PHARMACOK INETICS -THERA PEUTICS
Clin. Pharmacokinet. 23 (5): 380-390, 1992 0312-5963/92/00 I 0-0380/$05.50/0 © Adis International Limited. All rights reserved. CPK1227
Optimisation of Immunosuppressive Therapy Using Pharmacokinetic Principles Joachim Grevel Division of Clinical Pharmacology, Department of Pharmacology, The University of Texas Medical School, Houston, Texas, USA
Contents 380 38 J 381 38 J 382 383 384 384 384 384 385 387 387
Summary
Summary I. Corticosteroids 2. Cyclosporin 2.1 Analytical Methods 2.2 Pharmacokinetic Parameters of Cyclosporin 2.3 Significance of Cyclosporin Binding 2.4 Significance of Cyclosporin in Lymph 2.5 Significance of Cyclosporin Metabolites 2.6 Pharmacodynamic Monitoring 2.7 Trough Concentration Monitoring 2.8 Pharmacokinetic (Area Under the Curve) Monitoring 3. New Immunosuppressive Agents 4. Therapeutic Implications
Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-A-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.
Optimisation of Immunosuppression
Therapeutic immunosuppression plays a critical role in the prevention of graft rejection after solid organ transplantation and of graft-versus-host disease after bone marrow transplantation. Furthermore, selective immunosuppressive agents are now being used in autoimmune diseases such as psoriasis. The first drugs known to affect the immune system were antineoplastic agents, but their use as immunosuppressants has rapidly declined after the arrival of more specific agents. Optimal dosage strategies of oncolytic drugs have recently been reviewed (Moore & Erlichman 1987). Azathioprine is the only antimetabolite drug which is still widely used in immunosuppression, but its dosage is not problematic due to a wide therapeutic range and low pharmacokinetic variability. Also, the dosage of polyclonal antibodies (muromonab-CD3, OKT3) does not require individualisation and is, therefore, not covered in the present review, which instead focuses on the optimal use of corticosteroids and cyclosporin, also mentioning some of the newer agents presently in development.
1. Corticosteroids The glucocorticoids most frequently used in immunosuppression are prednisolone and methylprednisolone. Other corticosteroids which are used for their anti-inflammatory properties are not discussed here. Prednisone and methyl prednisone are prodrugs which are reversibly metabolised to prednisolone and methylprednisolone, the biologically active moieties. It is generally accepted that corticosteroids not bound to plasma proteins diffuse through the cell membrane to bind to their intracellular receptor and exert their effects (Jusko 1990). After therapeutic doses, corticosteroids do not cause acute toxicity, but their long term use is associated with the risk of Cushingoid disorders, osteoporosis and muscle wasting. These sequelae are evidently not closely related to the dosage of prednisone and/ or methylprednisolone. Consequently no range of therapeutic blood concentrations has yet been established (Jusko & Ludwig 1991). Still, long term toxicity of prednisone seems to have some pharmacokinetic contribution insomuch as renal trans-
381
plant patients with a low clearance of prednisolone were more likely to suffer from steroid diabetes, osteoporosis and viral infections as well as graft rejection (Ost et al. 1984). The clearance of prednisolone can be approximated by a complete pharmacokinetic profile at steady-state or by a timed blood sample at 6h postdose (Hill et al. 1990). Such clearance could be adequate for therapeutic monitoring, but it remains an apparent parameter, even when calculated by the area method, because of the reversible metabolism between prednisolone and prednisone. While methylprednisolone clearance is independent of the dose (Szefler et al. 1986), prednisolone clearance exhibits nonlinearity due to nonlinear binding to transcortin in plasma (Jusko & Ludwig 1991). Despite the fact that prednisolone binding to albumin is not saturable, a low albumin concentration was related to an increased incidence of prednisolonerelated side effects (Jusko & Ludwig 1991). Young children have a greater clearance of prednisolone normalised to bodyweight than adults. This inverse relationship with age does not exist with methylprednisolone (Hill et al. 1990). Obesity influences prednisolone but not methylprednisolone clearance; consequently, the dosage of prednisolone and methylprednisolone should be based on total and ideal bodyweight, respectively. Metabolism of prednisone and methylprednisolone is induced by phenobarbital, phenytoin and rifampicin. The metabolism of methylprednisolone but not prednisone is inhibited by erythromycin and ketoconazole. Cyclosporin and cimetidine do not influence the pharmacokinetics of either prednisone or methylprednisolone. Neither hepatic nor renal impairment change their clearance to a degree requiring adjustment of oral dosage (Jusko & Ludwig 1991).
