Optimizing drug therapy in liver transplantation:For better patient outcomes

In this thesis we showed that adapting immunosuppressive agents based on patients’ comorbidities and side effects is essential in order to modify and minimize immunosuppressive related toxicity (i.e. renal insufficiency, hypertension, post-transplant diabetes mellitus). We showed that 1) once-daily low-dose SRL combined with low-dose extended-release tacrolimus does ultimately not provide less chronic kidney disease grade ≥3 at 36 months compared to normal-dose extended release tacrolimus (LOL study) and 2) LCP-tacrolimus provides better results compared to ER-tacrolimus (MOTTO study). Based on findings in this thesis we suggested that low-dose ribavirin for at least 180 days has a positive effect on hepatitis E virus clearance in solid organ transplant recipients. Next, immunosuppressive agents affecting the B lymphocytes reduce the immunogenicity of vaccination in LT recipients. This should be considered when vaccinating LT recipients. Finally, until the start of this thesis, in the Netherlands clinical pharmacists were solely involved in therapeutic drug monitoring of immunosuppressive agents and computerized medication monitoring. In this thesis, we showed that clinical pharmacists can have an added value in the clinical and outpatient transplant care and increase the medication safety and efficacy for these patients. Overall, we added new insights to the field of optimizing drug therapy for LT recipients to improve patient outcomes.<br/

Optimizing drug therapy in liver transplantation:For better patient outcomes

In this thesis we showed that adapting immunosuppressive agents based on patients’ comorbidities and side effects is essential in order to modify and minimize immunosuppressive related toxicity (i.e. renal insufficiency, hypertension, post-transplant diabetes mellitus). We showed that 1) once-daily low-dose SRL combined with low-dose extended-release tacrolimus does ultimately not provide less chronic kidney disease grade ≥3 at 36 months compared to normal-dose extended release tacrolimus (LOL study) and 2) LCP-tacrolimus provides better results compared to ER-tacrolimus (MOTTO study). Based on findings in this thesis we suggested that low-dose ribavirin for at least 180 days has a positive effect on hepatitis E virus clearance in solid organ transplant recipients. Next, immunosuppressive agents affecting the B lymphocytes reduce the immunogenicity of vaccination in LT recipients. This should be considered when vaccinating LT recipients. Finally, until the start of this thesis, in the Netherlands clinical pharmacists were solely involved in therapeutic drug monitoring of immunosuppressive agents and computerized medication monitoring. In this thesis, we showed that clinical pharmacists can have an added value in the clinical and outpatient transplant care and increase the medication safety and efficacy for these patients. Overall, we added new insights to the field of optimizing drug therapy for LT recipients to improve patient outcomes.<br/

Differences in CYP3A genotypes of a liver transplant recipient and the donor liver graft and adjustment of tacrolimus dose

Tacrolimus (Tac) is well established as main immunosuppressant in most immunosuppressive regimens in solid organ transplantation. Due to the narrow therapeutic window, pre dose Tac levels (C0) are monitored in all patients receiving Tac to reach optimal therapeutic levels. Tac is metabolized in the liver and intestine by the cytochrome P450 3A (CYP3A) isoforms CYP3A4 and CYP3A5. We present a case of an African American woman who underwent a liver transplantation in which adequate Tac levels were difficult to accomplish due to differences in cytochrome P450 3A4/5 (CYP3A4/5) polymorphisms of the transplant recipient and the donor liver graft. This case report highlights that genotyping the liver transplant recipient and the donor liver graft might provide data which could be used to predict the tacrolimus metabolism post transplantation

Medication-Related Problems in Liver Transplant Recipients in the Outpatient Setting: A Dutch Cohort Study

Background: After liver transplantation (LTx), adherence to immunosuppressive medication and avoidance of contra-indicated drugs is essential for long-term survival. This study aimed to investigate the prevalence, types and severity of medication-related problems (MRPs) and interventions initiated by a clinical pharmacist (CP) in a cohort of LTx recipients in the outpatient setting. Method: This study was a retrospective, observational study in LTx recipients that visited the outpatient clinic for an annual check-up. A 20-minutes consultation with a CP consisted of medication reconciliation and consultation about medication, adherence, and adverse drug reactions (ADRs). Discrepancies between actual and intended drug use, and MRPs were identified and the severity of MRPs was assessed. Potential interventions were discussed with the patient and the treating physician and evaluated after one year. Results: The CP counseled 64 LTx recipients and found 96 discrepancies in 37 patients. Most discrepancies (60.4%, n = 58) concerned missing medications. In total, 98 MRPs were identified in 53 patients (median 2; range 1-5 per patient), with a total of 113 interventions. Most frequent MRPs were: ADRs (22.4%, n = 22), nonadherence (19.3%, n = 19), unnecessary drugs (16.3%, n = 16) and undertreatment (12.2%, n = 12). Interventions most frequently proposed included optimization of dosage regimen (21.2%, n = 24), individualized recommendation regarding compliance (16.8%, n = 19) and drug discontinuation (12.4%, n = 14). After one year, 15 of the 19 patients (79%) experienced no longer compliance issues and 27 of the 29 patients (93%) used no drugs with indication issues anymore. Conclusion: The CP in an outpatient monitoring program for LTx recipients can signal relevant discrepancies and MRPs. This leads to interventions that are accepted by both the patients and the physicians, with a positive effect after one year

