Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype.

BACKGROUND: Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requi rements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting. AIM: To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype. METHODS: Single-arm, prospective, single-center, open-label, observational study (ClinicalTrials.gov: NCT037 13645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion. RESULTS: Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients. CONCLUSION: Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacro limus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Update on the Teratogenicity of Maternal Mycophenolate Mofetil.

Mycophenolic acid (MPA) products, namely mycophenolate mofetil and mycophenolate sodium, are immunosuppressive medications used to prevent rejection in solid organ transplant recipients and to treat various autoimmune disorders. Mycophenolate therapy is considered to be teratogenic based on observational studies of pregnancies exposed to MPA, which demonstrated an increased incidence of miscarriages in pregnancies exposed to MPA during their first trimester and a pattern of birth defects in the offspring of some pregnancies exposed to MPA. Herein, we have detailed case and series reports in a comprehensive literature review summarizing what is known to date regarding fetal exposure to MPA. Based on evidence from the literature, results of postmarketing surveillance, and information from registries such as the National Transplantation Pregnancy Registry in the United States, it is advised that pregnancy be avoided by women taking MPA. Preconception planning offers the opportunity to explore the alternatives to protect the mother, her transplanted organ, and minimize fetal risk. How to proceed in cases of unplanned pregnancies exposed to MPA in transplant recipients is a complex issue. Research involving large epidemiological studies is expected to be sparse as women heed the warnings about becoming pregnant on MPA. Published recommendations for managing MPA in women of childbearing potential include discontinuing the medication prior to conception, switching the MPA to another medication, or discontinuing the MPA when the pregnancy is discovered.

Pharmacy students' perspectives on a PharmD/MPH dual degree program at a large metropolitan school of pharmacy.

OBJECTIVE: To determine doctor of pharmacy (PharmD) students' perceptions of a PharmD and master of public health (MPH) dual degree program. METHODS: A seven-item survey instrument was developed and distributed to students at a large metropolitan school of pharmacy during scheduled class time in April 2012. RESULTS: Among the 611 students enrolled in the PharmD program, 447 (73%) responded. Of those who responded, 72.3% were either "very likely" or "likely" to consider enrolling in such a PharmD/MPH dual degree program, and 77.4% believed that it would be attractive to future students. The most commonly identified potential limitations to pursuing the dual degree were time commitment (19.9%), increased workload and stress (11.2%), and tuition cost (10.3%). The most notable advantages documented were increased job opportunities for public health-related pharmacy positions (26.9%), increased ability to serve patients and the community (13.4%), and increased marketability for future jobs (8.7%). CONCLUSIONS: PharmD student participants demonstrated overall positive attitudes and interest towards a PharmD/MPH dual degree program.

Pharmacy Students’ Perspective on a Dual Degree PharmD/MPH Program at a Large Metropolitan School of Pharmacy / Perspectivas de los estudiantes de farmacia sobre un programa de grado doble pharmd/MPH en una gran facultad de farmacia metropolitana

Objective: To determine doctor of pharmacy (PharmD) students’ perceptions of a PharmD and master of public health (MPH) dual degree program. Methods: A seven-item survey instrument was developed and distributed to students at a large metropolitan school of pharmacy during scheduled class time in April 2012. Results: Among the 611 students enrolled in the PharmD program, 447 (73%) responded. Of those who responded, 72.3% were either "very likely" or "likely" to consider enrolling in such a PharmD/MPH dual degree program, and 77.4% believed that it would be attractive to future students. The most commonly identified potential limitations to pursuing the dual degree were time commitment (19.9%), increased workload and stress (11.2%), and tuition cost (10.3%). The most notable advantages documented were increased job opportunities for public health-related pharmacy positions (26.9%), increased ability to serve patients and the community (13.4%), and increased marketability for future jobs (8.7%). Conclusions: PharmD student participants demonstrated overall positive attitudes and interest towards a PharmD/MPH dual degree program (AU)

Objetivo: Determinar las percepciones de los estudiantes de un programa de grado doble PharmD y Master en Salud Pública (MPH).Métodos: Se desarrolló un cuestionario de 7 preguntas y se distribuyó entre los estudiantes de una gran facultad de farmacia metropolitana durante el periodo de clases de abril 2012. Resultados: De los 611 estudiantes inscritos en el programa de PharmD, respondieron 447 (73%). De los que respondieron, el 72,3% estaban considerando "muy probablemente" o "probablemente" inscribirse en el programa de grado doble PharmD/MPH, y el 77,4% creía que sería atractivo para futuros estudiantes. Las posibles limitaciones mas frecuentemente identificadas para seguir el grado doble eran el tiempo requerido (19,9%), el incremento de trabajo y estrés (11,2%), y los costes de matrícula (10,3%). Las mayores ventajas documentadas fueron el aumento de oportunidades de trabajo en puestos de farmacia relacionados con la salud pública (26,9%), la mayor capacidad de servir a los pacientes y a la comunidad (13,4%) y la mayor facilidad de mercado para futuros puestos de trabajo (8,7%).Conclusiones: Los estudiantes de PhamD que participaron demostraron actitudes generales positivas e interés hacia un programa de grado doble PharmD/MPH (AU)

Impact of Donor Specific HLA Antibody Monitoring After Kidney Transplantation.