2. Cyc/osporin 2.1 Analytical Methods Ever since the first clinical trials of cyclosporin a number of analytical techniques to measure concentrations in whole blood or plasma/serum were developed simultaneously (for recent reviews see
Clin. Pharmacokinet. 23 (5) 1992
382
Kivisto 1992 and Rodighiero 1989). Presently 4 distinct assay types can be differentiated according to their specificity for the unchanged cyclosporin molecule. High pressure liquid chromatographic methods are the only ones truly specific for the parent compound cyclosporin. Immunoassays using either a radiolabelled or an enzyme-labelled tracer and a so-called 'specific monoclonal antibody' (Sandoz Ltd, Switzerland) detect unmetabolised cyclosporin and some metabolites to the extent that measurements are generally 10% higher than by liquid chromatography. Immunoassays based on polyclonal antibodies are less specific and detect large portions of the major human cyclosporin metabolite (AM 1). The least specific of the commercially available assays use a 'nonspecific monoclonal antibody' (Sandoz) which regularly measures more of the metabolites than any other assay. The clinical utility of the different assays has recently been discussed (Kahan et al. 1990). 2.2 Pharmacokinetic Parameters of Cyclosporin The clinical pharmacokinetics of cyclosporin have been reviewed several times over the past years (McMillan 1989; Ptachcinski et al. 1986; Ro-
dighiero 1989). The present review makes no attempt to completely list the average pharmacokinetic parameters from the many studies in small (n < 10) groups of patients or volunteers, but rather draws attention to 2 recent reports which, because of the magnitude of data, can be classified as describing population pharmacokinetic data on cyclosporin (table I). Specifically, the analysis of Mallet et al. (1988) succeeds in presenting a realistic picture of the variability of cyclosporin pharmacokinetics in transplant patients. The key questions for the optimisation of immunosuppressive therapy by cyclosporin are: (a) what are the sources of the pharmacokinetic variability; (b) to which degree can changes in cyclosporin pharmacokinetics be anticipated; and (c) can certain sources of variability be eliminated? A list of identified causes of pharmacokinetic variability is provided in table II. The following factors have predictable effects on clearance and/ or bioavailability, albeit not precisely quantified: small bowel length in children after liver transplantation, availability of bile in the small intestine after liver transplantation, young age of patient, interaction with other drugs which induce or inhibit the metabolising enzymes, and the time after transplantation. The only source of variability
Table I. Population pharmacokinetic parameters of cyclosporin during the first week after transplantation
Parameter
Symbol (unit)
Assay
Clearance
CL (L/h) CL/F (ml/min' kg) Vc (L)
PLtpR/Nsa
Volume of distribution
Vz (L) Vz/F (L) Terminal half-life
tv",(h)
tv", (h)
WB/HP/Spb
Mean ± SO
5th-95th percentile
Reference
24
4-78
Mallet et al. (1988)
24.2 ± 15.3
PL/PR/Nsa PL/PR/Nsa WB/HP/Spb PLtpR/Nsa WB/HP/Spb
Median
Awni et al. (1989) 18
2-65
Mallet et al. (1988)
94
13-285
4.3
1.9-13.9
Mallet et al. (1988) Awni et al. (1989) Mallet at al. (1988) Awni et al. (1989)
27.2 ± 18.4 15.1 ± 9.6
a Nonspecific polyclonal radioimmunoassay in plasma. The median is based on 188 patients with bone marrow transplants. b Specific high pressure liquid chromatography in whole blood. The mean is based on 21 patients with renal transplants. Abbreviations: CL = clearance; F = bioavailability; Vc = volume of central compartment; Vz = apparent volume of distribution during terminal phase; tv", = terminal half-life.
