Nilufar Partovi

A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes.

Background. We hypothesized that transplantation of islets into type 1 diabetics could improve outcomes of glucose metabolism, renal function, retinopathy, and neuropathy compared with intensive medical therapy. Methods. We conducted a prospective, crossover, cohort study of intensive medical therapy (group 1) versus islet cell transplantation (group 2) in 42 patients. All were enrolled in group 1 then 31 crossed over with group 2 when islet donation became available. Transplantation was performed by portal venous embolization of more than 12,000 islet equivalents/kg body weight under cover of immunosuppression with antithymocyte globulin, tacrolimus, and mycophenolate. Outcome measures were HbA1c, change in glomerular filtration rate (GFR), progression of retinopathy, and change in nerve conduction velocity. This report details interim analysis of outcomes after 34±18 months (group 1) and 38±18 months (group 2). Results. HbA1c (%) in group 1 was 7.5±0.9 versus 6.6±0.7 in group 2 (P<0.01). GFR (mL/min/month) declined in both groups (group 1 −0.45±0.7 vs. group 2 −0.12±0.7, P=0.1). Slope of the GFR decline in group 1 was significantly more than 0. Retinopathy progressed in 10 of 82 eyes in group 1 versus 0 of 51 in group 2 (P<0.01). Nerve conduction velocity (m/sec) remained stable in group 1 (47.8±5 to 47.1±5 m/sec) and group 2 (47.2±4.5 to 47.7±3.5). Conclusion. Islet transplantation yields improved HbA1c and less progression of retinopathy compared with intensive medical therapy during 3 years follow-up.

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.

Sirolimus : The evidence for clinical pharmacokinetic monitoring

This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world. Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays--high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay. Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4-12 microg/L (measured via chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12-20 microg/L is recommended. Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5-7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised.

Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past.

Solid organ transplant (SOT) recipients are at risk for Pneumocystis pneumonia (PCP), especially in the first year post transplant. Although trimethoprim‐sulfamethoxazole (TMP‐SMX) prophylaxis substantially decreases this risk, there is little data or consensus on optimal duration of prophylaxis. Consequently, there is lack of standardization of prophylaxis duration (3 months to lifelong, depending on organ group) in SOT programs.

Drug Interactions With Direct-Acting Antivirals for Hepatitis C: Implications for HIV and Transplant Patients

Objective: Review pharmacokinetics of new direct-acting antivirals (DAAs) for hepatitis C (HCV) infection and interactions with concomitant immunosuppressant and antiretroviral therapies (ART). Data Sources: MEDLINE (1948-January 2015), EMBASE (1964-January 2015), International Pharmaceutical Abstracts (1970-January 2015), Google, and Google Scholar were searched combining the terms simeprevir, sofosbuvir, ledipasvir, daclatasvir, paritaprevir, ABT-450, ombitasvir, dasabuvir, pharmacokinetics, drug interaction, drug metabolism, HIV, antiretroviral, immunosuppressant, transplant. Articles, conference proceedings, abstracts, and product monographs were reviewed. Study Selection and Data Extraction: Literature on pharmacokinetic or pharmacodynamic interactions with DAAs and immunosuppressants or ART was considered for inclusion. Pertinent information was extracted and summarized in the review. In the absence of data, pharmacokinetic and pharmacodynamic principles were used to predict the likelihood of interactions. Data Synthesis: DAA pharmacokinetics are reviewed and drug interaction data are presented with provision of management strategies. Fixed-dose combination paritaprevir/ritonavir/ombitasvir plus dasabuvir is most susceptible to drug interactions with immunosuppressants and ART mainly due to the influence of ritonavir on multiple enzymes. Simeprevir is also prone to drug interactions because of cytochrome P450(CYP) 3A4, CYP1A2, P-glycoprotein, and OATP1 involvement and is not recommended for use in combination with several HIV antiretrovirals (ARVs). Close therapeutic drug monitoring of calcineurin inhibitors is required with concomitant simeprevir. Few clinically significant interactions are expected with sofosbuvir or ledipasvir. Limited data suggest that daclatasvir may be coadministered with immunosuppressants but requires dose adjustments with certain ARVs. Conclusions: None of the DAAs are completely free of drug interactions. Awareness and management of drug interactions is critical to optimize outcomes and minimize adverse effects in these patient populations.

Pharmacokinetics and protein binding of mycophenolic acid in stable lung transplant recipients.

