Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial.

BACKGROUND: Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. METHODS: A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). RESULTS: Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. CONCLUSIONS: The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.

Body mass index, weight-adjusted immunosuppression and the risk of acute rejection and infection after kidney transplantation: a cohort study.

BACKGROUND: Body mass index (BMI) is associated with patient outcomes after kidney transplantation. We hypothesized that immunosuppression (IS) dosing is a contributing factor. METHODS: Using Australia and New Zealand Dialysis and Transplant registry data, we included all adult kidney-only transplant recipients over 2000-14 treated with prednisolone, mycophenolate and tacrolimus/cyclosporin (n = 7919). The exposure was BMI and the outcomes were time to: (i) acute rejection, (ii) fatal infection, (iii) cancer and (iv) graft; and (v) patient survival. We modelled BMI and IS dosing (in quartiles) as time-varying covariates in extended Cox models. RESULTS: Compared with a BMI of 25 kg/m2, a BMI of 35 was associated with acute rejection after adjusting for demographics and comorbidities [adjusted hazard ratio (aHR) = 1.29, 95% confidence interval (CI) 1.12-1.49]. This association virtually disappeared after correcting for IS (aHR = 1.09, 95% CI 0.93-1.29). A BMI of 35 was non-significantly associated with fewer fatal infections (aHR = 0.91, 95% CI 0.66-1.25), but this reversed after adjusting for IS (aHR = 1.54, 95% CI 1.03-2.28). Results for cancer were not significantly altered after adjusting for IS. Results for lower BMI were similarly not significantly altered though generally associated with worse outcomes. CONCLUSIONS: Our findings show that the associations between high BMI, acute rejection and fatal infection after kidney transplantation were significantly altered after correcting for IS suggesting that relative under-dosing of obese patients may partially explain these associations.

Effect of gastric acid suppression with pantoprazole on the efficacy of sevelamer hydrochloride as a phosphate binder in haemodialysis patients: a pilot study.

Sevelamer hydrochloride (HCL) is thought to require an appropriately acidic environment in order to bind gastrointestinal phosphate. Changes in gastric acidity with acid suppressants may therefore alter the efficacy of sevelamer HCL. Given the widespread use of acid suppression therapy in chronic kidney disease patients, there is potential for a common significant drug interaction to occur. This pilot study evaluated the in vivo effect of gastric acid suppression with pantoprazole on the efficacy of sevelamer HCL as a phosphate binder in maintenance haemodialysis patients. The study protocol was a cross-over, double-blinded, randomized, placebo-controlled trial in 10 haemodialysis patients randomly assigned to pantoprazole 40 mg daily or placebo for two consecutive 6-week periods. Serum phosphate was not significantly altered during pantoprazole compared with placebo treatment (1.61 ± 0.45 mmol/L vs 1.76 ± 0.42 mmol/L, P = 0.204). There were no differences in serum calcium, parathyroid hormone and bicarbonate. This pilot study demonstrates preliminary in vivo evidence for no effect of gastric acid suppression on the effectiveness of sevelamer HCL. Our results are limited by small sample size and therefore, larger experimental studies should be conducted. Although our study did not find a significant drug interaction, given the high prevalence of acid suppressant use in dialysis patients, physicians should be aware of the potential influence of acid suppression on the efficacy of phosphate binders and regularly assess the clinical need for acid suppression therapy.

Effect of gastric acid suppression with pantoprazole on the efficacy of calcium carbonate as a phosphate binder in haemodialysis patients.

AIM: Metallic phosphate binders require acidity to dissociate to the free metallic ion and bind phosphorus. Altered gastric acidity may, therefore, influence phosphate-binding efficacy. We evaluated the clinical effect of pantoprazole on the efficacy of calcium carbonate phosphate binders in haemodialysis patients. METHODS: The study had two parts: a cross-sectional study (n = 67), and an interventional, crossover, double-blind, randomized, placebo-controlled trial in 26 patients given pantoprazole 40 mg daily or placebo for two consecutive 6-week periods. RESULTS: The cross-sectional study showed no difference between those on and off acid suppressants in phosphate (1.43 ± 0.45 vs 1.46 ± 0.31 mmol/L, P = 0.782) or other parameters except age (72.2 ± 9.8 vs 63.8 ± 14.8 years, P = 0.01). In the interventional study, phosphate was higher during pantoprazole than placebo (1.59 ± 0.3 vs 1.42 ± 0.3 mmol/L, P = 0.005). Serum calcium (2.37 ± 0.2 vs 2.46 ± 0.2 mmol/L, P = 0.012) and ionized calcium (1.17 ± 0.1 vs 1.22 ± 0.1 mmol/L, P = 0.013) were lower during pantoprazole treatment. CaxPO(4) (3.76 ± 0.7 vs 3.48 ± 0.7 mmol(2) /L(2) , P = 0.032) and intact parathyroid hormone (31.9 ± 21.4 vs 23.6 ± 17.7 pmol/L, P = 0.004) were higher on pantoprazole. CONCLUSION: These results demonstrate clinical evidence for an adverse effect of gastric acid suppression on the effectiveness of calcium carbonate phosphate binders. Given their frequent co-prescription, this interaction may be a minor but common reason why some patients fail to control hyperphosphataemia. Clinicians should regularly assess the need for acid suppressants. Further studies are needed to investigate interactions with other phosphate binders.