Optimisation of Immunosuppression
383
Table II. Sources of pharmacokinetic variability of cyclosporin
Source
Pharmacokinetic parameter affected
Clinical consequence
References
Small bowel length in children after liver transplantation (absorption window) Availability of bile in the small intestine
CL/F
The longer the small bowel the smaller the oral dosage
Whitington et al. (1990) Grevel (1986)
F
Naoumov et al. (1989)
Meal of high fat content
CL, F
Oral dosage in the morning or evening
CL/F
Intestinal metabolism
F
Young age
CL
Body size in adult patients
CL
Liver function
CL
Drug interactions Time after transplantation
CL, F CL/F
Oral dosage can only start after liver transplantation when biliary drainage through the T-tube has stopped Both bioavailability and clearance increase. The oral clearance and the required oral dosage are unlikely to change During twice daily administration, the area is larger when the dose is given in the evening. Circadian variations play no role during once-daily administration The low bioavailability of cyclosporin seems to be caused by both incomplete absorption and intestinal metabolism The younger the children, the higher the clearance when normalised for bodyweight In adult patients, body size in general and obesity in particular do not determine the oral dosage With poor liver function the dosage requirements of cyclosporin decrease Refer to recent review As the oral clearance decreases, the oral dosage can be reduced
Gupta et al. (1990)
Canafax et al. (1988)
Tredger et al. (1991)
Burckart et al. (1984) Flechner et al. (1989) Grevel et al. (1989a) Grevel et al. (1989a) Yee & McGuire (1990) Awni et al. (1989)
Abbreviations: CL = clearance; F = bioavailability; CL/F = oral clearance.
which can potentially be eliminated is the interaction with other drugs. It is generally accepted that the only effective way to protect the patient from the potential risks caused by the pharmacokinetic variability of cyc\osporin is a tight schedule oftherapeutic drug concentration monitoring and dosage adjustments. 2.3 Significance of Cyc\osporin Binding Cyc\osporin as a very lipophilic compound is highly bound to lipoproteins in plasma (Gurecki et al. 1985). This binding is characterised by a low affinity and high capacity (Sgoutas et al. 1986). The apparent free and unbound fraction is dependent upon the methods of measurement. With ultracen-
trifugation, a free fraction in plasma of 4 to 12% was reported (Legg & Rowland 1987). A much lower fraction of 0.5 to 4.2% (Lindholm & Henricsson 1989) was determined with equilibrium dialysis. It is unlikely that only free cyc\osporin is pharmacologically active and susceptible to drug metabolism (Grevel 1988). Indeed, treatment failure manifested as graft rejection in renal transplant patients was more likely in patients with a high free fraction (Lindholm & Henricsson 1989) or those with a low concentration oflow density lipoprotein (Kasiske et al. 1988). Moreover, in vitro it was shown that the addition of low density lipoprotein augmented the inhibitory potency of cyc\osporin in a lymphocyte proliferation assay (Rodl & Khoshsorur 1990). The most logical explanation seems to
384
be that cyclosporin like other lipophilic compounds in plasma (e.g. cholesterol) is transported to its site of action by lipoproteins and that cyclosporin enters the cell via lipoprotein receptors. Once in the cell the specific high affinity binding to cyclophilin (Handschumacher et al. 1984) dominates its mechanism of action. Toxic effects of cyclosporin, however, seem to be blunted by a high blood lipid content (Nemunaitis et al. 1986). 2.4 Significance of Cyclosporin in Lymph The original assumption that cyclosporin should express its immunosuppressive effects in the lymphatic circulation was based on 2 observations: (a) lymph contains the highest concentration of circulating T-lymphocytes; and (b) cyclosporin reaches higher concentrations in lymph than in plasma (Albrechtsen et al. 19.85). This hypothesis, however, began to shake when it was shown that oral and intravenous doses of cyclosporin are equally efficacious despite the fact that cyclosporin concentrations in lymph are 10 times higher than in plasma only after oral but not after intravenous administration. These experiments were first performed in rats (Albrechtsen et al. 1985) and later confirmed in renal transplant patients (Ono et al. 1988). 2.5 Significance of Cyclosporin Metabolites Cyclosporin is eliminated predominantly by metabolism in the liver. Numerous unconjugated metabolites are circulating in blood and distributing into tissue compartments. They, as well as parent cyclosporin, are excreted mainly in bile. A fairly complete listing and updated nomenclature has recently been published (Kahan et al. 1990). There is not a single metabolite whose therapeutic or toxic effects would warrant its specific monitoring (e.g. by liquid chromatography) after therapeutic doses of cyclosporin (ibid). More for the purpose of standardisation than based on experimental evidence, a specific assay of cyclosporin in whole blood was recommended by a panel of experts (Shaw et al. 1987). At the same time it was
