). Changing the CsA dosing interval without a change in total daily CsA dose can have a major effect on blood or plasma concentrations. In a small number of renal transplant patients who received the same daily CsA dose but had their dosing interval changed from every 24 to every 12 to every 8 hours, average steady-state CsA blood concentrations increased from 497 to 800 to 1,241 ng/mL, respectively.5 Dose-dependent changes in drug absorption or elimination must Table 1. Desired Trough Cyclosporine Concentrations From Major Transplant Cantarl Desired Cyclosporine Transplant Biological Concentrations Population Fluid Assay (ng/mL) Liver1 Whole blood HPlC 100-400 Renal" . Whole blood HPlC 100-200 Renal" Whole blood HPlC 150-300 Renal, first month 10 Plasma RIA <500 Renal, long-term 10 Plasma RIA <50-150 Renal" Serum RIA 100-400 Renal" Serum RIA 100-500 Renal" Serum RIA 150-300 Renal" Serum RIA 100-200 Bone marrow" Serum RIA 100-250 Heart" Plasma RIA 100-200 HeartH Serum RIA 200-500 liver'" Whole blood RIA 800-1000 190 be considered when interpreting trough CsA concentrations after a dose or dosing interval alteration. RIA:HPLC CONCENTRATIONS Concentrations obtained by RIA analysis are consistently higher than those obtained by HPLC due to the cross-reactivity of CsA metabolites with the antiserum used in the RIA kits. '9•2o The percentage of cross-reactiv-ity of some of the metabolites tested ranges from 4% to 32%. The RIA:HPLC ratio of CsA concentrations in blood, plasma, and serum is highly variable'9,21,22 and depends on the patient's liver function, the time of blood sampling in reference to the time of drug administration, the absolute CsA concentra-tion, and whether the patient is receiving other drugs that alter hepatic metabolizing enzyme function. Assay results from the RIA should be used with particular caution during periods of impaired hepatic function. In the first 2 weeks following liver transplantation, during liver rejection, or in the event of a technical failure (eg, hepatic artery thrombosis), the RIA:HPLC ratio is dramatically increased.23 Table 2 presents examples of the peak RIA: HPLC ratios observed early in the postopera-tive course of ten liver transplant patients. The ratio of trough concentrations measured by the two assays stabilized in the RIA:HPLC ratio of 1.7 to 4.2 if hepatic function was also improving. A similar observation has been ., - Tible 2. Ratio of RIA:HPLC Trough Blood Concentrations In Ten Liver Transplant Patients E.tyP .... Stable Patient Ratio Postoperative Dey Ratio PostOl*ltive dey 1 4.7 3 2.2 17 2 . 4.8 6 2.0 9 3 5.2 6 1.7 10 4 10.0 4 3.0 13 6 6.4 2 2.7 5 6 4.7 2 2.1 13 7 7.5 2 4.2 7 8 3.3 2 1.7 5 9 6.6 1 2.8 7 10 B.2 6 2.4 9 BURCKART ET Al made in two OLT patients by Blyden et al 24 who also report a positive correlation betwe~n the total serum bilirubin concentration and the RIA:HPLC ratio. In an earlier report,21 we also noted that significant increases in the RIA:HPLC ratio to greater than 10 in Ol T patients with rises in bilirubin were associated with rejection or a technical complication. Smaller increases in the RIA:HPLC ratio were occasionally associated with increases in liver enzymes without a change in bilirubin. Patients with severe liver disease have the ability to metabolize CsA as evidenced by their 0.8 to 4.8 mL/min/kg clearance rate~ but have a significant impairment in their ability to excrete CsA metabolites. CsA blood concentration v time data in a patient with liver disease as analyzed by RIA and HPLC are presented in Figure 2. The RIA:HPLC ratio changes over the dosing interval studied (from 1:1 to 1:4), and the pharmacokinetic parameters calculated are differentS depend-ing on the analytical procedure used. The time of the trough blood sampling for CsA can significantly affect the RIA:HPLC ratio. In Fig I, sampling eight hours after the oral CsA dose would have