Ida Robertsen

Use of generic tacrolimus in elderly renal transplant recipients: precaution is needed.

Background Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years. Methods Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio). Results Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve0–12 ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10–1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35–1.65). The generic formulation also showed a shorter time to Cmax (Tmax) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80). Conclusion Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.

Rimonabant affects cyclosporine A, but not tacrolimus pharmacokinetics in renal transplant recipients.

Background. Obesity is a common problem following renal transplantation. Rimonabant, a cannabinoid-1 receptor blocker, offers a new approach for reducing obesity. Methods. The potential pharmacokinetic interaction between rimonabant and cyclosporine A (CsA, n=10) and tacrolimus (Tac, n=8) was assessed in stable renal transplant recipients 6.2 (0.9–21.7) years posttransplant. A 12-hour pharmacokinetic profile was obtained before and after two months of concomitant treatment with 20 mg rimonabant each morning. Results. Rimonabant treatment induced a moderate, but significant increase in CsA AUC0–12 (19.8±16.1 %, P=0.005). Cmax and C2 values tended to increase whereas C0 remained unaffected. Tac pharmacokinetics was not significantly affected by rimonabant treatment. Eleven of 18 patients experienced adverse events. Two patients reported depressions and one reported severe nightmares. Conclusions. The effect on CsA pharmacokinetics is probably of marginal clinical relevance since trough concentrations were unaltered, but CsA concentrations should probably be more closely monitored if rimonabant treatment is initiated, preferably by C2 monitoring.

Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients

BackgroundIn the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections. Previous studies indicate that intracellular ciclosporin A (CsA) concentration may be a sensitive acute rejection marker in renal transplant recipients. The aims of this study were to evaluate the relationships between CsA concentrations at different target sites as potential therapeutic drug monitoring (TDM) tools in heart transplant recipients.MethodsTen heart transplant recipients (8 men, 2 women) on CsA-based immunosuppression were enrolled in this prospective single-center pilot study. Blood samples were obtained once to twice weekly up to 12 weeks post-transplant. One of the routine biopsies was allocated to this study at each sampling time. Whole blood, intralymphocyte, and endomyocardial CsA concentrations were determined with validated HPLC-MS/MS-methods. Mann–Whitney U test was used when evaluating parameters between the two groups of patients. To correlate whole blood, intralymphocyte, and endomyocardial CsA concentrations linear regression analysis was used.ResultsThree patients experienced mild rejections. In the study period, the mean (range) intralymphocyte CsA trough concentrations were 10.1 (1.5 to 39) and 8.1 (1.3 to 25) ng/106 cells in the rejection and no-rejection group, respectively (P=0.21). Corresponding whole blood CsA concentrations were 316 (153 to 564) and 301 (152 to 513) ng/mL (P=0.33). There were no correlations between whole blood, intralymphocyte, or endomyocardial concentrations of CsA (P >0.11).ConclusionsThe study did not support an association between decreasing intralymphocyte CsA concentrations and acute rejections. Further, there were no association between blood concentrations and concentrations at sites of action, potentially challenging TDM in these patients.

High tacrolimus clearance is a risk factor for acute rejection in the early phase after renal transplantation.

Background Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes. Methods A retrospective study in all renal transplant patients treated with tacrolimus at our center from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [&mgr;g/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated. Results In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. Conclusions High estimated clearance is significantly associated with increased risk of BPAR the first 90 days posttransplantation and may predict an increased risk of rejection in the early phase after renal transplantation.

More potent lipid-lowering effect by rosuvastatin compared with fluvastatin in everolimus-treated renal transplant recipients.