Clin. Pharmacokinet. 23 (5) 1992
shown, however, both in patients with bone marrow (Yee et al. 1986) and renal transplants (Kunzendorf et al. 1989) that nonspecific assays differentiate between rejectors and nonrejectors while the specific liquid chromatographic methods detect no difference. 2.6 Pharmacodynamic Monitoring When standard dosage rates of cyclosporin in transplant patients led to variable outcomes, the search started for parameters which could predict the success of immunosuppressive therapy. Based on the results of in vitro experiments of cyclosporin inhibiting the activation of T-lymphocytes, serum samples of renal transplant patients were tested for the ability to suppress a mixed lymphocyte reaction (Rogers et al. 1984). Despite the identification of 4 distinct patterns of immunosuppression during a steady-state dosage interval of 24h, and despite a correlation between these patterns and clinical outcome, such pharmacodynamic monitoring could not prospectively support clinical decisions, since the required incubation took 6 days. Also other immunological assays are far too timeconsuming to satisfy the informational need of a physician pressed for a therapeutic decision (for reviews see Awni 1992 and Kahan 1985). 2.7 Trough Concentration Monitoring Concentrations of cyclosporin in blood can be readily obtained and they have been generally accepted as a means to verify patient compliance. Moreover, cyclosporin concentrations at steadystate measured just before a new dose is given ('trough concentration') correlated with the rate of rejection, toxicity and infection in renal transplant patients (Irschik et al. 1984) and with the rate of graft-versus-host disease in patients with bone marrow transplants (Yee et al. 1988). Thus, trough concentrations have proven to be useful intermediate end-points. Out of a concern that trough concentrations could not correctly represent the overall exposure of a patient to cyclosporin, it was proposed instead to measure peak concentrations
Optimisation of Immunosuppression
385
Table III. Pharmacokinetic strategy for cyclosporin dosage adjustment. The strategy is suitable for all transplantations except for liver and intestine. It has been extensively evaluated in adult and paediatric recipients of renal transplants
Pharmacokinetic calculations
Time
Dosage
Blood samples
Pretransplant
IV cyclosporin 200mg for adults or 5 mg/kg for
Clin. Pharmacokinet. 23 (5): 380-390, 1992 0312-5963/92/00 I 0-0380/$05.50/0 © Adis International Limited. All rights reserved. CPK1227
Optimisation of Immunosuppressive Therapy Using Pharmacokinetic Principles Joachim Grevel Division of Clinical Pharmacology, Department of Pharmacology, The University of Texas Medical School, Houston, Texas, USA
Contents 380 38 J 381 38 J 382 383 384 384 384 384 385 387 387
Summary
Summary I. Corticosteroids 2. Cyclosporin 2.1 Analytical Methods 2.2 Pharmacokinetic Parameters of Cyclosporin 2.3 Significance of Cyclosporin Binding 2.4 Significance of Cyclosporin in Lymph 2.5 Significance of Cyclosporin Metabolites 2.6 Pharmacodynamic Monitoring 2.7 Trough Concentration Monitoring 2.8 Pharmacokinetic (Area Under the Curve) Monitoring 3. New Immunosuppressive Agents 4. Therapeutic Implications
Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-A-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.
Optimisation of Immunosuppression
Therapeutic immunosuppression plays a critical role in the prevention of graft rejection after solid organ transplantation and of graft-versus-host disease after bone marrow transplantation. Furthermore, selective immunosuppressive agents are now being used in autoimmune diseases such as psoriasis. The first drugs known to affect the immune system were antineoplastic agents, but their use as immunosuppressants has rapidly declined after the arrival of more specific agents. Optimal dosage strategies of oncolytic drugs have recently been reviewed (Moore & Erlichman 1987). Azathioprine is the only antimetabolite drug which is still widely used in immunosuppression, but its dosage is not problematic due to a wide therapeutic range and low pharmacokinetic variability. Also, the dosage of polyclonal antibodies (muromonab-CD3, OKT3) does not require individualisation and is, therefore, not covered in the present review, which instead focuses on the optimal use of corticosteroids and cyclosporin, also mentioning some of the newer agents presently in development.
