Desired cyclosporine concentrations differ between the various types of transplants, change with time during the posttransplantation phase, and are often determined by protocols specific to the transplantation service and institution.^1,3,4,6–10 Thus, it is especially important for clinicians to be aware of these various factors, as acceptable cyclosporine concentrations under these different circumstances may be different than those listed by their clinical laboratory or those given in this text.

For patients receiving cyclosporine after a hematopoietic stem cell transplantation, the goal of therapy is to prevent graft-versus-host disease while avoiding adverse effects of immunosuppressant therapy.^3,10 Graft-versus-host disease is a result of donor T-lymphocytes detecting antigens on host tissues and producing an immunologic response against these antigens and host tissues. Acute graft-versus-host disease usually occurs within the first 100 days after transplantation of donor cells, and causes epithelial tissue damage in organs. The most common tissues attacked are skin, gastrointestinal tract, and liver. To prevent acute graft-versus-host disease from occurring in allogenic hematopoietic stem cell transplantation patients with HLA-matched donors, cyclosporine therapy is usually instituted a few days before or on the day of stem cell transplant (day 0), and doses are adjusted to provide therapeutic trough concentrations. Methotrexate or glucocorticoids are usually also given in conjunction with cyclosporine treatment to hematopoietic stem cell transplantation patients. If prophylaxis of acute graft-versus-host disease is successful, cyclosporine doses start to be tapered between posttransplant day 50 and 100, with the goal of drug discontinuation by about posttransplant day 180. For allogeneic hematopoietic stem cell transplantation patients with HLA-mismatched or HLA-matched unrelated donors, the risk of acute graft-versus-host disease is higher, so cyclosporine therapy may be more prolonged for these patients. After posttransplantation day 100, chronic graft-versus-host disease may occur, and severe cases or patients with systemic signs and symptoms of the disease are usually treated with prednisone.

For patients receiving solid organ transplants such as kidney, liver, heart, lung, or heart-lung transplantation, the goal of cyclosporine therapy is to prevent acute or chronic rejection of the transplanted organ while minimizing drug side effects.^1,6–9 In this case, the recipient’s immune system detects foreign antigens on the donor organ which produces an immunologic response against the graft. This leads to inflammatory and cytotoxic effects directed against the transplanted tissue, and produces the risk of organ tissue damage and failure. In the case of a rejected kidney transplant, it is possible to remove the graft and place the patient on a form of dialysis to sustain their life. However, for other solid organ transplantation patients, graft rejection can result in death. Because cyclosporine can cause nephrotoxicity, some centers delay cyclosporine therapy in renal transplant patients for a few days or until the kidney begins functioning to avoid untoward effects on the newly transplanted organ. Also, desired cyclosporine concentrations in renal transplant patients are generally lower to avoid toxicity in the new renal graft than for other transplant patients (typically 100-200 ng/mL versus 150-300 ng/mL using whole blood with a specific, high-pressure liquid chromatograph assay). For other solid organ transplant patients, cyclosporine therapy may be started several hours before surgery or, for patients with poor kidney function, held until after transplantation to avoid nephrotoxicity. During the immediate postoperative phase, intravenous cyclosporine may be given to these patients. For long-term management of immunosuppression in solid organ tissue transplant patients, cyclosporine doses are gradually tapered to the lowest concentration and dose possible over a 6- to 12-month time period as long as rejection episodes do not occur. In some cases, it may be possible to completely discontinue cyclosporine therapy.