Background Dyslipidemia is a risk factor for premature cardiovascular morbidity and mortality in renal transplant recipients (RTRs). Pharmacotherapy with mTOR inhibitors aggravates dyslipidemia, thus necessitating lipid-lowering therapy with fluvastatin, pravastatin, or atorvastatin. These agents may not sufficiently lower lipid levels, and therefore, a more potent agent like rosuvastatin maybe needed. Methods We have aimed to assess the lipid-lowering effect of rosuvastatin as compared with fluvastatin in RTR receiving everolimus. Safety was assessed as the pharmacokinetic (PK) interaction potential of a rosuvastatin/everolimus combination in RTR. A 12-hour everolimus PK investigation was performed in 12 stable RTR receiving everolimus and fluvastatin (80 mg/d). Patients were then switched to rosuvastatin (20 mg/d), and a follow-up 12/24-hour PK investigation of everolimus/rosuvastatin was performed after 1 month. All other drugs were kept unchanged. Results In RTR already receiving fluvastatin, switching to rosuvastatin further decreased LDL cholesterol and total cholesterol by 30.2±12.2% (P<0.01) and 18.2±9.6% (P<0.01), respectively. Everolimus AUC0–12 was not affected by concomitant rosuvastatin treatment, 80.3±21.3 &mgr;g*h/L before and 78.5±21.9 &mgr;g*h/L after, respectively (P=0.61). Mean rosuvastatin AUC0-24 was 157±61.7 ng*h/mL, approximately threefold higher than reported in the literature for nontransplants. There were no adverse events, and none of the patients had or developed proteinuria. Conclusion Rosuvastatin showed a superior lipid-lowering effect compared to fluvastatin in stable RTR receiving everolimus. The combination of everolimus/rosuvastatin seems to be as safe as the everolimus/fluvastatin combination.

High-Dose Fish Oil Supplementation Increase Tacrolimus Exposure in Stable Renal Transplant Recipients

Introduction Development of cardiovascular (CV) disease due to unwanted side effects of immunosuppression is common following renal transplantation. Tacrolimus (Tac) is known to have negative impact on CV risk factors. In this setting, high-dose fish oil supplementation may have beneficial effects on both renal function and CV risk profile. However, it is not known if administration of fish oil affects Tac concentrations. The aim of the present study was to investigate the potential effects of fish oil on once-daily Tac pharmacokinetics in renal transplant recipients. Methods A single center prospective study was conducted. Fifteen stable renal transplant recipients receiving once-daily tacrolimus (Advagraf®), mycophenolate and a steroid-based immunosuppression were included in the study. Two 8-hr pharmacokinetic investigations were performed before and after 4 weeks of fish oil administration (2.55 g/day). Tac dosing remained unchanged during the treatment period. Standard non-compartmental methods were used to determine pharmacokinetic parameters and the European Medicines Agency guidelines for bioequivalence studies to assess the possible pharmacokinetic interaction. Results Twelve patients, median age 59 years (range 28-75) provided 2 evaluable pharmacokinetic Tac profiles. Concomitant administration of fish oil induced a 25 ± 30% increase in tacrolimus AUC0-8 (P< 0.01). The bioequivalence criteria were not fulfilled; the mean before:after AUC0-8 and Cmax ratios were 1.22 (90% CI: 1.08-1.37) and 1.20 (90% CI: 1.11-1.30), respectively. Tac trough concentrations also tended to increase from 5.5 ± 1.2 &mgr;g/L before to 6.3 ± 1.8 &mgr;g/L after administration of fish oil (P=0.19). Conclusions In renal transplant recipients, fish oil administration significantly increased the exposure of once-daily Tac. It is therefore advisable and warranted to closely monitor Tac concentrations following initiation and discontinuation of high-dose fish oil supplementation.

High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study

Patients with high tacrolimus clearance are more likely to experience transient under‐immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1‐year post‐transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1‐year post‐transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11–2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18–3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.

Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL)

Introduction Roux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups. Methods and analysis This open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUCoral/AUCiv) of midazolam (CYP3A4 probe), systemic exposure (AUCoral) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers. Ethics and dissemination The COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants. Trial registration number NCT02386917.