1. Corticosteroids The glucocorticoids most frequently used in immunosuppression are prednisolone and methylprednisolone. Other corticosteroids which are used for their anti-inflammatory properties are not discussed here. Prednisone and methyl prednisone are prodrugs which are reversibly metabolised to prednisolone and methylprednisolone, the biologically active moieties. It is generally accepted that corticosteroids not bound to plasma proteins diffuse through the cell membrane to bind to their intracellular receptor and exert their effects (Jusko 1990). After therapeutic doses, corticosteroids do not cause acute toxicity, but their long term use is associated with the risk of Cushingoid disorders, osteoporosis and muscle wasting. These sequelae are evidently not closely related to the dosage of prednisone and/ or methylprednisolone. Consequently no range of therapeutic blood concentrations has yet been established (Jusko & Ludwig 1991). Still, long term toxicity of prednisone seems to have some pharmacokinetic contribution insomuch as renal trans-
381
plant patients with a low clearance of prednisolone were more likely to suffer from steroid diabetes, osteoporosis and viral infections as well as graft rejection (Ost et al. 1984). The clearance of prednisolone can be approximated by a complete pharmacokinetic profile at steady-state or by a timed blood sample at 6h postdose (Hill et al. 1990). Such clearance could be adequate for therapeutic monitoring, but it remains an apparent parameter, even when calculated by the area method, because of the reversible metabolism between prednisolone and prednisone. While methylprednisolone clearance is independent of the dose (Szefler et al. 1986), prednisolone clearance exhibits nonlinearity due to nonlinear binding to transcortin in plasma (Jusko & Ludwig 1991). Despite the fact that prednisolone binding to albumin is not saturable, a low albumin concentration was related to an increased incidence of prednisolonerelated side effects (Jusko & Ludwig 1991). Young children have a greater clearance of prednisolone normalised to bodyweight than adults. This inverse relationship with age does not exist with methylprednisolone (Hill et al. 1990). Obesity influences prednisolone but not methylprednisolone clearance; consequently, the dosage of prednisolone and methylprednisolone should be based on total and ideal bodyweight, respectively. Metabolism of prednisone and methylprednisolone is induced by phenobarbital, phenytoin and rifampicin. The metabolism of methylprednisolone but not prednisone is inhibited by erythromycin and ketoconazole. Cyclosporin and cimetidine do not influence the pharmacokinetics of either prednisone or methylprednisolone. Neither hepatic nor renal impairment change their clearance to a degree requiring adjustment of oral dosage (Jusko & Ludwig 1991).
2. Cyc/osporin 2.1 Analytical Methods Ever since the first clinical trials of cyclosporin a number of analytical techniques to measure concentrations in whole blood or plasma/serum were developed simultaneously (for recent reviews see
Clin. Pharmacokinet. 23 (5) 1992
382
Kivisto 1992 and Rodighiero 1989). Presently 4 distinct assay types can be differentiated according to their specificity for the unchanged cyclosporin molecule. High pressure liquid chromatographic methods are the only ones truly specific for the parent compound cyclosporin. Immunoassays using either a radiolabelled or an enzyme-labelled tracer and a so-called 'specific monoclonal antibody' (Sandoz Ltd, Switzerland) detect unmetabolised cyclosporin and some metabolites to the extent that measurements are generally 10% higher than by liquid chromatography. Immunoassays based on polyclonal antibodies are less specific and detect large portions of the major human cyclosporin metabolite (AM 1). The least specific of the commercially available assays use a 'nonspecific monoclonal antibody' (Sandoz) which regularly measures more of the metabolites than any other assay. The clinical utility of the different assays has recently been discussed (Kahan et al. 1990). 2.2 Pharmacokinetic Parameters of Cyclosporin The clinical pharmacokinetics of cyclosporin have been reviewed several times over the past years (McMillan 1989; Ptachcinski et al. 1986; Ro-
