*4.1.1.3. Two hours post dose concentration monitoring (C2)*

This approach, which is termed 'absorption profiling', has the underlying rationale that the 4 hour absorption phase following administration provides measurements that are more informative than C0 monitoring in the assessment of likely CsA exposure and subsequent clinical response [86,87]. AUC0-4h monitoring is a sensitive tool used to optimize CsA immu‐ nosuppression in renal transplant recipients. However, the tool is not practical in the clinical setting because of 3 drawbacks: (1) it requires multiple sampling of blood for determination of the AUC0-4h, (2) the actual value requires a mathematical calculation step, and (3) the test may be too expensive for many clinical hospitals or institutions because of the use of added costly laboratory tests for CsA concentrations and the subsequent increase in workload. Therefore, the search for a single blood-sampling point that best reflects the sensitivity of AUC0-4h was the focus of several research initiatives that resulted in a broad approval for C2 monitoring [82,85]. This method is done by measuring either the area under the blood CsA concentration-time curve in the first hours after dose, AUC0-4 or, more simply, by measuring the blood CsA concentration at 2 hours after dose, C2 [82].

has been demonstrated, as yet, through or predose whole blood concentration monitoring

Clinical Pharmacology and Therapeutic Drug Monitoring of Immunosuppressive Agents

http://dx.doi.org/10.5772/54910

327

TRL whole-blood through concentrations have been found to correlate well with the area under the concentration-time curve measurements in liver, kidney and bone marrow trans‐ plant recipients (r= 0.91-0.99). Thus, through concentrations are good index of overall drug exposure, and are currently used for routine monitoring as part of patient care posttransplan‐ tation [91,92]. This approach offers the opportunity to reduce the pharmacokinetic variability by implementing drug dose adjustments based on plasma/blood concentrations. Drug levels are obtained as predose (12 hours after previous dose) trough concentrations in whole blood [88]. These trough levels correlate reasonably well with area under the curve, with total area

Therapeutic ranges of TRL after kidney transplantation are reported as a range for various times after transplant: 0-1 month, 15-20 μg/L; 1-3 months, 10-15 μg/L; and more than 3 months, 5-12 μg/L [95]. TRL blood concentrations are monitored 3 to 7 days a week for the first 2 weeks, at least three times for the following 2 weeks, and whenever the patient comes for an outpatient visit thereafter [96]. On the basis of the terminal half-life of TRL, it was suggested to start monitoring blood concentrations 2 to 3 days after initiation of TRL treatment after the drug has reached steady state. However it is important to reach effective drug concentrations early after transplantation to decrease the risk of acute rejection and to avoid excessive early calcineurin inhibitors concentrations that may be severely damaging after reperfusion of the

The frequency of TDM of TRL should be increased in the case of suspected adverse events or rejection, when liver function is deteriorating, after dose adjustments of the immunosuppres‐ sants, change of route of administration, or change of drug formulations, when drugs that are known to interact with CYP3A or P-gP are added or discontinued, or when their doses are changed, in case of severe illness that may affect drug absorption or elimination such as severe

In 1995, for preventing rejection in renal transplant patients, MMF, the morpholinoethyl ester prodrug from MPA was approved for clinical use. This drug has since become the predominant anti-metabolite immunosuppressive used in the transplant setting. Although the current labeling information for MMF does not indicate any need for therapeutic monitoring of plasma MPA concentrations, there were a number of studies showing a re‐ lationship between MPA pharmacokinetics and clinical outcome [99]. Definitive determi‐ nation of the pharmacokinetics of the drug in renal allograft recipients after transplantation is not without difficulty. In principle, substantial changes in pharmacoki‐ netics could be produced by changes following transplantation, both in the immediate post-transplant period (reflecting rapid alterations in drug therapy, renal function, hemo‐

under the curve being an accurate measure of drug exposure [94].

immune reactions and sepsis, or if noncompliance is suspected [98].

is still the method of choice [55].

*4.2.1. Therapeutic monitoring*

transplanted organ [97].

**4.3. Mycophenolic acid (MPA)**

In *the novo* patients this monitoring method has led to result in the following clinical benefits compared with trough concentration monitoring [88]: (1) reduced incidence of acute rejection, (2) reduced severity of rejection episodes and (3) reduced incidence of nephrotoxicity.

#### *4.1.1.4. Bayesian forecasting*

The initial pharmacokinetic models for CsA were complicated by the nonlinear, segmented, zero order absorption of the drug from the gut [77,89]. Bayesian forecasting is a TDM tool that has been successfully used clinically in the monitoring of drugs that have a narrow therapeutic index, including antiepileptic drugs, theophylline and aminoglycosides; however, although Bayesian forecasting has proven useful clinically with other drugs, this is not the case with CsA [78]. Bayesian forecasting, in its modern form, was first proposed in 1979 by Sheiner et al. [90]. Since that time, user-friendly computer programs that perform this technique have become widely available. These programs are capable of calculating dosage regimens and pharmacokinetic parameters, as well as predicting drug concentrations by blending popula‐ tion values with patient-specific values [78]. However, these methods were technically complex and were not practical or successful for individualizing CsA therapy in a routine clinical setting and therefore did not gain widespread use. The introduction of Neoral, with its less variable and more predictable blood concentration profile, has rekindled interest in the pharmacokinetic modeling of CsA and in the use of Bayesian forecasting to predict CsA blood concentrations [77].