yielded an RIA:HPLC ratio of 2.8, but sampling at 12 hours following the dose would change the results and ratio to 9.8. This difference in the 2000 e Z 1000 Q I- 500 < 0: l-ffi~ 200 u! ZCl 0.5 100 u o o o ..J 1:0 \, ·00 ~ I. o 0 0 0 I 0 0 • I • • I o 7 14 21 26 35 42 49 56 TIME (HOURS) Fig 2. Blood concentrations of cycIoaporina v tima in e liver failure patient foRowing a single IV drug do ... M .. _ementa ara by HPlC 1., end RIA 101. i , I \ I , I I ! I csA TR' 160( 8 o ;, IZOC 4 i eoc 40( Fig HPLC i solid Ii RIA: expla conce resul' and comf subst cone: mOf( high the e grea~ mea' CsA F' RIA:' trat, tran Notf asse fme~ BURCKART ET AI. :ents by Blyden et al 2. :ve correlation betwe~n bin concentration and In an earlier report.2! ificant increases in the eater than lOin OL T lirubin were aSSOCiated :chnical complication. the RIA:HPLC ratio iated with increases in change in bilirubin. liver disease have the '::sA as evidenced b)' in/kg clearance rate' impairment in their ·etabolites. CsA blood Ita in a patient with 1 by RIA and HPLC , 2. The RIA:HPLC )sing interval studied the pharmacokinetic re different5 depend. ;edure used. h blood sampling for fect the RIA:HPLC eight hours after the have yielded an but sampling at 12 ! would change the 'his difference in the o o • • • " 35 42 49 56 'OURS) of cyc:losporine " time : a single IV drug dos •. ndRIAIO). t I I J (;SA TROUGH CONCENTRATION IN LIVER TX 8 ~::r 9 1200 til .g a: 800 , 800 1200 1600 2000 HPLC BLOOD Fig 3. Blood concentrations measured by RIA " HPLC in a single patient over one dosing interval. The lolid line represents a 1:1 HPLC:RIA ratio. RIA:HPLC ratio over a dosing interval is explained by two observations. First, higher concentrations of CsA measured by HPLC result in better agreement between the RIA and HPLC assays because the parent CsA compound then comprises the majority of substance measured by RIA. At lower CsA concentrations in blood or plasma, the RIA is more likely to overestimate CsA, resulting in a higher RIA:HPLC ratio (see Fig 3). Second, the elimination half-life measured by RIA is greater than the CsA elimination half-life measured by HPLC. Therefore, the fall in CsA concentration in blood or plasma during RIA ng/ml 4 HPLC 600 191 a dosing interval measured by RIA will not parallel the decline measured by HPLC. Other pharmacologic agents may affect the formation or elimination of CsA metabolites, thereby affecting the RIA:HPLC ratio. For example, previous reports2S•26 have shown that CsA concentrations measured by RIA increase when methylprednisolone is adminis-tered concurrently with CsA. Our own obser-vations in paC .lts receiving high-dose meth-ylprednisolone have not demonstrated any dif-ference in CsA clearance measured by HPLC when compared with a control period.27 When patient trough concentrations were monitored by RIA and HPLC, an increase in the RIA:HPLC ratio was observed coincident with the administration of pulse doses of methylprednisolone (Fig 4). Methylpredniso-lone affects the metabolism of CsA by enhancing the production of metabolites that react with the RIA but that have little effect on HPLC measurements. The effect of other drugs on the RIA:HPLC ratio is unknown but should be carefully monitored when pharma-cologic agents known to alter CsA blood or plasma concentrations are taken concurrently with CsA (see Table 3). The importance of alterations in the RIA:HPLC ratio will become clearer as the ng/ml 200 ~~!!!!!!!!!!!!!!!!!!!!!! Fig 4. The ratio of RIA:HPLC blood trough concen-tretion measuremants in a transplant patient over time. Note the increase in the ratio in association with Solu-Medrol Imethylprednisolone) dOling. SOLU- 1000 MEDROL mg/doy IV Cy A 250 1500 DOSE 500 P.O. ~------~~~----~ 2 4 6 8 10 12 14 16 18 20 22 24 26 28 DAY 192 BURCKART ET AI. Table 3. Drug Interactions With Cyclosporine That Alter Blood or Plasme Measurements