dighiero 1989). The present review makes no attempt to completely list the average pharmacokinetic parameters from the many studies in small (n < 10) groups of patients or volunteers, but rather draws attention to 2 recent reports which, because of the magnitude of data, can be classified as describing population pharmacokinetic data on cyclosporin (table I). Specifically, the analysis of Mallet et al. (1988) succeeds in presenting a realistic picture of the variability of cyclosporin pharmacokinetics in transplant patients. The key questions for the optimisation of immunosuppressive therapy by cyclosporin are: (a) what are the sources of the pharmacokinetic variability; (b) to which degree can changes in cyclosporin pharmacokinetics be anticipated; and (c) can certain sources of variability be eliminated? A list of identified causes of pharmacokinetic variability is provided in table II. The following factors have predictable effects on clearance and/ or bioavailability, albeit not precisely quantified: small bowel length in children after liver transplantation, availability of bile in the small intestine after liver transplantation, young age of patient, interaction with other drugs which induce or inhibit the metabolising enzymes, and the time after transplantation. The only source of variability
Table I. Population pharmacokinetic parameters of cyclosporin during the first week after transplantation
Parameter
Symbol (unit)
Assay
Clearance
CL (L/h) CL/F (ml/min' kg) Vc (L)
PLtpR/Nsa
Volume of distribution
Vz (L) Vz/F (L) Terminal half-life
tv",(h)
tv", (h)
WB/HP/Spb
Mean ± SO
5th-95th percentile
Reference
24
4-78
Mallet et al. (1988)
24.2 ± 15.3
PL/PR/Nsa PL/PR/Nsa WB/HP/Spb PLtpR/Nsa WB/HP/Spb
Median
Awni et al. (1989) 18
2-65
Mallet et al. (1988)
94
13-285
4.3
1.9-13.9
Mallet et al. (1988) Awni et al. (1989) Mallet at al. (1988) Awni et al. (1989)
27.2 ± 18.4 15.1 ± 9.6
a Nonspecific polyclonal radioimmunoassay in plasma. The median is based on 188 patients with bone marrow transplants. b Specific high pressure liquid chromatography in whole blood. The mean is based on 21 patients with renal transplants. Abbreviations: CL = clearance; F = bioavailability; Vc = volume of central compartment; Vz = apparent volume of distribution during terminal phase; tv", = terminal half-life.
Optimisation of Immunosuppression
383
Table II. Sources of pharmacokinetic variability of cyclosporin
Source
Pharmacokinetic parameter affected
Clinical consequence
References
Small bowel length in children after liver transplantation (absorption window) Availability of bile in the small intestine
CL/F
The longer the small bowel the smaller the oral dosage
Whitington et al. (1990) Grevel (1986)
F
Naoumov et al. (1989)
Meal of high fat content
CL, F
Oral dosage in the morning or evening
CL/F
Intestinal metabolism
F
Young age
CL
Body size in adult patients
CL
Liver function
CL
Drug interactions Time after transplantation
CL, F CL/F
Oral dosage can only start after liver transplantation when biliary drainage through the T-tube has stopped Both bioavailability and clearance increase. The oral clearance and the required oral dosage are unlikely to change During twice daily administration, the area is larger when the dose is given in the evening. Circadian variations play no role during once-daily administration The low bioavailability of cyclosporin seems to be caused by both incomplete absorption and intestinal metabolism The younger the children, the higher the clearance when normalised for bodyweight In adult patients, body size in general and obesity in particular do not determine the oral dosage With poor liver function the dosage requirements of cyclosporin decrease Refer to recent review As the oral clearance decreases, the oral dosage can be reduced
Gupta et al. (1990)
Canafax et al. (1988)
Tredger et al. (1991)
Burckart et al. (1984) Flechner et al. (1989) Grevel et al. (1989a) Grevel et al. (1989a) Yee & McGuire (1990) Awni et al. (1989)
Abbreviations: CL = clearance; F = bioavailability; CL/F = oral clearance.