Hypertension, nephrotoxicity, hyperlipidemia, tremor, hirsutism, and gingival hyperplasia are all typical adverse effects of cyclosporine treatment.^1–4 Hypertension is the most common side effect associated with cyclosporine therapy, and is treated with traditional antihypertensive drug therapy. Nephrotoxicity is separated into acute and chronic varieties. Acute nephrotoxicity is concentration- or dose-dependent and reverses with a dosage decrease. Renal damage in this situation is thought to be due to renal vasoconstriction, which results in increased renal vascular resistance, decreased renal blood flow, and reduced glomerular filtration rate. Chronic nephrotoxicity is accompanied by kidney tissue damage, including interstitial fibrosis, nonspecific tubular vacuolization, and structural changes in arteries, arterioles, and proximal tubular epithelium. Increased serum creatinine and blood urea nitrogen (BUN) values, hyperkalemia, hyperuricemia, proteinuria, and increased renal sodium excretion occur with cyclosporine-induced nephrotoxicity. The clinical features of cyclosporine nephrotoxicity and acute graft rejection in renal transplant patients are similar, so renal biopsies may be conducted to differentiate between these possibilities.¹ Because biopsy findings are similar between cyclosporine-induced nephrotoxicity and chronic rejection of kidney transplants, this technique is of less help in this situation. Hyperlipidemia is treated using dietary counseling and antilipid drug therapy. Cyclosporine dosage decreases may be necessary to decrease tremor associated with drug therapy while hirsutism is usually addressed using patient counseling. Gingival hyperplasia can be minimized through the use of appropriate and regular dental hygiene and care.

CLINICAL MONITORING PARAMETERS

Hematopoietic stem cell transplantation patients should be monitored for the signs and symptoms associated with graft-versus-host disease.³ These include a generalized maculopapular skin rash, diarrhea, abdominal pain, ileus, hyperbilirubinemia, and increased liver function tests (alkaline phosphatase and serum transaminases). Patients with severe chronic graft-versus-host disease may have involvement of the skin, liver, eyes, mouth, esophagus, or other organs similar to what might be seen with systemic autoimmune diseases.

Solid organ transplant patients should be monitored for graft rejection consistent with the transplanted organ. For renal transplant patients, increased serum creatinine, azotemia, hypertension, edema, weight gain secondary to fluid retention, graft tenderness, fever, and malaise may be due to an acute rejection episode. Hypertension, proteinuria, a continuous decline in renal function (increases in serum creatinine and blood urea nitrogen levels), and uremia are indicative of chronic rejection in renal transplant patients.^1,6 For hepatic transplant patients, acute rejection signs and symptoms include fever, lethargy, graft tenderness, increased white blood cell count, change in bile color or amount, hyperbilirubinemia, and increased liver function tests. Chronic rejection in a liver transplant patient may be accompanied only by increased liver function tests and jaundice.^1,7 For heart transplant patients, acute rejection is accompanied by low-grade fever, malaise, heart failure (presence of S₃ heart sound), or atrial arrhythmia. Chronic rejection in heart transplant patients, also known as cardiac allograft vasculopathy, is characterized by accelerated coronary artery atherosclerosis and may include the following symptoms: arrhythmias, decreased left ventricular function, heart failure, myocardial infarction, and sudden cardiac death.^1,9 For lung transplant patients, acute rejection may result in no or nonspecific symptoms (cough, dyspnea, hypoxemia, low-grade fever, inspiratory crackles, interstitial infiltrates, declining lung function). Chronic rejection in lung transplant patients, also called bronchiolitis obliterans syndrome, is characterized by decreased airflow and can resemble acute bronchitis.⁸ For all solid organ transplant patients, tissue biopsies may be taken from the transplanted tissue to confirm the diagnosis of organ rejection.^1,6–9

Typical adverse effects of cyclosporine treatment include hypertension, nephrotoxicity, hyperlipidemia, tremor, hirsutism, and gingival hyperplasia.^1–4 The management of these more common drug side effects are discussed in the previous section. Other cyclosporine adverse drug reactions that occur less frequently include gastrointestinal side effects (nausea, vomiting, diarrhea), headache, hepatotoxicity, hyperglycemia, acne, leukopenia, hyperkalemia, and hypomagnesemia.

