Dose‐response Study of 22‐Oxacalcitriol in Patients with Secondary Hyperparathyroidism

Abstract

The dose-response relationships and the safety of administering 22-oxacalcitriol (OCT) to patients with secondary hyperparathyroidism (2HPT) under regular three-times-weekly hemodialysis (HD) were evaluated by double-blind parallel group design. A total of 203 patients with 2HPT were randomly allocated into four groups, and 5 mg (Group L), 10 mg (Group M), or 15 mg (Group H) OCT, or placebo (Group P) was administrated at the end of every HD for 12 weeks. Reductions of intactparathyroid hormone (iPTH) concentration greater than 30% from baseline were observed in 7.7% of Group P as compared to 77.3% of the pooled OCT groups after 12 weeks of treatment (Mantel test: P < 0.001). Timetrends (slopes) of log-iPTH concentration calculated by least-squares line fitting to each patient's data during treatment differed between Group P and the pooled OCT groups (t-test: P < 0.001) and these iPTH slopes decreased dose-dependently (linear trend by t-test: P < 0.001). Slopes of serum calcium corrected for albumin (corrected-sCa) concentrations also differed between Group P and the pooled OCT groups (t-test: P < 0.001), and increased dose-dependently (linear trend by t-test: P < 0.0001). Serum phosphorus and Ca ¥ P product increased significantly only in high dose groups. Slopes of log(iPTH) and corrected-sCa concentrations were reciprocally related. Most adverse events were hypercalcemia and doserelated, but occasionally comprised pruritus or increased serum creatinine phosphokinase. These results indicate that OCT produced a strong and dose-dependent suppression of PTH and an increase of corrected-sCa concentration in patients with 2HPT. The recommended initial dosages of OCT would appear to be 5 mg when pretreatment iPTH concentrations are less than 500 pg/ mL, and 10 mg when greater than 500 pg/mL for safe and effective treatment. As in the case of PTH, calcium and phosphorus showed dose-dependent increases. It is therefore essential to take precautions as to possible increases in calcium and phosphorus.

Vitamin D analogs: Therapeutic applications and mechanisms for selectivity

“…Clinical trials in hemodialysis patients confirmed that OCT was effective in suppressing PTH levels (Akizawa et al, 2002(Akizawa et al, , 2004Hayashi et al, 2004;Tamura et al, 2005;Yasuda et al, 2003). Initial studies attained the targeted reduction in PTH (À30%) in 51% of the patients in a 1-year protocol (Akizawa et al, 2002), and in 44% (Yasuda et al, 2003) and 77% (Akizawa et al, 2004) of the patients treated for 12 weeks.…”

“…Initial studies attained the targeted reduction in PTH (À30%) in 51% of the patients in a 1-year protocol (Akizawa et al, 2002), and in 44% (Yasuda et al, 2003) and 77% (Akizawa et al, 2004) of the patients treated for 12 weeks. As expected, higher doses suppressed PTH more effectively and were associated with higher frequency of hypercalcemia (Akizawa et al, 2004).…”

“…Initial studies attained the targeted reduction in PTH (À30%) in 51% of the patients in a 1-year protocol (Akizawa et al, 2002), and in 44% (Yasuda et al, 2003) and 77% (Akizawa et al, 2004) of the patients treated for 12 weeks. As expected, higher doses suppressed PTH more effectively and were associated with higher frequency of hypercalcemia (Akizawa et al, 2004). Comparison of IV OCT (thrice weekly) to oral 1,25(OH) 2 D 3 (twice weekly) over 24 weeks, with dose adjustments to minimize hypercalcemia, yielded similar decreases in PTH levels (-35%) and increases in serum calcium levels (0.7-0.8 mg/dl), and no significant differences in episodes of elevated Ca  P product (Tamura et al, 2005).…”

The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease

“…Maxacalcitol has been shown to result in less hypercalcemia in animal models, but this has not translated into clinical trials 230 . In humans maxacalcitol has been shown to be effective in suppressing PTH levels 231–233 , but in a study of 124 dialysis patients treated with maxacalcitol, 41 experienced hypercalcemia 232 . There is a dose-dependent relationship between the dose of maxacalcitol and risk of hypercalcemia 231 .…”

CKD-MBD: impact on management of kidney disease

“…1,4,62 However, treatment with these drugs is limited in many cases because of hypercalcemia and hyperphosphatemia, particularly when they are used in conjunction with Ca-containing P binders. 1,2,63 Consequently, hypercalcemia, hyperphosphatemia, and a high Ca × P product lead to vascular and soft tissue calcifi cation.…”