The association between tacrolimus exposure and tremor, headache and insomnia in adult kidney transplant recipients: A systematic review.

PURPOSE: Tremor, headache and insomnia have been linked to the immunosuppressant, tacrolimus. The aim of this systematic review was to determine if there is a correlation between tacrolimus exposure and new-onset tremor, headache and insomnia experienced by adult kidney transplant recipients. METHODS: PubMed, Embase, Cochrane Library and CINAHL databases were searched up to 11 April 2023 for published studies which reported on tacrolimus exposure in adult kidney transplant recipients, alongside information on treatment-emergent neurologic manifestations, including tremor, headache and insomnia. Review articles, case studies, conference abstracts and articles not published in English in peer-reviewed journals were excluded. The Physiotherapy Evidence Database and Newcastle-Ottawa Quality Assessment Scales were used to assess risk of bias. Extracted data was analysed via a narrative synthesis. RESULTS: Eighteen studies involving 4030 patients in total were included in the final analysis. These comprised five randomised control trials and thirteen observational studies. Studies failed to find significant association between tacrolimus trough concentrations in whole blood and the incidence of neurologic side effects such as tremor, headache and insomnia; however, in one study the incidence of toxicity requiring a dose reduction increased with increasing, supratherapeutic targeted levels. Females, especially Black females, and older age were positively associated with the prevalence of neurologic adverse effects. Results were conflicting regarding whether extended-release formulations were associated with fewer neurologic complications than immediate-release formulations. CONCLUSION: The varied study designs and criteria for reporting tremor, headache and insomnia impacted on the quality of the data for exploring the relationship between tacrolimus exposure and the onset of neurologic manifestations experienced after kidney transplantation. Studies that examine defined neurologic complications as the primary outcome, and that consider novel markers of tacrolimus exposure while assessing the potential contribution of multiple covariate factors, are required.

Enhanced primary care after hospitalization: General practitioner, pharmacist and patient feedback from the REMAIN HOME trial.

BACKGROUND: Pharmacist and general practitioner (GP) collaborative models of care are continuing to evolve in the Australian primary care setting. The REMAIN HOME study investigated whether a pharmacist integrated into 14 different primary care teams in general practice (the "practice pharmacist model") reduces readmission to hospital for patients prescribed five or more long term medicines or high risk comorbidities. The aim of this paper is to describe the attitudes of GPs, patients, and practice pharmacists towards this model of pharmacist and GP collaboration. METHODS: To explore the views and opinions about the model of care (pharmacist integration into general practice), participating GPs were invited to complete a survey that included the 13-item validated Attitudes Toward Collaboration Instrument for GPs (ATCI-GP) one month after the pharmacist had been integrated into the practice. Survey instruments were also created for patients and pharmacist participating in the intervention. These were deployed after the initial consultation and at the end of the intervention period respectively, to elicit each stakeholders' views and experiences of the service. Data were analysed using descriptive statistics. RESULTS: In total, 48 GPs, 43/101 patients (43%) and 11/13 practice pharmacists (85%) completed the survey. The majority of GPs strongly agreed or agreed with all statements of the ATCI-GP, indicating support for the practice-integrated pharmacist model. Most patients agreed that there was a role for a pharmacist in their general practice (n = 28, 76%), and that they would like to see the pharmacist again (n = 34, 79%). Pharmacists indicated that they enjoyed the role (n = 11, 91%) and found the position professionally satisfying (n = 9, 82%). Most pharmacists agreed that co-location (inside the general practice itself, rather than in a co-located pharmacy) was beneficial (n = 8, 73%) and all pharmacists (100%) acknowledged the benefits of having access to patient medical records. Free text comments from GPs were enthusiastic overall, although some concerns about the financial viability of the model in the current setting were raised. The primary limitation of the study is the anonymous nature of the survey, meaning clustering of responses across the 14 sites could not be determined. CONCLUSIONS: A practice pharmacist model of care in the Australian primary care setting appears to be accepted by GPs, patients and practice pharmacists and provides promising evidence that this model of care is likely to be well accepted if implemented more broadly in the Australian healthcare setting, provided that it can be appropriately remunerated.

Exploring Transplant Medication-Taking Behaviours in Older Adult Kidney Transplant Recipients: A Qualitative Study of Semi-Structured Interviews.