Kidney transplantation (KT) recipients with donor specific HLA antibodies (DSA) encounter higher rates of acute rejection and inferior allograft survival. We report our single center experience with prospective DSA monitoring and provide details of treatments utilized to overcome the potential impact of DSA in a cohort of predominantly African American adult KT recipients. Seventy-five flow crossmatch negative KT recipients underwent periodic screening for DSA utilizing the single antigen bead assay at 3, 6, 9, and 12 months post-transplant. Allograft biopsies were performed in the presence of DSA and/or evidence of graft dysfunction. The incidence of DSA was 23%, with a predominance of Class II antibodies. The rate of rejection was 6 times higher in DSA positive KT recipients compared to DSA negative patients (41% versus 7%, p = 0.004). In the DSA positive group, rejections occurred exclusively in the presence of de novo DSA and were predominantly antibody-mediated or mixed rejections. Despite a higher incidence of rejection in KT recipients with DSA, there were no significant differences in serum creatinine, graft survival, and patient survival between DSA positive and negative recipients at median follow-up of 18 months. DSA positive patients had significantly higher proteinuria compared to DSA negative recipients at 6 months, 1 year, and 3 years of follow-up. In conclusion, the detrimental effects of DSA on allograft function could be mitigated by serial DSA surveillance, protocol biopsies, and alterations in immunosuppression. With these measures, the improvement in graft survival in DSA positive KT recipients, at least at short-term, is encouraging.

The essential research curriculum for doctor of pharmacy degree programs.

In 2008, the American College of Clinical Pharmacy appointed the Task Force on Research in the Professional Curriculum to review and make recommendations on the essential research curriculum that should be part of doctor of pharmacy (Pharm.D.) degree programs. The essential research curriculum provides all students with critical and analytical thinking and lifelong learning skills, which will apply to current and future practice and stimulate some students to pursue a career in this field. Eight key curricular competencies are as follows: identifying relevant problems and gaps in pharmacotherapeutic knowledge; generating a research hypothesis; designing a study to test the hypothesis; analyzing data results using appropriate statistical tests; interpreting and applying the results of a research study to practice; effectively communicating research and clinical findings to pharmacy, medical, and basic science audiences; interpreting and effectively communicating research and clinical findings to patients and caregivers; and applying regulatory and ethical principles when conducting research or using research results. Faculty are encouraged to use research-related examples across the curriculum in nonresearch courses and to employ interactive teaching methods to promote student engagement. Examples of successful strategies used by Pharm.D. degree programs to integrate research content into the curriculum are provided. Current pharmacy school curricula allow variable amounts of time for instructional content in research, which may or may not include hands-on experiences for students to develop research-related skills. Therefore, an important opportunity exists for schools to incorporate the essential research curriculum. Despite the challenges of implementing these recommendations, the essential research curriculum will position pharmacy school graduates to understand the importance of research and its applications to practice. This perspective is provided as an aid and a challenge to those in leadership and teaching positions within schools and colleges of pharmacy.

Drug interactions and toxicities associated with the antiviral management of cytomegalovirus infection.

PURPOSE: Drug interactions and toxicities associated with the antiviral management of cytomegalovirus (CMV) infection are described. SUMMARY: The use of current antiviral treatments for CMV in patients undergoing solid organ or hematopoietic stem cell transplantation is categorically characterized by high-toxicity profiles and drug-drug interactions. The consequences of hematologic toxicities may be manifested clinically in several ways, including increased rates of infections and bleeding, more pronounced bone marrow suppression, and the development of anemia. Moreover, patients undergoing solid organ or stem cell transplantation have difficulty tolerating the nephrotoxic effects of current treatments, because their renal function is often already compromised by infection, sepsis, or the administration of other commonly used nephrotoxic drugs. Patients undergoing transplantation have an especially high risk of drug interactions, because multiple drugs are often administered to prevent allograft rejection, to treat or prevent infection, to control pain, and to treat a number of possible comorbid conditions. Commonly used antiviral agents for the management of CMV infection include cidofovir, CMV i.v. immunoglobulin, foscarnet, ganciclovir, and valganciclovir. Drug interactions associated with the use of ganciclovir and foscarnet sodium are numerous and potentially dangerous. At this time, such toxicities are managed by dosage adjustments, temporary discontinuations of medications, and careful monitoring of the patient. CONCLUSION: Clinically important drug-drug interactions can occur in immunocompromised transplant recipients who are treated for CMV infection. Because of the high toxicity and narrow therapeutic range of the antiviral medications available for CMV management, patients should be carefully monitored for any potential adverse effects from such interactions.