which can potentially be eliminated is the interaction with other drugs. It is generally accepted that the only effective way to protect the patient from the potential risks caused by the pharmacokinetic variability of cyc\osporin is a tight schedule oftherapeutic drug concentration monitoring and dosage adjustments. 2.3 Significance of Cyc\osporin Binding Cyc\osporin as a very lipophilic compound is highly bound to lipoproteins in plasma (Gurecki et al. 1985). This binding is characterised by a low affinity and high capacity (Sgoutas et al. 1986). The apparent free and unbound fraction is dependent upon the methods of measurement. With ultracen-
trifugation, a free fraction in plasma of 4 to 12% was reported (Legg & Rowland 1987). A much lower fraction of 0.5 to 4.2% (Lindholm & Henricsson 1989) was determined with equilibrium dialysis. It is unlikely that only free cyc\osporin is pharmacologically active and susceptible to drug metabolism (Grevel 1988). Indeed, treatment failure manifested as graft rejection in renal transplant patients was more likely in patients with a high free fraction (Lindholm & Henricsson 1989) or those with a low concentration oflow density lipoprotein (Kasiske et al. 1988). Moreover, in vitro it was shown that the addition of low density lipoprotein augmented the inhibitory potency of cyc\osporin in a lymphocyte proliferation assay (Rodl & Khoshsorur 1990). The most logical explanation seems to
384
be that cyclosporin like other lipophilic compounds in plasma (e.g. cholesterol) is transported to its site of action by lipoproteins and that cyclosporin enters the cell via lipoprotein receptors. Once in the cell the specific high affinity binding to cyclophilin (Handschumacher et al. 1984) dominates its mechanism of action. Toxic effects of cyclosporin, however, seem to be blunted by a high blood lipid content (Nemunaitis et al. 1986). 2.4 Significance of Cyclosporin in Lymph The original assumption that cyclosporin should express its immunosuppressive effects in the lymphatic circulation was based on 2 observations: (a) lymph contains the highest concentration of circulating T-lymphocytes; and (b) cyclosporin reaches higher concentrations in lymph than in plasma (Albrechtsen et al. 19.85). This hypothesis, however, began to shake when it was shown that oral and intravenous doses of cyclosporin are equally efficacious despite the fact that cyclosporin concentrations in lymph are 10 times higher than in plasma only after oral but not after intravenous administration. These experiments were first performed in rats (Albrechtsen et al. 1985) and later confirmed in renal transplant patients (Ono et al. 1988). 2.5 Significance of Cyclosporin Metabolites Cyclosporin is eliminated predominantly by metabolism in the liver. Numerous unconjugated metabolites are circulating in blood and distributing into tissue compartments. They, as well as parent cyclosporin, are excreted mainly in bile. A fairly complete listing and updated nomenclature has recently been published (Kahan et al. 1990). There is not a single metabolite whose therapeutic or toxic effects would warrant its specific monitoring (e.g. by liquid chromatography) after therapeutic doses of cyclosporin (ibid). More for the purpose of standardisation than based on experimental evidence, a specific assay of cyclosporin in whole blood was recommended by a panel of experts (Shaw et al. 1987). At the same time it was
Clin. Pharmacokinet. 23 (5) 1992
shown, however, both in patients with bone marrow (Yee et al. 1986) and renal transplants (Kunzendorf et al. 1989) that nonspecific assays differentiate between rejectors and nonrejectors while the specific liquid chromatographic methods detect no difference. 2.6 Pharmacodynamic Monitoring When standard dosage rates of cyclosporin in transplant patients led to variable outcomes, the search started for parameters which could predict the success of immunosuppressive therapy. Based on the results of in vitro experiments of cyclosporin inhibiting the activation of T-lymphocytes, serum samples of renal transplant patients were tested for the ability to suppress a mixed lymphocyte reaction (Rogers et al. 1984). Despite the identification of 4 distinct patterns of immunosuppression during a steady-state dosage interval of 24h, and despite a correlation between these patterns and clinical outcome, such pharmacodynamic monitoring could not prospectively support clinical decisions, since the required incubation took 6 days. Also other immunological assays are far too timeconsuming to satisfy the informational need of a physician pressed for a therapeutic decision (for reviews see Awni 1992 and Kahan 1985). 2.7 Trough Concentration Monitoring Concentrations of cyclosporin in blood can be readily obtained and they have been generally accepted as a means to verify patient compliance. Moreover, cyclosporin concentrations at steadystate measured just before a new dose is given ('trough concentration') correlated with the rate of rejection, toxicity and infection in renal transplant patients (Irschik et al. 1984) and with the rate of graft-versus-host disease in patients with bone marrow transplants (Yee et al. 1988). Thus, trough concentrations have proven to be useful intermediate end-points. Out of a concern that trough concentrations could not correctly represent the overall exposure of a patient to cyclosporin, it was proposed instead to measure peak concentrations
Optimisation of Immunosuppression
385
Table III. Pharmacokinetic strategy for cyclosporin dosage adjustment. The strategy is suitable for all transplantations except for liver and intestine. It has been extensively evaluated in adult and paediatric recipients of renal transplants
Pharmacokinetic calculations
Time
Dosage
Blood samples
Pretransplant
IV cyclosporin 200mg for adults or 5 mg/kg for