Because of the pivotal role that cyclosporine plays as an immunosuppressant in transplant patients, as well as the severity of its concentration- and dose-dependent side effects, cyclosporine concentrations should be measured in every patient receiving the drug. If a patient experiences signs or symptoms of graft-versus-host disease or organ rejection, a cyclosporine concentration should be checked to ensure that levels have not fallen below the therapeutic range. If a patient encounters a possible clinical problem that could be an adverse drug effect of cyclosporine therapy, a cyclosporine concentration should be measured to determine if levels are in the toxic range. During the immediate posttransplantation phase, cyclosporine concentrations are measured daily in most patients even though steady-state may not yet have been achieved in order to prevent acute rejection in solid organ transplant patients or acute graft-versus-host disease in hematopoietic stem cell transplantation patients.

After discharge from the hospital, cyclosporine concentrations continue to be obtained at most clinic visits. In patients receiving allogeneic hematopoietic stem cell transplantations from HLA-matched donors, it is usually possible to decrease cyclosporine doses and concentrations about 2 months after the transplant and stop cyclosporine therapy altogether after about 6 months posttransplant if no or mild acute rejection episodes have taken place. However, in allogeneic hematopoietic stem cell transplantation patients with HLA-mismatched related or HLA-identical unrelated donors and most solid organ transplant patients, chronic cyclosporine therapy is usually required. In these cases, cyclosporine doses and concentrations are decreased to the minimum required level to prevent graft-versus-host reactions or rejection episodes in order to decrease drug adverse effects. Methods to adjust cyclosporine doses using cyclosporine concentrations are discussed later in this chapter. Although newer data is available that suggests determination of cyclosporine area under the concentration-time curve using multiple concentrations^11–15 or 2-hour postdose cyclosporine concentrations^16–19 may provide better outcomes for some transplant types, many transplant centers continue to use predose trough cyclosporine concentration determinations to adjust drug doses.

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Cyclosporine is almost completely eliminated by hepatic metabolism (>99%).²⁰ Hepatic metabolism is mainly via the CYP3A4 enzyme system, and the drug is a substrate for p-glycoprotein. There are more than 25 identified cyclosporine metabolites.^5,21 None of these metabolites appear to have significant immunosuppressive effects in humans. Most of the metabolites are eliminated in the bile. Less than 1% of a cyclosporine dose is recovered as unchanged drug in the urine. Within the therapeutic range, cyclosporine follows linear pharmacokinetics.²²

There is a large amount of intrasubject variability in cyclosporine concentrations obtained on a day-to-day basis, even when the patient should be at steady-state. There are many reasons for this variability. Cyclosporine has low water solubility, and its gastrointestinal absorption can be influenced by many variables.^5,21,23,24 To improve the consistency of absorption rate and bioavailability for original dosage form (Sandimmune, Novartis), a microemulsion version of the drug (Neoral, Novartis) was marketed to help reduce absorption variability. While use of microemulsion cyclosporine does decrease steady-state concentration variability (10%-30% for Neoral versus 16%-38% for Sandimmune for trough concentrations), there are still substantial day-to-day changes in cyclosporine concentrations regardless of the dosage form used.²⁵ The fat content of meals has an influence on the absorption of oral cyclosporine.²⁶ Food containing a large amount of fat enhances the absorption of cyclosporine. Oral cyclosporine solution is prepared with olive oil and alcohol to enhance the solubility of the drug. The solution is mixed in milk, chocolate milk, or orange juice using a glass container immediately before swallowing. When the entire dose has been given, the glass container should be rinsed with the diluting liquid and immediately consumed. If microemulsion cyclosporine solution is administered, it should be mixed in a similar fashion using apple or orange juice. In either case, grapefruit juice should not be used since this vehicle inhibits CYP3A4 and/or p-glycoprotein contained in the gastrointestinal tract and markedly increases bioavailability. Variation in cyclosporine solution absorption is dependent on how accurately the administration technique for each dose is reproduced. After liver transplantation, bile production and flow may not begin immediately, or bile flow may be diverted from the gastrointestinal tract using a T tube.^27,28 In the absence of bile salts, the absorption of cyclosporine can be greatly decreased. Bile appears to assist in the dissolution of cyclosporine which increases the absorption of the drug. Diarrhea also impairs cyclosporine absorption,^29,30 and hematopoietic stem cell transplantation patients may experience diarrhea as a part of graph-versus-host disease.³ Other drug therapy can also increase or decrease the intestinal first-pass clearance of cyclosporine.³¹