Drug Mechanism Effect Observed Ketoconazole'·-30 Impairment of cyclosporine me-tabolism Increased blood concentrations of cyclospo-rine leading to nephrotoxicity Erythromycin" Impairment of cyclosporine me-tabolism Increased blood concentrations of cyclospo-rine Methylprednisolone (high-dose)"·2e Not known Increased plasma and blood concentrations of cyclosporine as measured by RIA; un-changed blood concentrations of cyclospo-rine as measured by HPLC; significance un-known Phenytoin32•n Induces cyclosporine metabolism Lowering of cyclosporine blood concentra-tions with associated rejection of trans-planted organs Rifampicin"'" Induces cyclosporine metabolism Lowering of cyclosporine blood concentra-tions with associated rejection of tr __ planted organs Phenobarbitone'" Induces cyclosporina metabolism lowering of cyclosporine blood concentra-tions with associated rejection of trans-planted organs Sulphadimidine-trimethoprim (lV)37 Not known immunologic and toxicologic elf ects of CsA metabolites are defined. At present, the metabolites of CsA are considered to have little pharmacologic activity.38 If this observa-tion is true, RIA trough CsA measurements could be misleading during periods of hepatic dysfunction or when other agents, such as methylprednisolone. alter the RIA:HPLC ratio. Trough CsA concentrations measured by RIA have been associated with both the nephrotoxicity of CsA IS and the tremors that the drug can induce.2" The RIA can provide useful trough CsA measurements on OL T patients who have stable hepatic function but should be used in conjunction with HPLC during -tne immediate postoperative weeks, '. during periods of changing hepatic function, and when other pharmacologic agents are administered that could alter the metabolism ofCsA. SUMMARY Trough blood or plasma concentration mea-surements of CsA must be carefully inter-preted in OLT patients in relation to hepatic function. sample timing, assay specificity, and concurrent drug therapy. The RIA:HPLC Decrease in serum cyclosporine levels; signifi-cance unknown ratio of blood or plasma measurements will vary with the patient's liver function, the time of blood sampling in reference to the time of drug administration, the absolute CsA con-centration, and concurrent use of drugs that may alter the metabolism of CsA. The RIA assay should be used in conjunction with HPLC for trough blood or plasma measure-ment during the first postoperative weeks, during periods of changing hepatic function, and during changing drug regimens. In the future, the specific measurement of active or toxic metabolites of CsA should improve trough CsA concentration monitoring in OL T patients. REFERENCES 1. Burckart GJ, Venkataramanan R, Ptachcinski Rl, et al: J Clin Pharmacol (in press) 2. Ptachcinski RJ, Carpenter BJ, Burckan GJ, et al: N Engl J Med 313:1416,1985 3. Pachcinski RJ, Burckart GJ, Venkataramanan R: J Clin Pharmacol 26:358, 1986 4. Ptachcinski RJ, Venkataramanan R, Rosenthal JT, et al: Clin Pharmacol Ther 38:296. 1985 5. Ptachcinski RJ, Venkataramanan R, Burckart GJ: Clin Pharmacokinet 11 :107, 1986 6. Venkataramanan R, Yang S, Burckart GJ, et al: Ther Drug Monit (in press) ASa CYCLe used disease (G roW trans; CsA schec. usually a j between . accepted ( high interi the drug J( 3 therapeL clinical USt side effect been desc and clinic ... ilh CsA byperlens side effect to the Cs-P as hepalo: altera tion. l· and urem ing CsA t The in I drugs COl Some dn.! leading Ie azole,14 I Ione,17 al decrease GVHD; cin,20 an Furtherrr I From th. 1 ratory. Rer Immuno-H is; and the Lollis HosJ Address Of)' and P Ctiller, 5, e 19861 0041-/; 194 

Cyclosporine through concentration monitoring in liver transplant patients

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Cyclosporine through concentration monitoring in liver transplant patients

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