Laura A. Williams

Comparative Mortality Risks of Chronic Dialysis and Cadaveric Transplantation in Black End-Stage Renal Disease Patients

In view of the relatively low mortality risk on dialysis and the high risk of allograft loss among black compared with white end-stage renal disease (ESRD) patients, we studied the relative mortality risks of all black renal transplant candidates in Michigan from 1984 to 1989. There were 770 black ESRD patients followed from wait-listing for cadaveric (CAD) kidney transplantation until the time of transplantation, death, or December 31, 1989. The time on dialysis prior to wait-listing exceeded 1 year in 24% of these patients. Black diabetic patients on the waiting list have more than twofold relative mortality risk (RR) compared with nondiabetic individuals (RR = 2.73, P < 0.001) while the RR by diabetes status among CAD transplant recipients was small. Overall, CAD transplantation was associated with elevated risk of mortality in the first month posttransplantation (RR = 3.39, P < 0.03). Cadaveric donor transplant and wait-listed dialysis patients have equal death rates 112 days after transplantation. Thereafter, death rates were lower for transplant recipients compared with transplant candidates on dialysis. One year after transplantation, CAD transplant recipients on the average have approximately half the risk of death compared with dialysis patients who remain on the waiting list (RR = 0.49, P < 0.03). The cumulative survival probabilities are superior in transplant recipients just beyond 1 year after transplantation. Therefore, CAD transplantation in black ESRD patients is associated with a high risk of mortality in the early period after transplantation. Beyond 1 year, black transplant recipients have a substantial survival advantage over corresponding dialysis patients on the waiting list.

Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis.

Background/Aims: Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD). Methods: Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week’s intact PTH (iPTH) level as well as calcium and Ca × P product levels. The primary end points were efficacy (two consecutive iPTH decreases of ≧30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed. Results: Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH ≤500 pg/ml and iPTH >500 pg/ml were 3.9 and 7.6 µg, respectively. A statistically significant decrease in iPTH was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive ≧30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo. Conclusion: Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

Differential Effects of Paricalcitol and Calcitriol on Intestinal Calcium Absorption in Hemodialysis Patients

Background/Aims: Increased parathyroid activity associated with chronic kidney disease is often managed with calcitriol, which can elevate serum calcium (Ca) by increasing bone resorption and intestinal absorption, whereas paricalcitol promotes less bone resorption. This study compared intestinal Ca absorption in hemodialysis patients treated with calcitriol versus paricalcitol (dose ratio 1:3). Methods: Patients (n = 22) aged ≧20 years, on maintenance hemodialysis for ≧2 months with intact parathyroid hormone (iPTH) levels of >200 pg/ml were enrolled in a single-center, double-blind, active-controlled, randomized, crossover trial. Mean fractional intestinal Ca absorption (±SE) was measured by the single-tracer method (42Ca) and evaluated with an analysis of variance crossover model. Results: Mean fractional intestinal Ca absorption was significantly lower after paricalcitol (0.135 ± 0.006) versus calcitriol treatment (0.158 ± 0.006, p = 0.022), a 0.023 difference in absolute Ca absorption fraction. Overall Ca absorption was low in the study population, indicating that regulation of Ca absorption may be dysfunctional. There were no significant differences in serum PTH, Ca, phosphorus (P), or Ca × P. Conclusion: Overall, paricalcitol-treated patients absorbed ∼14% less Ca compared with calcitriol-treated patients with similar effects on PTH. In hemodialysis patients, paricalcitol may provide a benefit by lowering the Ca available for removal by dialysis and/or for deposit in bone or soft tissues.

A Comparison of Dosing Regimens of Paricalcitol Capsule for the Treatment of Secondary Hyperparathyroidism in CKD Stages 3 and 4

Background: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. Methods: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. Results: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive ≧30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca × P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. Conclusions: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive ≧30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca × P product as compared with placebo or intermittent dosing.

Health-Economic Comparison of Paricalcitol, Calcitriol and Alfacalcidol for the Treatment of Secondary Hyperparathyroidism during Haemodialysis

This study evaluated the health-economic consequences of use of intravenous paricalcitol (Zemplar®), oral calcitriol or oral and intravenous alfacalcidol for the treatment of patients with secondary hyperparathyroidism, focusing on a third-party payer perspective through inclusion of medication and hospital costs, survival rates and utilities. Cost values were based on German treatment recommendations and prices. Reference values for survival rates and utilities were based on the results of a MEDLINE search. The analysis showed a clear advantage for intravenous paricalcitol with respect to costs, effectiveness and utilities compared with treatment with oral calcitriol or intravenous alfacalcidol. Since the results were very cost sensitive with respect to selected diagnosis-related groups (DRGs) for kidney disease with dialysis, a sensitivity analysis was performed. This demonstrated first-order dominance of intravenous paricalcitol for a wide range of hospitalisation costs. In conclusion, this analysis suggested a clear benefit from the perspective of a third-party payer for intravenous paricalcitol compared with oral calcitriol and intravenous alfacalcidol in the treatment of patients with secondary hyperparathyroidism.

Pharmacoeconomic analysis of paricalcitol and calcitriol in the treatment of secondary hyperparathyroidism in haemodialysis: impact of hospitalisations and survival

Summary The objective of this study was to evaluate the cost effectiveness of paricalcitol injection compared with calcitriol injection when used to reduce parathyroid hormone levels in patients undergoing haemodialysis. A decision tree was developed to model the 1-year costs and outcomes of therapy for secondary hyperparathyroidism from a US government payers perspective (2005 US

Exposure—Clinical Response Analysis of Paricalcitol in Patients With Chronic Kidney Disease (Stage 5) on Hemodialysis or Peritoneal Dialysis

). Probabilities of hospitalisations and survival with paricalcitol and calcitriol were obtained from published observational studies. When only drug costs and survival were considered, the incremental cost effectiveness of paricalcitol over calcitriol was

Antiproteinuric effect of oral paricalcitol in chronic kidney disease

9,900 per life saved. When utilities were included, the incremental cost-effectiveness ratio for paricalcitol compared with calcitriol was

Paricalcitol Capsule for the Treatment of Secondary Hyperparathyroidism in Stages 3 and 4 CKD

13,200 per quality-adjusted life year. When both drug and hospitalisation costs were included in a cost analysis, paricalcitol treatment was cost saving compared with calcitriol, and when hospitalisation costs were included in both the cost-effectiveness analysis and cost-utility analysis paricalcitol demonstrated first-order dominance, cost savings and cost effectiveness. This decision analysis demonstrated that paricalcitol injection is both cost effective and cost saving compared with calcitriol injection.

Intravenous Paricalcitol for Treatment of Secondary Hyperparathyroidism in Children on Hemodialysis

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure‐response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure—clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC50; and bone—specific alkaline phosphatase on calcium EC50 (CRIT). This exposure‐response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.