Lillian S. L. Ting

Corticosteroid Interactions with Cyclosporine, Tacrolimus, Mycophenolate, and Sirolimus: Fact or Fiction?

OBJECTIVE To review the current clinical evidence on the effects of corticosteroid interactions with the immunosuppressive drugs cyclosporine, tacrolimus, mycophenolate, and sirolimus. DATA SOURCES Articles were retrieved through MEDLINE (1966-February 2008) using the terms corticosteroids, glucocorticoids, immunosuppressants, cyclosporine, tacrolimus, mycophenolate, sirolimus, drug interactions, CYP3A4, P-glycoprotein, and UDP-glucuronosyltransferases. Bibliographies were manually searched for additional relevant articles. STUDY SELECTION AND DATA EXTRACTION All English-language studies dealing with drug interactions between corticosteroids and cyclosporine, tacrolimus, mycophenolate, and sirolimus were reviewed. DATA SYNTHESIS Corticosteroids share common metabolic and transporter pathways, the cytochrome P450 and P-glycoprotein (P-gp/ABCB1) systems, respectively, with cyclosporine, tacrolimus, and sirolimus. As a group, corticosteroids induce the CYP3A4 and P-gp pathways; however, a few exceptions exist and the impact on a patients immunosuppressant regimen may be critical. Corticosteroids also have demonstrated an induction effect on the uridine diphosphate-glucuronosyltransferase enzymes and multidrug resistance-associated protein 2 involved in mycophenolates disposition. Successful corticosteroid withdrawal regimens have been reported; however, only few studies have examined the effects of steroid withdrawal on the remaining immunosuppressive regimens. To date, the clinical impact of steroid withdrawal on disposition of other immunosuppressive agents is not well characterized, and reports of such drug-drug interactions are conflicting. CONCLUSIONS While our understanding of the clinical impact of steroid-immunosuppressant interactions is limited, it remains a fact that corticosteroids have complex induction and inhibition interactions with common metabolic and transport pathways. Given the complex interaction of corticosteroids on crucial metabolic enzymes and transporter proteins, monitoring of immunosuppressive agents during steroid withdrawal is warranted to ensure optimal treatment outcomes.

Pharmacokinetics of mycophenolic acid and its phenolic-glucuronide and ACYl glucuronide metabolites in stable thoracic transplant recipients.

Mycophenolate mofetil is an immunosuppressant commonly used in solid organ transplantation. Its active metabolite, mycophenolic acid (MPA), is metabolized to the inactive 7-O-mycophenolic acid glucuronide (MPAG) and the active acyl glucuronide (AcMPAG). Most pharmacokinetic (PK) studies have been focused on MPA, but not its metabolites, in kidney transplant recipients. Pharmacokinetic studies of MPA and its metabolites in thoracic transplant recipients are scarce. Because neither the heart nor lung is involved in MPA metabolism or excretion, the thoracic transplant population may exhibit unique PKs. This open-label study aimed to characterize and compare PKs of MPA and its metabolites in stable lung or heart transplant recipients. Fifty thoracic (27 lung, 23 heart) transplant recipients were recruited. Subjects were also taking cyclosporine (11 lung, 14 heart) or tacrolimus (16 lung, nine heart), and prednisone (27 lung, one heart). Blood samples were obtained at 0, 20, 40, 60, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose. Plasma was used for drug level analysis (MPA, MPAG, and AcMPAG) by a high-performance liquid chromatography-ultraviolet detection method; in a subset of subjects, free MPA concentrations were also determined. Conventional PK parameters (dose-normalized) were determined by noncompartmental methods. There was wide interpatient variability of MPA, MPAG, and AcMPAG PKs with coefficients of variation exceeding 70% for most PK parameters measured. Other findings (P < 0.05) included: lower MPA area under the curve, maximum concentration, and minimum concentration; higher apparent clearance and MPAG/MPA metabolic ratio in the lung versus heart transplant group; lower MPA area under the curve and minimum concentration, and higher apparent clearance and MPAG/MPA metabolic ratio in lung transplant recipients concurrently taking cyclosporine versus tacrolimus; and lower minimum concentration in heart transplant recipients taking cyclosporine versus tacrolimus. Despite large interpatient variability in the PKs of MPA, MPAG, and AcMPAG among thoracic transplant recipients, there appear to be significant differences between lung and heart patients, which warrant further study.