BACKGROUND: Today, older adult patients routinely undergo kidney transplantation. To support graft survival, patients must take immunosuppressant medicines for the rest of their lives. The post-transplant medication regimen is complex, and barriers to medication taking are likely confounded by both functional and intrinsic changes associated with advancing age. To develop diverse and innovative approaches to support best health outcomes in this vulnerable age group, it is imperative that the degree to which patients' needs are currently being met, be identified. AIM: The aim of this study was to examine medication-taking behaviours of kidney transplant recipients transplanted at 60 years of age or older. METHODS: This qualitative study used semi-structured patient interviews to explore how kidney transplant recipients currently manage their immunosuppressant regimen and how they cope after transplantation with the complex routine. Data were themed using the principles of Grounded Theory methodology; with interviews conducted until data saturation was reached. RESULTS: Quantitative information was collected from 14 participants who ranged in age from 66 to 77 years (at time of interview), and were prescribed a median of 13 (min: 10, max: 26) medicines. The main themes that emerged from the interview were variability in health literacy toward medicines, the importance of support networks, the need to adjust health expectations, factors that were motivators for self-care, different approaches to medication management, and different approaches to medication taking. Overall, it was found that patients prioritised medication taking above all else, and gratitude to their donor was a powerful motivator to adhere. However, strategies to support medication taking were sometimes ineffective when patients' routine changed. CONCLUSIONS: Future interventions should consider approaches to foster adaptable medication taking behaviours that stand up to changes in the day-to-day routine.

Medication taking is complicated in transplant recipients, due to the number of medicines that need to be taken and the complex nature of the treatment regimen. Challenges in older transplant recipients may be more pronounced and varied compared with younger adults. There are multiple factors that may impact medication taking in older adults and each requires consideration, including level of dependence, living arrangements, level of mobility and manual dexterity, vision and memory, and social situation. To better identify the gaps in support, patients' current perspectives around medication taking and how they cope after transplantation must be explored. Therefore, this study aimed to identify how older adult transplant recipients currently manage their anti-rejection medicine regimen. Participants described several strategies around how they manage a complex medication regimen. These included cues such as an alarm and linking the time they should take their medication to already established habits such as eating meals. Most participants discussed at length their relationships, and it seems that these relationships are often crucial to post-transplant positivity. Additionally, extreme gratitude to the donor, relative improvement in their life quality (compared with the rapid deterioration in their health when on dialysis), and fear of consequences (particularly graft failure) were important facilitators of self-care and served as timely reminders to prioritise one's own health. To foster more robust medication-taking habits, future education needs to be tailored to each individual patient and include details about how to link medication taking to already established routines (coined 'habit stacking').

Benefits, challenges and contributors to the introduction of new hospital-based outpatient clinic pharmacist positions.

Background: Pharmacists working within interprofessional teams in the outpatient setting are well placed to address medication-related problems before and after hospital admission. Therefore, exploration of these roles is warranted. Objectives: To explore pharmacists' and other health professionals' perspectives of the impact of pharmacists working within interprofessional teams in outpatient clinics. Furthermore, we endeavoured to identify both the challenges and contributors to success with the introduction of pharmacists into these settings. Methods: This qualitative study involved semi-structured interviews with both hospital outpatient clinic pharmacists and other clinic health professionals to gain an in-depth understanding of how the introduction of pharmacists into clinics impacted clinic processes, patient care, and relationships with other health professionals. Participants were recruited from the outpatient clinics who had recently added a pharmacist to their service. Participants involved in setting up the roles were invited to participate in a voluntary interview, the transcripts from which were analysed into themes and sub-themes using an inductive and deductive approach. Results: A total of 34 staff were interviewed of which 68% were female and 74% were aged between 31 and 50 years. The cohort included 16 outpatient pharmacists, nine pharmacist team leaders, five clinic nurses and four clinic doctors (specialist consultant or registrar). Three overall themes were identified: the benefits, the contributors, and the challenges of introducing clinical pharmacy services to outpatient clinics. When establishing a clinic role, pharmacists' awareness, adaptability, and strong communication were shown to be key traits to building rapport and trustworthiness with the established clinic team. Conclusions: When pharmacists are integrated into multidisciplinary outpatient clinics they and their colleagues believe that they provide benefits to the patients and the clinics. Decision makers need to be cognizant of factors that contribute to, as well as those that impede, the successful implementation of outpatient pharmacist roles.

Comparison of free plasma versus saliva mycophenolic acid exposure following mycophenolate mofetil administration in adult kidney transplant recipients.