Cyclosporine is a low-to-moderate hepatic extraction ratio drug with an average liver extraction ratio of ~30%.³² Because of this, its hepatic clearance is influenced by unbound fraction in the blood (f_B), intrinsic clearance (Cl′_int), and liver blood flow (LBF). Cyclosporine binds primarily to erythrocytes and lipoproteins, yielding unbound fractions in the blood that are highly variable (1.4%-12%).^33–38 Erythrocyte concentrations vary in transplant patients, especially those who have received hematopoietic stem cell transplantation or kidney transplants. Lipoprotein concentrations also vary among patients, and hyperlipidemia is an adverse effect of cyclosporine. Hepatic intrinsic clearance is different among individuals, and there is a large amount of variability in this value within individual liver transplant patients that changes according to the viability of the graft and time after transplantation surgery. Other drug therapy can also increase or decrease the hepatic intrinsic clearance of cyclosporine.³¹ Liver blood flow exhibits a great deal of day-to-day intrasubject variability which will also change the hepatic clearance of cyclosporine. Of course, changing the unbound fraction in the blood, hepatic intrinsic clearance, or liver blood flow will also change the hepatic first-pass metabolism of cyclosporine. Taking all of these possible factors into consideration that alter absorption and clearance allows one to gain a better appreciation of why cyclosporine concentrations change on a day-to-day basis.

Cyclosporine capsules and solution are available in regular (25-mg and 100-mg capsules; 100-mg/mL solution) and microemulsion (25-mg, 50-mg, and 100-mg capsules; 100-mg/mL solution) form. Although the oral absorption characteristics are more consistent and bioavailability higher for microemulsion forms of cyclosporine, it is recommended that patients who switched from cyclosporine to microemulsion cyclosporine have doses converted on a 1:1 basis. Subsequent microemulsion cyclosporine dosage adjustments are based on concentration monitoring. Cyclosporine injection for intravenous administration is available at a concentration of 50 mg/mL. Before administration, each milliliter of the concentrate should be diluted in 20-100 mL of normal saline or 5% dextrose, and the total dose infused over 2-6 hours. For patients stabilized on oral cyclosporine, the initial intravenous dose should be about 33% of the oral dose. Anaphylactic reactions have occurred with this dosage form, possibly due to the castor oil diluent used to enhance dissolution of the drug. The initial dose of cyclosporine varies greatly among various transplant centers. Cyclosporine therapy is commonly started 4-12 hours before the transplantation procedure. According to a survey of transplant centers in the United States, the average initial oral dose (± standard deviation) for renal, liver, and heart transplant patients were 9 ± 3 mg/kg/d, 8 ± 4 mg/kg/d, and 7 ± 3 mg/kg/d.²⁵ For both rheumatoid arthritis and psoriasis, the recommended initial dose is 2.5 mg/kg/d administered twice daily as divided doses with maximal recommended doses of 4 mg/kg/d.

EFFECTS OF DISEASE STATES AND CONDITIONS ON CYCLOSPORINE PHARMACOKINETICS AND DOSING

Transplantation type does not appear to have a substantial effect on cyclosporine pharmacokinetics. The overall mean for all transplant groups is a clearance of 6 mL/min/kg, a volume of distribution equal to 5 L/kg, and a half-life of 10 hours for adults.^5,21,23,24 Average clearance is higher (10 mL/min/kg) and mean half-life is shorter (6 hours) in children (≤16 years old).^5,21,23,24 The determination of cyclosporine half-life is difficult for patients receiving the drug on a twice daily dosage schedule because only a few concentrations can be measured in the postabsorption, postdistribution phase. Because of this, half-life measurements were taken from studies that allowed at least 24 hours between doses. These results, as with the other pharmacokinetic parameters discussed in this chapter, are based on a specific high-pressure liquid chromatography assay method conducted using whole blood samples. As discussed in a previous section, nonspecific cyclosporine assays measure metabolite concentrations in addition to parent drug, and concurrently measured plasma or serum concentrations are lower than whole blood concentrations.