Pharmacogenetic Impact of UDP-Glucuronosyltransferase Metabolic Pathway and Multidrug Resistance—Associated Protein 2 Transport Pathway on Mycophenolic Acid in Thoracic Transplant Recipients: An Exploratory Study

Study Objective. To assess the contribution of polymorphisms in the uridine diphosphate glucuronosyltransferase gene (UGT) and the multidrug resistance‐associated protein 2 gene (ABCC2) to mycophenolic acid (MPA) pharmacokinetics and clinical outcomes in thoracic transplant recipients.

Limited Sampling Strategy for Predicting Area Under the Concentration-Time Curve of Mycophenolic Acid in Adult Lung Transplant Recipients

Study Objective. To develop limited sampling strategies for estimation of mycophenolic acid exposure (by determining area under the concentration‐time curve [AUC]) in lung transplant recipients by using sampling times within 2 hours after drug administration and a maximum of three plasma samples.

Pharmacokinetics of Mycophenolic Acid and Its Glucuronidated Metabolites in Stable Lung Transplant Recipients

Background: Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, an immunosuppressive agent commonly used in solid organ transplantation. MPA is metabolized to the inactive metabolite 7-O-mycophenolic acid glucuronide (MPAG) and the active metabolite acyl glucuronide (AcMPAG). Pharmacokinetic profiling of MPA by determining AUC is a tool for determining drug exposure. Many studies, conducted primarily in kidney and some heart and liver transplant recipients, have shown wide interpatient variability in MPAs pharmacokinetic parameters. There have been few studies in the lung transplant group and, even though the lung is not involved in drug elimination, these patients may have different MPA pharmacokinetic characteristics. Objective: To characterize the pharmacokinetic parameters and metabolic ratios of MPA in stable adult lung transplant recipients. Methods: In an open-label manner, lung transplant recipients were recruited. Blood samples were obtained at 0, 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours postdose. Plasma was separated and acidified for drug concentration analysis (MPA, MPAG, AcMPAG) by an HPLC–ultraviolet detection method. Conventional pharmacokinetic parameters were determined via noncompartmental methods. Results: There was large interpatient variability in all pharmacokinetic parameters of MPA, MPAG, and AcMPAG. Similar variability was observed after stratifying patients into concomitant medication groups: cyclosporine and tacrolimus. There was a trend for the tacrolimus group to have a higher dose-normalized AUC, higher AUC, lower apparent clearance, and lower AUC ratio of AcMPAG/MPA compared with the cyclosporine group. In addition, the cyclosporine group had a lower minimum concentration and higher AUC ratio of MPAG/MPA than did the tacrolimus group (p < 0.05). Conclusions: Because of the large interpatient variability in the pharmacokinetic parameters of MPA, MPAG, and AcMPAG, therapeutic drug monitoring of MPA and its metabolites in lung transplant recipients may be beneficial.

A Systematic Review of Limited Sampling Strategies for Platinum Agents Used in Cancer Chemotherapy