Outcomes of renal transplantation in older high risk recipients: is there an age effect?

BACKGROUND: The purpose of this study was to evaluate long-term outcomes in high risk renal transplant recipients over 60 years of age compared with those younger than 60 years of age. MATERIALS AND METHODS: We analyzed outcomes in 131 consecutive renal transplant recipients at our institution between November 2001 and December 2007. Primary outcomes included incidence of delayed graft function (DGF), acute rejection, graft survival, patient survival, and incidence of infections and neoplasms. RESULTS: Older recipients (Over 60 group, n = 45) received more organs from extended criteria donors (ECD) or donation after cardiac death donors (DCD) compared with younger recipients (Under 60 group, n = 86), 42% versus 17% respectively, P = 0.001. Multivariate analyses revealed that African American ethnicity and DCD donation had the greatest impact on the incidence of DGF in both groups; P < 0.05. Patient survival and graft survival beyond 1 y were similar between the two groups. CONCLUSION: Our data suggest that long-term transplant outcomes in older, high risk renal transplant recipients are similar to those of younger, high risk recipients. Older recipients' age and high-risk characteristics, such as African American ethnicity and increased sensitization, should not be a contraindication to renal transplantation in the elderly.

Targeting alloantibody production with bortezomib: does it make more sense?

BACKGROUND: The effectiveness of current therapies for humoral rejection and decreasing antibody production directed against human leukocyte antigens (HLA) remains controversial. Standard regimens are unable to abrogate alloantibody production long term, most likely due to a lack of a direct effect on inhibiting and depleting mature plasma cells. Bortezomib (BZ) may be more effective at removing long-lived plasma cells compared to standard regimens that modulate alloantibody production by different mechanisms. METHODS: We report a kidney transplant recipient with several episodes of mixed antibody mediated and cellular rejection treated with numerous therapies including BZ. Monitoring included serial measurements of donor specific antibodies (DSA) by Luminex assay and repeated allograft biopsies. RESULTS: One cycle of BZ was able to reverse humoral rejection and graft dysfunction. DSA levels to multiple donor HLA antigens which were not affected by previous therapies were reduced to undetectable levels post BZ. Abrogation of DSA was only transient. Despite continued stable renal function post-BZ, the patient had a reemergence of DSA, and evidence of humoral rejection detected by allograft biopsy. CONCLUSIONS: Despite the promise of BZ as a therapy for humoral rejection, current data on how it should be used and its efficacy long-term remains limited.

Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus.

BACKGROUND: Animal and limited human studies have raised concerns as to the safety of in utero exposure to mycophenolate mofetil (MMF) and sirolimus (SRL) in transplant recipients. This study examined the outcomes of pregnancies with exposure to MMF or SRL from 30 female transplant recipients (39 pregnancies) who have reported pregnancies to the National Transplantation Pregnancy Registry. METHODS: Data were collected via questionnaires, phone interviews and medical records. RESULTS: There were 18 kidney recipients reporting 26 pregnancies with exposure to MMF: 15 livebirths (LB), 11 spontaneous abortions (SA). Structural malformations were reported in four of the 15 children (26.7%) including: hypoplastic nails and shortened fifth fingers (one), microtia with cleft lip and palate (one), microtia alone (one), and neonatal death with multiple malformations (one). One kidney/pancreas (K/P) recipient reported one SA. Three liver recipients reported three pregnancies; two LB (no malformations), and one second trimester SA. Two heart recipients reported one LB (no malformations) and two SA. SRL exposures included seven recipients (four kidney, one K/P and two liver) reporting four LB (one infant whose mother was switched from MMF to SRL during late pregnancy had cleft lip and palate and microtia) and three SA. CONCLUSIONS: A higher incidence of structural malformations was seen with MMF exposures during pregnancy compared to the overall kidney transplant recipient offspring, while no structural defects have as yet been reported with early pregnancy sirolimus exposures. Centers are encouraged to report all pregnancy exposures in transplant recipients.

Concomitant clotrimazole therapy more than doubles the relative oral bioavailability of tacrolimus.

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.