Mycophenolate mofetil (MMF) use is increasing in solid organ transplantation. Mycophenolic acid (MPA), the active metabolite of MMF, is highly protein bound and only free MPA is pharmacologically active. The average MPA free fraction in healthy adult individuals, stable renal transplant recipients, and heart transplant recipients is approximately 2 to 3%. However, no data are currently available on MPA protein binding in stable lung transplant recipients and little is known regarding MPAs pharmacokinetic characteristics after lung transplantation. The purpose of this study was to characterize the pharmacokinetic profile and protein binding of MPA in this patient population. Seven patients were entered into the study. On administration of a steady-state morning MMF dose, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 9, 10, and 12 hours post-dose. Total MPA concentrations were measured by a validated HPLC method with UV detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), trough concentration (Cmin), free fraction (f), and free MPA AUC were calculated by traditional pharmacokinetic methods. Patient characteristics included; 3 males and 4 females, an average of 4.4 years post-lung transplant (range, 0.3–11.5 yr), mean (± SD) age of 50 ± 10 years and weight 69 ± 20 kg. Mean albumin concentration was 37 ± 3 g/L and serum creatinine was 142 ± 49 &mgr;mol/L. All patients were on cyclosporine and prednisone. MMF dosage ranged from 1 to 3 g daily (35.5 ± 14.1 mg/kg/d; range, 15.2–60.0 mg/kg/d). Mean (± SD) AUC was 45.78 ± 18.35 &mgr;g · h/mL (range, 16.56–74.22 &mgr;g · h/mL), Cmax was 17.37 ± 7.69 &mgr;g/mL (range, 4.92–26.63 &mgr;g/mL), Tmax was 1.2 ± 0.4 hours (range, 1.0–2.0 h), Cmin was 3.12 ± 1.41 &mgr;g/mL (range, 1.47–4.82 &mgr;g/mL), f was 2.90 ± 0.56% (range, 2.00–3.40%), and free MPA AUC was 1.29 ± 0.50 &mgr;g · h/mL (range, 0.54–1.88 &mgr;g · h/mL). This is the first study to determine these pharmacokinetic characteristics of MPA in the lung transplant population. Further studies should focus on identification of MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.

The use of infliximab for treatment of hospitalized patients with acute severe ulcerative colitis.

BACKGROUND/AIM The use of infliximab in severe ulcerative colitis (UC) is established; however, its role in severe acute UC requires clarification. The present multicentre case series evaluated infliximab in hospitalized patients with steroid-refractory severe UC. METHODS Patients from six hospitals were retrospectively evaluated. Data collection included demographics, duration of disease and previous treatments. The primary end point was response to in-hospital infliximab; defined as discharge without colectomy. RESULTS Twenty-one patients (median age 26 years) were admitted between May 2006 and May 2008 with severe UC requiring intravenous steroids and given infliximab (median time to infusion eight days). Sixteen (76%) patients were discharged home without colectomy; three of these underwent colectomy at a later date. Of the remaining 13 patients (62%), all but two did not require further courses of steroids; six patients had infliximab as a bridge to azathioprine and seven patients were maintained on regular infliximab. Five patients required in-hospital colectomy after the initial infliximab. CONCLUSIONS In this real-life experience of infliximab in patients with steroid-refractory severe UC, infliximab appears to be a viable rescue therapy. The majority of patients were discharged without surgery and 62% maintained response either as a bridge to azathioprine or maintenance infliximab.

Ganciclovir in solid organ transplant recipients: is there a role for clinical pharmacokinetic monitoring?

The authors use a previously published decision-making algorithm to address the role of clinical pharmacokinetic monitoring of ganciclovir, the drug of choice for prophylaxis and treatment of cytomegalovirus (CMV) in solid organ transplant recipients. Ganciclovir pharmacokinetics have been studied in solid organ transplant recipients with a wide range of peak and trough concentrations reported. Numerous assays are available to measure plasma concentrations of ganciclovir, but no clear correlation has been established between peak or trough concentrations and either efficacy or toxicity of the drug. For patients receiving treatment, the pharmacological response of ganciclovir is assessed initially by clinical response. Monitoring prophylactic therapy in asymptomatic patients poses a greater challenge. Although monitoring of antigenemia or polymerase chain reaction (PCR) deoxyribonucleic acid (DNA) is not yet part of routine clinical practice, studies have shown a role for these techniques in monitoring response to antiviral therapy. Studies of subpopulations of renal failure patients show a prolonged ganciclovir half-life that requires dosage adjustments. However, ganciclovir clearance is closely correlated with creatinine clearance, which is an appropriate approach to adjusting dosages. Studies in pediatric patients also demonstrate a close correlation between dose per kilogram and AUC, suggesting that monitoring of ganciclovir levels may not be necessary. Based on the evidence presented in this review, routine clinical pharmacokinetic monitoring of ganciclovir does not appear to be warranted in solid organ transplant recipients.