#### **4.2. Tacrolimus (TRL)**

The therapeutic range for TRL used by most transplantation centers is 5–20 ng/mL in blood. Although, plasma TRL concentrations have been measured and an equivalent ther‐ apeutic range in this matrix suggested (0.5–2 ng/mL), the two most widely used assays for the drug use blood samples. Because this drug is extensively bound to erythrocytes, blood concentrations average about 15 times greater than concurrently measured serum or plasma concentrations [57,79,91]. As a result, whole blood has become the principal sample used for TRL concentration monitoring, with extraction accomplished through cell lysis and protein denaturation steps that are similar or identical to those used for CsA analysis [51]. The pharmacokinetics of TRL is highly variable. Since TRL shares many of the pharmacokinetic and pharmacodynamic problems associated with CsA the rationale for TDM is similar. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, through or predose whole blood concentration monitoring is still the method of choice [55].

#### *4.2.1. Therapeutic monitoring*

setting because of 3 drawbacks: (1) it requires multiple sampling of blood for determination of the AUC0-4h, (2) the actual value requires a mathematical calculation step, and (3) the test may be too expensive for many clinical hospitals or institutions because of the use of added costly laboratory tests for CsA concentrations and the subsequent increase in workload. Therefore, the search for a single blood-sampling point that best reflects the sensitivity of AUC0-4h was the focus of several research initiatives that resulted in a broad approval for C2 monitoring [82,85]. This method is done by measuring either the area under the blood CsA concentration-time curve in the first hours after dose, AUC0-4 or, more simply, by measuring

In *the novo* patients this monitoring method has led to result in the following clinical benefits compared with trough concentration monitoring [88]: (1) reduced incidence of acute rejection, (2) reduced severity of rejection episodes and (3) reduced incidence of nephrotoxicity.

The initial pharmacokinetic models for CsA were complicated by the nonlinear, segmented, zero order absorption of the drug from the gut [77,89]. Bayesian forecasting is a TDM tool that has been successfully used clinically in the monitoring of drugs that have a narrow therapeutic index, including antiepileptic drugs, theophylline and aminoglycosides; however, although Bayesian forecasting has proven useful clinically with other drugs, this is not the case with CsA [78]. Bayesian forecasting, in its modern form, was first proposed in 1979 by Sheiner et al. [90]. Since that time, user-friendly computer programs that perform this technique have become widely available. These programs are capable of calculating dosage regimens and pharmacokinetic parameters, as well as predicting drug concentrations by blending popula‐ tion values with patient-specific values [78]. However, these methods were technically complex and were not practical or successful for individualizing CsA therapy in a routine clinical setting and therefore did not gain widespread use. The introduction of Neoral, with its less variable and more predictable blood concentration profile, has rekindled interest in the pharmacokinetic modeling of CsA and in the use of Bayesian forecasting to predict CsA blood

The therapeutic range for TRL used by most transplantation centers is 5–20 ng/mL in blood. Although, plasma TRL concentrations have been measured and an equivalent ther‐ apeutic range in this matrix suggested (0.5–2 ng/mL), the two most widely used assays for the drug use blood samples. Because this drug is extensively bound to erythrocytes, blood concentrations average about 15 times greater than concurrently measured serum or plasma concentrations [57,79,91]. As a result, whole blood has become the principal sample used for TRL concentration monitoring, with extraction accomplished through cell lysis and protein denaturation steps that are similar or identical to those used for CsA analysis [51]. The pharmacokinetics of TRL is highly variable. Since TRL shares many of the pharmacokinetic and pharmacodynamic problems associated with CsA the rationale for TDM is similar. Although the feasibility of a limited sampling scheme to predict AUC

the blood CsA concentration at 2 hours after dose, C2 [82].

326 Current Issues and Future Direction in Kidney Transplantation

*4.1.1.4. Bayesian forecasting*

concentrations [77].

**4.2. Tacrolimus (TRL)**

TRL whole-blood through concentrations have been found to correlate well with the area under the concentration-time curve measurements in liver, kidney and bone marrow trans‐ plant recipients (r= 0.91-0.99). Thus, through concentrations are good index of overall drug exposure, and are currently used for routine monitoring as part of patient care posttransplan‐ tation [91,92]. This approach offers the opportunity to reduce the pharmacokinetic variability by implementing drug dose adjustments based on plasma/blood concentrations. Drug levels are obtained as predose (12 hours after previous dose) trough concentrations in whole blood [88]. These trough levels correlate reasonably well with area under the curve, with total area under the curve being an accurate measure of drug exposure [94].

Therapeutic ranges of TRL after kidney transplantation are reported as a range for various times after transplant: 0-1 month, 15-20 μg/L; 1-3 months, 10-15 μg/L; and more than 3 months, 5-12 μg/L [95]. TRL blood concentrations are monitored 3 to 7 days a week for the first 2 weeks, at least three times for the following 2 weeks, and whenever the patient comes for an outpatient visit thereafter [96]. On the basis of the terminal half-life of TRL, it was suggested to start monitoring blood concentrations 2 to 3 days after initiation of TRL treatment after the drug has reached steady state. However it is important to reach effective drug concentrations early after transplantation to decrease the risk of acute rejection and to avoid excessive early calcineurin inhibitors concentrations that may be severely damaging after reperfusion of the transplanted organ [97].

The frequency of TDM of TRL should be increased in the case of suspected adverse events or rejection, when liver function is deteriorating, after dose adjustments of the immunosuppres‐ sants, change of route of administration, or change of drug formulations, when drugs that are known to interact with CYP3A or P-gP are added or discontinued, or when their doses are changed, in case of severe illness that may affect drug absorption or elimination such as severe immune reactions and sepsis, or if noncompliance is suspected [98].