Because the drug is primarily eliminated by hepatic metabolism, clearance is lower (3 mL/min/kg) and half-life prolonged (20 hours) in patients with liver failure.^5,21,39 Immediately after liver transplantation, cyclosporine metabolism is depressed until the graft begins functioning in a stable manner. Additionally, patients with transient liver dysfunction, regardless of transplantation type, will have decreased cyclosporine clearance and increased half-life values. Immediately after transplantation surgery, oral absorption of cyclosporine, especially in liver transplant patients with T tubes, is highly variable.^27,28 Obesity does not influence cyclosporine pharmacokinetics, so doses should be based on ideal body weight for these individuals.^40–44 Renal failure does not change cyclosporine pharmacokinetics, and the drug is not significantly removed by hemodialysis or peritoneal dialysis.^45–47 The hemofiltration sieving coefficient for cyclosporine is 0.58, which indicates significant removal.^48,49 Replacement doses during hemoperfusion should be determined using cyclosporine concentrations.

DRUG INTERACTIONS

Drug interactions with cyclosporine fall into two basic categories. The first are agents known to cause nephrotoxicity when administered by themselves.³¹ The fear is that administration of a known nephrotoxin with cyclosporine will increase the incidence of renal damage over that observed when cyclosporine or the other agent are given separately. Drugs in this category of drug interactions include aminoglycoside antibiotics, vancomycin, cotrimoxazole (trimethoprim-sulfamethoxazole), amphotericin B, and anti-inflammatory drugs (azapropazone, diclofenac, naproxen, other nonsteroidal anti-inflammatory drugs). Other agents are melphalan, ketoconazole, cimetidine, ranitidine, and tacrolimus.

The second category of drug interactions involves inhibition or induction of cyclosporine metabolism. Cyclosporine is metabolized by CYP3A4 and is a substrate for p-glycoprotein, so the potential for many pharmacokinetic drug interactions exists with agents that inhibit these pathways or are also cleared by these mechanisms.³¹ Because both of these drug elimination systems also exist in the gastrointestinal tract, inhibition drug interactions may also enhance cyclosporine oral bioavailability by diminishing the intestinal and hepatic first-pass effects. Drugs that inhibit cyclosporine clearance include the calcium channel blockers (verapamil, diltiazem, nicardipine), azole antifungals (fluconazole, itraconazole, ketoconazole), macrolide antibiotics (erythromycin, clarithromycin), antivirals (indinavir, nelfinavir, ritonavir, saquinavir), steroids (methylprednisolone, oral contraceptives, androgens), psychotropic agents (fluvoxamine, nefazodone), and as well as other agents (amiodarone, chloroquine, allopurinol, bromocriptine, metoclopramide, cimetidine, grapefruit juice). Inducing agents include other antibiotics (nafcillin, rifampin, rifabutin), anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), barbiturates, aminoglutethimide, troglitazone, octreotide, and ticlopidine. Because of the large number of interacting agents, and the critical nature of the drugs involved in the treatment of transplant patients, complete avoidance of drug interactions with cyclosporine is not possible. Thus, most drug interactions with cyclosporine are managed using appropriate cyclosporine dosage modification with cyclosporine concentration monitoring as a guide.

Cyclosporine can also change the clearance of other drugs via competitive inhibition of CYP3A4 and/or p-glycoprotein.³¹ Drugs that may experience decreased clearance and increased serum concentrations when given with cyclosporine include prednisolone, digoxin, calcium channel blockers (verapamil, diltiazem, bepridil, nifedipine and most other dihydropyridine analogues, sildenafil), statins (atorvastatin, simvastatin, lovastatin, and rosuvastatin), ergot alkaloids, and vinca alkaloids.