Oral antibiotics lower mycophenolate mofetil drug exposure, possibly by interfering with the enterohepatic recirculation: A case series

Mycophenolate mofetil has an important role as immunosuppressive agent in solid organ transplant recipients. Exposure to the active mycophenolic acid (MPA) can be monitored using therapeutic drug monitoring. We present three cases in which MPA exposure severely decreased after oral antibiotic coadministration. By diminishing gut bacteria β-glucuronidase activity, oral antibiotics can prevent deglucuronidation of the inactive MPA-7-O-glucuronide metabolite to MPA and thereby possibly prevent its enterohepatic recirculation. This pharmacokinetic interaction could result in rejection, which makes it clinically relevant in solid organ transplant recipients, especially when therapeutic drug monitoring frequency is low. Routine screening for this interaction, preferably supported by clinical decision support systems, and pragmatic close monitoring of the MPA exposure in cases is advised

Modifying Tacrolimus-related Toxicity After Liver Transplantation Comparing Life Cycle Pharma Tacrolimus Versus Extended-released Tacrolimus:A Multicenter, Randomized Controlled Trial

Background:The aim of this open-label, multicenter, randomized controlled study was to investigate whether the life cycle pharma (LCP)-tacrolimus compared with the extended-release (ER)-tacrolimus formulation results in a difference in the prevalence of posttransplant diabetes, hypertension and chronic kidney disease (CKD) at 12 mo after liver transplantation.Methods:Patients were 1:1 randomized to either of the 2 tacrolimus formulations. The primary endpoint was defined as a composite endpoint of any of 3 events: sustained (&gt;3 mo postrandomization) posttransplant diabetes, new-onset hypertension, and/or CKD, defined as estimated glomerular filtration rate &lt;60 mL/min/1.73 m2 for &gt;3 m during the follow-up.Results:In total, 105 patients were included. In the intention-to-treat analysis, a statistically significant lower proportion of liver transplant recipients in the LCP-tacrolimus group reached the composite primary endpoint at 12 mo compared with the ER-tacrolimus group (50.9% [27/53], 95% confidence interval [CI], 37.9%-63.9% versus 71.2% [37/52], 95% CI, 57.7%-81.7%; risk difference: 0.202; 95% CI, 0.002-0.382; P = 0.046). No significant difference was found in the per protocol analysis. In the intention-to-treat and per protocol population, fewer liver transplant recipients in the LCP-tacrolimus group developed CKD and new-onset hypertension compared with the ER-tacrolimus group. No differences in rejection rate, graft and patient survival were found. Conclusions:A statistically significant and clinically relevant reduction in the prevalence of the composite primary endpoint was found in the LCP-tacrolimus group compared with the ER-tacrolimus group in the first year after liver transplantation with comparable efficacy.</p

Therapeutic drug monitoring of immunosuppressive drugs in hepatology and gastroenterology

Immunosuppressive drugs have been key to the success of liver transplantation and are essential components of the treatment of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). For many but not all immunosuppressants, therapeutic drug monitoring (TDM) is recommended to guide therapy. In this article, the rationale and evidence for TDM of tacrolimus, mycophenolic acid, the mammalian target of rapamycin inhibitors, and azathioprine in liver transplantation, IBD, and AIH is reviewed. New developments, including algorithm-based/computer-assisted immunosuppressant dosing, measurement of immunosuppressants in alternative matrices for whole blood, and pharmacodynamic monitoring of these agents is discussed. It is expected that these novel techniques will be incorporate into the standard TDM in the next few years

Evaluation of medication-related problems in liver transplant recipients with and without an outpatient medication consultation by a clinical pharmacist: a cohort study

Background: Transplant recipients undergo significant changes in their medication regimen during follow-up and are at an increased risk for medication-related problems (MRPs). Aim: This study aimed to compare the prevalence and types of MRPs and interventions in liver transplant recipients with and without an outpatient medication consultation by a clinical pharmacist as well as the satisfaction with information about medicines and medication adherence. Method: We performed a single-center, observational cohort study. A retro- and prospective cohort were used and subdivided in a group that did and did not receive a medication consultation. The prevalence and types of MRPs and interventions were identified and categorized. The satisfaction parameters were evaluated using validated questionnaires. Results: Included were 291 patients. In total, 368 MRPs were identified in 197 patients in the non-medication consultation cohort (median 1; range 1–3 per patient) and 248 MRPs in 94 patients in the medication consultation cohort (median 2; range 1–4 per patient). In the medication consultation cohort, significantly fewer MRPs as unnecessary drugs (17.3% versus 58.7%, p < 0.001), suboptimal therapy (2.4% versus 9.5%, p < 0.001), untreated indication (2.8% versus 6.8%, p = 0.040) and underdosed drugs (0.4% versus 6.3%, p < 0.001) were identified. In the non-medication consultation cohort significantly more patients used unnecessary drugs (72.1% versus 39.4%, p < 0.001) compared to the medication consultation cohort. Patients in both cohorts are satisfied with the information about medicines and reported a high medication adherence. Conclusion: Patients in the medication consultation cohort had significantly fewer MRPs and used significantly less unnecessary drugs. Including a clinical pharmacist to the post-transplant care has an added value