Monitoring mycophenolate in liver transplant recipients: Toward a therapeutic range

Abstract

Predose plasma mycophenolic acid (MPA) concentrations measured with a semi-automated enzyme-multiplied immunoassay were related to adverse events (e.g., rejection, leukopenia, infection), drug dose, and clinical status in 147 adult and 63 pediatric liver allograft recipients receiving adjunctive immunosuppression with mycophenolate mofetil (MMF). In 12 of 13 acute rejection episodes, predose MPA levels were below the 1 mg/L cut-off defined using receiver operating characteristic (ROC) curve analysis. The relative risk of developing infection or leukopenia increased more than 3-fold above predose MPA levels of 3 to 4 mg/L. Plasma MPA levels correlated weakly (r 2 ‫؍‬ 0.081) with MMF dose and the dose / level relationship was variably influenced by age, the indication for MMF, concentrations of serum albumin and creatinine, and comedication with tacrolimus or cyclosporine. The median mycophenolate dose required per unit mycophenolate level was 50% lower in children than in adults. Comparable drug requirements were also decreased by renal dysfunction (by 40 and 43% in adults and children, respectively), and in patients prescribed MMF alone rather than with tacrolimus or cyclosporine. However, in patients with serum albumin less than 35g/L, MMF dose requirements were higher than in those with normal albumin levels (by 2.1-and 2.6-fold in adults and children, respectively). In adults, 44.7% achieved clinically acceptable therapeutic MPA concentrations at a dose less than 1 g MMF twice daily and only 6.3% required 1.5 g twice daily as suggested by the manufacturer. The immunoassay was a rapid, reliable, and acceptably precise technique in which only 10.8% of measurements were unproductive. In conclusion, our data suggests that MPA predose level monitoring is both clinically-and cost-effective and that a therapeutic range of 1 to 3.5mg/L (by immunoassay) is applicable in liver allograft recipients given adjunctive MMF. (Liver Transpl 2004;10:492-502.)

Monitoring of mycophenolic acid and kidney function during combined immunosuppressive therapy

“…The increase in MPA level and the decrease in cyclosporine with the progression of renal impairment can be the consequence of both the dosage adjustment according to CKD stages and the change in the renal elimination, as MPA is excreted mainly by the kidneys. The individual variations in MPA levels may be connected to the renal and liver function, body mass and genetic polymorphisms in the enzymes and other proteins responsible for drug metabolism and transport (16,17). Since 2008, TDM of MPA is not suggested as a routine test after renal transplantation (8,18,19).…”

The Pharmacokinetics of Low-Dose Thalidomide in Japanese Patients with Refractory Multiple Myeloma

“…ROC curve analysis 14,15) was performed to examine the relationship between adverse events and AUC 0-∞ . ROC curve is a graphical plot of the sensitivity versus 1-specificity for a binary classifier system as its discrimination threshold is varied.…”

134 Impact of combined mycophenolate mofetil and low dose calcineurin inhibitor therapy on T cell function

“…Plasma MPA concentrations within patient groups were not closely correlated with the dose of mycophenolate mofetil but were dependent upon the indication for prescribing MMF, age and serum albumin and creatinine concentrations (Tredger et al, 2004). Tredger et al (Tredger et al, 2004) reported that a therapeutic range of predose MPA plasma levels of 1 to 3.5 mg/L (by immunoassay) is applicable in liver allograft recipients. The potential for MPA toxicity at higher predose plasma levels is in agreement with the findings in renal transplant recipients of Mourad and colleagues (Mourad et al, 2001) who identified at 3 mg/L threshold using ROC curve analysis.…”

“…The potential for MPA toxicity at higher predose plasma levels is in agreement with the findings in renal transplant recipients of Mourad and colleagues (Mourad et al, 2001) who identified at 3 mg/L threshold using ROC curve analysis. MMF with the benefit of MPA monitoring, only 6.3% were considered to need 1.5 g twice a day clinically, and 44.7% were prescribed less than 1 g twice a day (Tredger et al, 2004). The drug levels were also influenced by the type of immunosuppressive comedication (Shaw et al, 2002).…”