Randomized cross-over comparison of intravenous and subcutaneous darbepoetin dosing efficiency in haemodialysis patients.

BACKGROUND: Studies have consistently shown the superior dosing efficiency of subcutaneous (s.c.) compared to intravenous (i.v.) erythropoietin (r-HuEPO). Unlike r-HuEPO, data from pivotal darbepoetin trials support s.c. and i.v. dosing equivalence, however, no blinded cross-over randomized studies of s.c. and i.v. dose efficiency or intra-patient variability in response have been published. METHODS: During this 12-month study, 53 haemodialysis patients were randomized to s.c. or i.v. darbepoetin for a 6-month period and then switched to the alternative route for a second 6-month period. Darbepoetin dose was titrated during the first 4-months of each period to achieve a stable haemoglobin during the final 2-month observation period of each arm. RESULTS: Twenty-four patients were included in analysis. No significant difference between s.c. and i.v. administration was observed for any measured parameter. Patients achieved a non-significantly higher haemoglobin (123.6 +/- 3.76 vs 120.9 +/- 4.42 g/L, P = 0.11) from a non-significantly lower darbepoetin dose (40.8 +/- 10.7 vs 42.5 +/- 11.0 mcg/week, P = 0.23) with i.v. administration. The population-based weight normalized s.c./i.v. dose ratio was 1.04 (0.97-1.11). Despite no significant overall difference, some patients experienced changes in individual dose efficiency response. Three of 24 patients recorded a greater than 30% change, four of 24 recorded between a 20 and 30% change, and five of 24 patients recorded between a 10 and 20% change relative to i.v. dose efficiency. CONCLUSIONS: This study further supports s.c. and i.v. dosing equality and that overall the more convenient i.v. route can be used with equal dosing efficiency. However, patients switching routes of administration should be monitored due to the wide range in individual response.

Comparison of trough, 2-hour, and limited AUC blood sampling for monitoring cyclosporin (Neoral) at day 7 post-renal transplantation and incidence of rejection in the first month.

The use of alternative strategies to the traditional pre-dose/trough (C0) blood sampling for cyclosporine (CsA) therapeutic drug monitoring has the potential to revolutionize analytical practices which have, in many centers, been established for some 20 years. While the C0 sample has previously been recommended, current attitudes are increasingly proposing alternatives for assessing CsA exposure, including various limited sampling strategies of the AUC (lssAUC) in the early postdose period, or alternative single-point nontrough samples, such as a 2-hour postdose sample (C2). The present study has reviewed a series of consecutive renal transplant recipients over 18 months where CsA was the primary immunosuppressant. The lssAUC performed at around day 7 posttransplantation included drawing blood at 0, 2, and 4 hours postdose, giving AUC(0-4). The aim of this study was to review the occurrence of acute biopsy-proven rejection in the first month and consider which of (simultaneously measured) C0, C2 or AUC(0-4) was a better early indicator of this adverse outcome. The result was best described by comparing the data from rejectors (n = 13) and nonrejectors (n = 42) for these 3 indices of CsA exposure (i.e., C0, C2 or AUC(0-4)). There was no evidence that C0 predicted the likelihood of such adverse clinical outcomes. In contrast, rejectors tended to have lower mean C2 CsA concentrations, and the incidence of rejection was 0.0 when C2 exceeded 1200 microg/L (n = 10). While the data are limited in the higher C2 CsA concentration range, it is nevertheless consistent with more recent recommendations suggesting that the CsA at C2 should target 1700 microg/L in this first month posttransplantation. As 64% of the patients were also receiving a CsA-sparing agent (diltiazem [DTZ]), the relationships were also investigated to determine whether any affect of concomitant DTZ therapy could be demonstrated. However, in this small sample, no significant affect of DTZ was seen.