**4.3. Mycophenolic acid (MPA)**

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‐ dynamics and gastrointestinal motility) as well as more gradual changes (reflecting change in bodyweight, plasma proteins and organ function) [100]. The greatest variability in MPA pharmacokinetic is noted in the initial 2 months following transplantation, when adequate immunosuppression is critical to graft function and survival. It has also become apparent from longer term pharmacokinetic studies that exposure to MPA increases over time due to reduced clearance of the drug. A possible additional factor that could con‐ tribute to the higher oral clearance of MPA early after transplantation is corticosteroid therapy, which is significantly higher in that period but then is tapered to low dose lev‐ els or completely withdrawn. Based upon the marked pharmacokinetic variability ob‐ served with MPA and the pharmacodynamic relationship of pharmacokinetic parameters to rejection outcome, several scientific societies and consensus conferences have advocat‐ ed the use of concentration monitoring for patients undergoing treatment with MMF or enteric-coated MPA [101].

such as the trough concentration or others do not correlate well with the MPA AUC, especially

Clinical Pharmacology and Therapeutic Drug Monitoring of Immunosuppressive Agents

The dose interval MPA AUC0–12 h is generally regarded as the most reliable pharmacokinetic parameter index of risk for acute rejection but is impractical to measure in routine clinical practice. Single time-point samples such as the trough concentration or others, do not correlate well with the MPA AUC, especially in the early posttransplantation period renal transplant patients and for regimens that include MMF plus CsA, TRL, or SRL [104]. Therefore, assess‐ ment of whether C0 concentrations or other single time points correlate well with the AUC is important for establishing routine monitoring of the drug. Apart of the C0 level other single time points after MMF dosing are examined for their ability to predict full AUC values. A full MPA AUC typically requires at least eight blood samples during 12 hour dose interval. In clinical practice this is impractical; therefore, abbreviated sampling schemes involving the collection of there to five plasma samples have been investigated. The abbreviated sampling

approach has provided estimations of MPA AUC with high correlations (r2

models have been developed all of them in renal transplant patients [105-108].

SRL (formerly known as rapamycin) is a macrolide antibiotic with immunosuppressive properties that was introduced relatively recently (September 1999) into clinical practice for maintenance therapy in organ transplantation [109]. Pharmacokinetics studies of SRL in renal transplant patients have been shown great variability between patients. Several features contribute to the interpatient pharmacokinetic variability observed with SRL and can include any combination of the following: absorption, distribution, metabolism and/or excretion [110].

This drug presents a rapid gastrointestinal absorption (tmax from 0.33 to 5 hours) as well as a low (mean value 14%) and variable bioavailability. It has been reported that SRL is a substrate for the multidrug P-glycoprotein transporter and that the biotransformation of SRL is medi‐ ated by CYP3A enzymes. Accordingly, considerable variability in its pharmacokinetic parameters may be expected (apparent blood clearance rates after oral administration from 87 to 416 mL/h/kg). In addition, the disposition of SRL in humans includes a large volume of distribution, a long half-life (35 to 95 hours) and dose proportionality for Cmax and AUC. Also, some interracial variability and an influence of hepatic dysfunction have been noted with SRL [111]. Although structurally similar to TRL, SRL has a novel mechanism of action, which leads to synergy with CsA. The long half-life of the drug necessitates a loading dose to achieve therapeutic concentrations quickly, and also allows for once daily administration. Highly variable absorption and metabolism of the drug result in large differences in blood concen‐ trations among patients receiving the same dose. Efficacy for the prevention of acute rejection episodes, and the rate of common adverse effects (thrombocytopenia, leucopenia and hyper‐

>0.8). Several

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

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in the early posttransplantation period [103].

**4.4. Sirolimus (SRL)**

*4.3.1.2. Limited sampling strategies for estimation of MPA AUC*

triglyceridemia), are concentration-dependent [112].

#### *4.3.1. Therapeutic monitoring*

The incorporation of MMF into immunosuppressive regimens has been associated with decrease rates of acute rejection and decreased chronic allograft loss. Indications for TDM of mycophenolates were reviewed in a consensus meeting [101]. They included high-risk patients, patients with delayed graft function, or patients with immunosuppressive protocols excluding induction therapy or steroids or calcineurin inhibitor or patients with calcineurin minimization. Most of these patients (especially high-risk patients) are often excluded from the clinical trials. In fact, MPA TDM is currently only used in a few transplant centers on a routine basis, whereas a few others only checked MPA exposure in case of unexpected acute rejection or adverse event or drug interaction. Most of the centers never measure MPA. It is clear that the use of MPA TDM is conditioned by the faith of the physicians in its use, local availability of MPA measurements, and organization of the nursing staff [102].

### *4.3.1.1. Trough concentration (C0) monitoring*

Although a relationship between AUC and outcome exists, the clinical utility of concentration monitoring, particularly C0 monitoring for MMF, has been questioned. Over the past decade, several studies were conducted to evaluate the clinical utility of prospective concentration controlled MMF therapy. While these studies were anticipated to fully clarify the utility of monitored MMF therapy, the outcomes from these studies are conflicting and have done little to settle the controversies surrounding this area of therapeutic drug monitoring [100]. With trough concentration, plasma concentration of MPA is measured immediately before a dose, it is easy to measure because only -ask patient to return to give sample, it is immediately before a dose, and only requires single simple possible association between C0 and decreased rejection noted in transplant recipients. However this method represents some disadvantages. Timing may not be accurate (depends on remembering time of last dose). Timing may vary from the "ideal" (12 h after last dose) by several hours. There is no high-level evidence of a strong association between C0 and outcome, or between C0 and AUC0–12, C0 is not a very informative time point for estimation of individual pharmacokinetic parameters. Single time-point samples such as the trough concentration or others do not correlate well with the MPA AUC, especially in the early posttransplantation period [103].