Therapeutic monitoring (TDM) of mycophenolic acid (MPA) has the potential to improve drug inefficacy and toxicities in kidney transplantation. However, measurement of plasma MPA concentrations is laborious and invasive. This study examined the utility of saliva compared with plasma based TDM of MPA. Paired blood and saliva samples were collected from 47 adult kidney transplant recipients pre- and at 1-, 2-, and 4-hours post mycophenolate mofetil administration. No relationship was observed between saliva MPA concentrations and either total or free plasma MPA concentrations (p > 0.05). This suggests that saliva is a poor direct marker of plasma MPA concentrations and therefore should not be used for MPA TDM.

Pharmacokinetic and Pharmacodynamic Considerations in Relation to Calcineurin Usage in Elderly Kidney Transplant Recipients.

This review summarizes how possible age-related changes in tacrolimus and cyclosporine pharmacokinetics and pharmacodynamics may influence drug dosing and monitoring in the elderly, and highlights how micro-sampling may be useful in this cohort in the future. Advancing biological age leads to physiological changes that can affect drug absorption, distribution, metabolism and excretion, as well as immune system responsiveness. Some studies have shown that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors, suggesting that doses may need to be lowered in elderly recipients. Only one study has examined how aging effects drug target enzyme activity and demonstrated that age does not correlate with the calcineurin inhibitor half-maximal inhibitory concentration. Several studies have shown elderly kidney transplant recipients have increased risk of both morbidity and mortality, compared to younger adults due to increased susceptibility to immunosuppressant side effects, particularly cardiovascular disease, infection and malignancy. Current immunosuppressant dosing and monitoring protocols often make no adjustments for age. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established. Blood draw by micro-sampling may be useful for drug monitoring in this cohort in the future, as blood collection is minimally invasive and less painful than venepuncture. Micro-sampling could also make further pharmacokinetic, pharmacodynamics and outcome studies in the elderly more feasible.

Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients.

This review examines what is currently known about the pharmacokinetics and pharmacodynamics of commonly prescribed immunosuppressant medicines, tacrolimus, cyclosporine, mycophenolate and prednisolone, in elderly renal transplant recipients, and reported patient outcomes in this cohort. Renal transplantation is increasing rapidly in the elderly, however, currently, long-term patient outcomes are relatively poor compared to younger adults. Some studies have suggested that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors tacrolimus and cyclosporine; with one study reporting up to 50% reduction in tacrolimus exposure in the elderly. Elderly transplant recipients do not appear to have higher dosage-adjusted exposure to mycophenolic acid (MPA). The effects of ageing on the pharmacokinetics of prednisolone are unknown. Only one study has examined how aging effects drug target enzymes, reporting no difference in baseline inosine 5'-monophosphate dehydrogenase (IMPDH) activity and MPA-induced IMPDH activity in elderly compared to younger adult renal transplant recipients. In elderly transplant recipients, immunosenescence likely lowers the risk of acute rejection, but increases the risk of drug-related adverse effects. Currently, the three main causes of death in elderly renal transplant recipients are cardiovascular disease, infection and malignancy. One study has showed that renal transplant recipients aged over 65 years are seven times more likely to die with a functioning graft compared with young adults (aged 18-29 years). This suggests that an optimal balance between immunosuppressant medicine efficacy and toxicity is not achieved in elderly recipients, and further studies are needed to foster long-term graft and patient survival. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established.

Investigating barriers to immunosuppressant medication adherence in renal transplant patients.

AIM: Immunosuppressant medication non-adherence can result in allograft rejection and loss. The aim of this study was to investigate the prevalence of non-adherence and barriers to adherence with immunosuppressant medications, in an adult renal transplant cohort. METHODS: Kidney transplant recipients completed a self-report survey consisting of five validated questionnaires (Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS), Beliefs about Medicines Questionnaire, Immunosuppressant Therapy Barrier Scale, Brief-Illness Perception Questionnaire, and Multidimensional Health Locus of Control Scale), and provided sociodemographic information. Adherence was categorised according to BAASIS, with adherence barriers compared between the groups. RESULTS: One hundred and sixty-one patients in total completed the survey. Eighty-six participants (55%) were categorised as non-adherent, with 45% delaying doses, and 25% skipping doses. Non-adherent patients were more likely to forget doses (P = 0.005), and more likely to skip doses when their daily routine changed (P < 0.001) or when short of money (P = 0.03). Additionally, non-adherent patients had less self-reported understanding about their graft than adherent patients (P = 0.008). Adherence was not associated with a patient's medicine beliefs or perception of locus of control. CONCLUSION: Over half the patients self-reported non-adherence. The main modifiable barriers leading to non-adherence were forgetfulness and skipped doses. Personalised interventions focused on habit forming may improve adherence in this population.