INITIAL DOSAGE DETERMINATION METHODS

Several methods to initiate cyclosporine therapy are available. The Pharmacokinetic Dosing method is the most flexible of the techniques. It allows individualized target serum concentrations to be chosen for a patient, and each pharmacokinetic parameter can be customized to reflect specific disease states and conditions present in the patient. Literature-based recommended dosing is a very commonly used method to prescribe initial doses of cyclosporine. Doses are based on those that commonly produce steady-state concentrations in the lower end of the therapeutic range, although there is a wide variation in the actual concentrations for a specific patient.

Pharmacokinetic Dosing Method

The goal of initial dosing of cyclosporine is to compute the best dose possible for the patient in order to prevent graft rejection or graft-versus-host disease given their set of disease states and conditions that influence cyclosporine pharmacokinetics, while avoiding adverse drug reactions. In order to do this, pharmacokinetic parameters for the patient will be estimated using average parameters measured in other patients with similar disease state and condition profiles.

Clearance Estimate

Cyclosporine is almost completely metabolized by the liver. Unfortunately, there is no good way to estimate the elimination characteristics of liver-metabolized drugs using an endogenous marker of liver function in the same fashion that serum creatinine and estimated creatinine clearance are used to estimate the elimination of agents that are renally eliminated. Because of this, a patient is categorized according to the disease states and conditions that are known to change cyclosporine clearance, and the clearance previously measured in these studies is used as an estimate of the current patient’s clearance rate. For example, an adult transplant patient with normal liver function would be assigned a cyclosporine clearance rate equal to 6 mL/min/kg, while a pediatric transplant patient with the same profile would be assumed to have a cyclosporine clearance of 10 mL/min/kg.

Selection of Appropriate Pharmacokinetic Model and Equations

When given by intravenous infusion or orally, cyclosporine follows a two-compartment model.⁴⁷ When oral therapy is chosen, the drug is often erratically absorbed with variable absorption rates, and some patients may have a “double-peak” phenomenon occur where a maximum concentration is achieved 2-3 hours after dosage administration with a second maximum concentration 2-4 hours after that.^26,50 Because of the complex absorption profile and the fact that the drug is usually administered twice daily, a very simple pharmacokinetic equation that calculates the average cyclosporine steady-state serum concentration (Css in ng/mL = μg/L) is widely used and allows maintenance dose computation: Css = [F(D/τ)]/Cl or D = (Css • Cl • τ)/F, where F is the bioavailability fraction for the oral dosage form (F averages 0.3 or 30% for most patient populations and oral dosage forms), D is the dose of cyclosporine in mg, Cl is cyclosporine clearance in L/h, and τ is the dosage interval in hours. If the drug is to be given intravenously as intermittent infusions, the equivalent equation for that route of administration is Css = (D/τ)/Cl or D = Css • Cl • τ. If the drug is to be given as a continuous intravenous infusion, the equation for that method of administration is Css = k_o/Cl, or k_o = Css • Cl, where k_o is the infusion rate.

Steady-State Concentration Selection

The generally accepted therapeutic ranges for cyclosporine in blood, serum, or plasma using various specific and nonspecific (parent drug + metabolite) assays are given in Table 18-1. More important than these general guidelines are the specific requirements for each graft type as defined by the transplant center where the surgery was conducted. Clinicians should become familiar with the cyclosporine protocols used at the various institutions at which they practice. Although it is unlikely that steady-state has been achieved, cyclosporine concentrations are usually obtained on a daily basis, even when dosage changes were made the previous day, due to the critical nature of the therapeutic effect provided by the drug.