Mycophenolate Pharmacokinetics in Early Period Following Lung or Heart Transplantation

BACKGROUND: The available pharmacokinetic and pharmacodynamic data on mycophenolic acid (MPA), the pharmacologically active metabolite of mycophenolate mofetil (MMF), are derived largely from renal transplant patients, not thoracic transplant recipients. OBJECTIVE: To evaluate, in a pilot study, the pharmacokinetics of MPA at 3 different times in the early period (up to the first 9 mo) following lung or heart transplantation. METHODS: Nine patients were entered into this open-label study. Upon administration of a steady-state morning MMF dose, blood samples were collected at 0, 20, 40, 60, and 90 minutes and at 2, 4, 6, 8, 10, and 12 hours after the dose at 3 times (denoted as sampling periods 1, 2, and 3) in the early posttransplant period. Total MPA concentrations were measured by a validated HPLC method with ultraviolet detection and followed by ultrafiltration of pooled samples for unbound MPA concentrations. Pharmacokinetic parameters (maximal concentration [Cmax], dose-normalized Cmax, time to Cmax, minimum concentration, predose concentration, AUC, dose-normalized AUC, free fraction, free AUC) were calculated by traditional noncompartmental methods. RESULTS: Patient characteristics included 7 men and 2 women, 5 lung and 4 heart transplant recipients, mean ± SD age 53 ± 11 years, and weight 77 ± 14 kg. All patients were receiving prednisone and cyclosporine (with the exception of 2 pts. on tacrolimus during sampling periods 2 and 3). Sampling periods 1, 2, and 3 occurred on posttransplant days 15 ± 13, 56 ± 33, and 125 ± 73, respectively. No significant differences were found between sampling periods in any pharmacokinetic parameter. Drug exposure as evaluated by AUC was 39.95 ± 44.86, 25.24 ± 25.68, and 43.96 ± 38.67 μg•h/mL during sampling periods 1, 2, and 3, respectively, (p > 0.05). CONCLUSIONS: As of September 26, 2003, this is the first study to systematically evaluate MPA pharmacokinetics in thoracic transplant recipients at 3 different time points during the early posttransplant period. Wide interpatient variability in MPA pharmacokinetics was observed, thus emphasizing the need to individualize dosing of MMF and to further evaluate important pharmacokinetic/pharmacodynamic parameters and endpoints that impact on clinical outcomes. Further studies involving more patients and pharmacodynamic outcomes are underway to help identify optimal MMF strategies.

Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients.

Itraconazole is a synthetic triazole antifungal agent that is commonly used in the prophylaxis and treatment of fungal infection. A role for itraconazole drug monitoring has been suggested previously; however, the advent of new formulations and increased clinical evidence may aid in further defining this role. Consequently, we have used a previously published decision-making algorithm to determine whether clinical pharmacokinetic monitoring of itraconazole is warranted. First, itraconazole has proven efficacy for the prophylaxis and treatment of fungal infection in immunocompromised individuals such as neutropenic cancer, human immunodeficiency virus (HIV), and solid organ transplant patients. Several assays have been developed to quantify itraconazole and its main metabolite in patient plasma. Measurement of these plasma drug levels in many clinical studies has resulted in no clear definition of a relationship between concentration and efficacy. However, limited evidence suggests a correlation between itraconazole levels greater than 250 or 500 ng/mL and increased efficacy. Clinical monitoring of efficacy is difficult because of the challenges in diagnosis of fungal infections and nonspecific clinical symptoms associated with fungal infections. Pharmacokinetic studies of itraconazole indicate that significant inter- and intrapatient variability exists in both healthy and immunocompromised patient populations, although subpopulations such as neutropenic cancer and HIV patients appear to require more drug than their healthy counterparts to attain similar drug levels. A therapeutic range has not been defined for itraconazole, but because of its relatively minimal side effects, a narrow range is unlikely. Drug interactions can occur with itraconazole because it is both an inhibitor and substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein transporter systems. Protein binding alterations could also lead to differences in drug effect. Last, the duration of treatment of prophylaxis is significantly long to propose a potential benefit from drug monitoring. From weighing the available evidence, it appears that itraconazole drug level monitoring would provide more information on efficacy than clinical judgment alone in a subset of patients. Immunosuppressed patients requiring preventative therapy who have suspected poor absorption, are on concomitant enzyme inducers, or are suspected to be noncompliant would have the greatest benefit from itraconazole drug monitoring.