Despite evidence in the literature suggesting that a strong correlation exists between the pharmacokinetic parameters and pharmacodynamic effect of anticancer agents, many of these agents are still dosed by body surface area. Therapeutic drug monitoring with the aim of pharmacokinetic-guided dosing would not only maintain target concentrations associated with efficacy but may potentially minimise the likelihood of dose-related systemic toxicities.The pharmacokinetic parameter that displays the best correlation with the pharmacodynamics of anticancer drugs is the area under the plasma concentration-time curve (AUC). However, accurate determination of the AUC requires numerous blood samples over an extended interval, which is not feasible in clinical practice. Therefore, limited sampling strategies (LSSs) have been proposed as a means to accurately and precisely estimate pharmacokinetic parameters with a minimal number of blood samples. LSSs have been developed for many drugs, particularly ciclosporin and other immunosuppressants, as well as for certain anticancer drugs. This systematic review evaluates LSSs developed for the platinum compounds and categorises 18 pertinent citations according to criteria adapted from the US Preventive Services Task Force. Thirteen citations (four level I, six level II-1, three level II-2) pertained to LSSs for carboplatin, four citations (one level II-1, one level II-2, two level III) to cisplatin LSSs, and one citation (level II-2) to nedaplatin.Based on the current evidence, it appears that LSSs may be useful for pharmacokinetic-guided dosage adjustments of carboplatin in both adults and children with cancer. Although some validation studies suggest that LSSs can be extended to different cancer populations or different chemotherapy regimens, other studies dispute this finding.Although the use of LSSs to predict the pharmacokinetic parameters of cisplatin and nedaplatin appear promising, the quality of evidence from published studies does not support routine implementation at this time.LSSs represent one approach in which clinicians can make specific dosage adjustments for individual patients to optimise outcomes. However, the limitations of these strategies must also be taken into consideration. There is also a need for prospective studies to demonstrate that application of LSSs for platinum agents ultimately improves patient response and decreases systemic toxicities.

Performance of Limited Sampling Strategies for Predicting Mycophenolic Acid Area Under the Curve in Thoracic Transplant Recipients

BACKGROUND AND METHODS Eight limited sampling strategies (LSSs) for estimating mycophenolic acid area under the concentration-time curve (4 developed from lung transplant recipients at our center, 4 developed for heart transplant recipients from other research groups) were evaluated in 27 heart or heart-kidney transplant patients. RESULTS The LSSs from our lung transplant patients performed well when applied to the heart transplant population, with percent bias and percent precision within the acceptable limit of +/-15%. CONCLUSIONS The LSSs developed at our center are robust enough to be applied to both lung and heart transplant populations. Application of LSSs from other research groups yielded less optimal results, reinforcing the need to re-establish or re-validate LSSs for each specific center.

Pharmacokinetics of mycophenolic acid and its glucuronidated metabolites in stable islet transplant recipients.

Given the paucity of data on pharmacokinetics of mycophenolic acid (MPA) in islet transplant, the aim of this study was to characterize pharmacokinetic parameters of MPA and its 2 glucuronidated metabolites in stable islet transplant recipients. Sixteen subjects were entered into this open-label study after written informed consent. Upon administration of a steady-state morning mycophenolate mofetil dose, 12-hour serial concentrations of MPA and its phenolic glucuronide (MPAG) and acyl-glucuronide (AcMPAG) were measured by a validated high-performance liquid chromatography method and pharmacokinetic parameters analyzed by noncompartmental modeling. Subjects included 11 women and 5 men who had received 2.7 ± 0.8 islet transplants. Age was 50 ± 8 years, weight 64 ± 11 kg, serum albumin 4.2 ± 0.3 g/dL, and serum creatinine 1.1 ± 0.4 mg/dL. All patients were also on tacrolimus-based steroid-free immunosuppressant regimens. Mycophenolate mofetil dosage ranged from 1 to 2 g daily (25.4 ± 6.1 mg/kg/d). Pharmacokinetic parameters for MPA were area under the curve 42.9 ± 21.6 μg h/mL; dose-normalized AUC 52.9 ± 25.4 μg h/mL/g; maximal concentration (Cmax) 13.0 ± 6.2 μg/mL; time to Cmax (tmax) 1.2 ± 0.4 hours; minimum concentration (Cmin) 1.4 ± 1.0 μg/mL; and MPA-free fraction 1.2% ± 1.0%. Area under the curve ratios of MPAG/MPA and AcMPAG/MPA were 17.8 ± 12.4 and 0.1 ± 0.1, respectively. The wide interpatient variability in all pharmacokinetic parameters of MPA and metabolites are consistent with results from the only other published pharmacokinetic study in islet transplant recipients. A population model and a search for significant covariates may help reduce this variability. Pharmacokinetic parameters calculated in the present study, coupled with findings from the only other published MPA study in islet transplant, form a preliminary base on which to build a population model for future multicenter studies of this little-studied transplant subpopulation.