Literature-Based Recommended Dosing

Because of the large amount of variability in cyclosporine pharmacokinetics, even when concurrent disease states and conditions are identified, many clinicians believe that the use of standard cyclosporine doses for various situations is warranted. Indeed, most transplant centers use doses that are determined using a cyclosporine dosage protocol. The original computation of these doses were based on the Pharmacokinetic Dosing method described in the previous section, and subsequently modified based on clinical experience. In general, the expected cyclosporine steady-state concentration used to compute these doses is dependent upon the type of transplanted tissue and the posttransplantation time line. Generally speaking, initial oral doses of 8-18 mg/kg/d or intravenous doses of 3-6 mg/kg/d (1/3 the oral dose to account for ~ 30% oral bioavailability) are used and vary greatly from institution to institution.^1–4 For obese individuals (> 30% over ideal body weight), ideal body weight should be used to compute initial doses.^40–44 Initial doses for children are 15 mg/kg/d orally or 5-6 mg/kg/d intravenously infused over 2-6 hours.⁵¹ If the drug is started intravenously, pediatric patients are converted to an oral dose as soon as feasible. Then, the oral dose is tapered by 5% per week until it equals 3-10 mg/kg/d administered once or twice daily. To illustrate how this technique is used, the same patient examples utilized in the previous section will be repeated for this dosage approach for comparison purposes.

USE OF CYCLOSPORINE CONCENTRATIONS TO ALTER DOSES

Because of the large amount of pharmacokinetic variability among patients, it is likely that doses computed using patient population characteristics will not always produce cyclosporine concentrations that are expected or desirable. Because of pharmacokinetic variability, the narrow therapeutic index of cyclosporine, and the severity of cyclosporine adverse side effects, measurement of cyclosporine concentrations is mandatory for patients to ensure that therapeutic, nontoxic levels are present. In addition to cyclosporine concentrations, important patient parameters (transplanted organ function tests or biopsies, clinical signs and symptoms of graft rejection or graft-versus-host disease, potential cyclosporine side effects, etc) should be followed to confirm that the patient is responding to treatment and not developing adverse drug reactions.

For hematopoietic stem cell transplantation patients, steady-state trough concentrations are typically measured for cyclosporine. For solid organ transplant patients, the optimal times and strategies for measurement of steady-state concentrations are somewhat controversial.^4,52 At first, it was assumed that the predose trough concentration would be best as it represents the lowest concentration during the dosage interval. However, recent studies have found that the steady-state cyclosporine concentration 2 hours after a dose (C2) reflects cyclosporine area under the curve better than a trough concentration. Finally, some clinicians believe that since cyclosporine is such a critical component of transplant therapy, that multiple postdose cyclosporine concentrations should be measured to obtain the best estimate of area under the curve that is possible. Currently, most transplant centers measure a single steady-state cyclosporine concentration as either a predose trough or 2 hours postdose, while some conduct multiple measurements to determine cyclosporine area under the curve estimates.

When cyclosporine concentrations are measured in patients and a dosage change is necessary, clinicians should seek to use the simplest, most straightforward method available to determine a dose that will provide safe and effective treatment. In most cases, a simple dosage ratio can be used to change cyclosporine doses assuming the drug follows linear pharmacokinetics. Sometimes, it is useful to compute cyclosporine pharmacokinetic constants for a patient and base dosage adjustments on these. In this case, it may be possible to calculate and use pharmacokinetic parameters to alter the cyclosporine dose. Another approach involves measuring several postdose steady-state cyclosporine concentrations to estimate the area under the concentration-time curve (AUC) and adjusting the cyclosporine dose to attain a target AUC. Finally, computerized methods that incorporate expected population pharmacokinetic characteristics (Bayesian pharmacokinetic computer programs) can be used in difficult cases where concentrations are obtained at suboptimal times or the patient was not at steady-state when concentrations were measured.

Linear Pharmacokinetics Method

Because cyclosporine follows linear, dose-proportional pharmacokinetics,²² steady-state concentrations change in proportion to dose according to the following equation: D_new/C_ss,new = D_old/C_ss,old or D_new = (C_ss,new/C_ss,old)D_old, where D is the dose, Css is the steady-state concentration, old indicates the dose that produced the steady-state concentration that the patient is currently receiving, and new denotes the dose necessary to produce the desired steady-state concentration. The C_ss

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