Efficacy and Side Effects of Intermittent Intravenous and Oral Doxercalciferol (1␣-Hydroxyvitamin D2) in Dialysis Patients With Secondary Hyperparathyroidism: A Sequential Comparison Hla M. Maung, MD, Loganathan Elangovan, MD, Joa˜o M. Fraza˜o, MD, PhD, John D. Bower, MD, Bobby J. Kelley, MD, Sergio R. Acchiardo, MD, Hector J. Rodriguez, MD, PhD, Keith C. Norris, MD, Jerald F. Sigala, MD, Mark Rutkowski, MD, John A. Robertson, MD, William G. Goodman, MD, Barton S. Levine, MD, Russell W. Chesney, MD, Richard B. Mazess, PhD, Darlene M. Kyllo, RAC, Laura L. Douglass, RN, Charles W. Bishop, PhD, and Jack W. Coburn, MD ● Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1␣D2) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1␣D2; the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 ⴞ 0.14 and 9.67 ⴞ 0.11 mg/dL during oral and intravenous 1␣D2 treatment, respectively (P ⴝ not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 ⴞ 0.21 and 5.60 ⴞ 0.21 mg/dL, respectively (P ⴝ NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1␣D2 reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1␣D2 therapy, suggesting that intravenous 1␣D2 therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Intact parathyroid hormone (iPTH); renal osteodystrophy; secondary hyperparathyroidism; hemodialysis (HD); renal failure; 1␣-hydroxyvitamin D2 (1␣D2); doxercalciferol (1␣D2); intravenous trial; oral trial; vitamin D; hypercalcemia; hyperphosphatemia.
From Medical and Research Services, Veterans Affairs West Los Angeles Healthcare Center; Department of Medicine, Cedars Sinai Medical Center, University of California at Los Angeles School of Medicine; Department of Medicine, Charles R. Drew University, Los Angeles, CA; Departments of Pediatrics and Medicine, University of Tennessee at Memphis, TN; Nephrology Division, University of Mississippi, Jackson, MS; and Bone Care International, Inc, Madison, WI. Received July 25, 2000; accepted in revised form October 6, 2000. Supported in part by a grant from Bone Care International, Inc, and grant no 1 P20 RR11145-01 from the National Institutes of Health, National Center for Research Resources (K.C.N.). Address reprint requests to Jack W. Coburn, MD, Nephrology Section (111L), VA West Los Angeles Healthcare Center, 11301 Wilshire Blvd, Los Angeles, CA 90073. E-mail:
[email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3703-0009$35.00/0 doi:10.1053/ajkd.2001.22077 532
RAL DOXERCALCIFEROL (1␣-hydroxyvitamin D2 [1␣D2]) has been shown to be highly effective in reducing plasma intact parathyroid hormone (iPTH) levels in hemodialysis patients with moderate to severe secondary hyperparathyroidism.1,2 The same total weekly dose of 1␣D2 suppressed iPTH levels similarly, independent of whether 1␣D2 was administered on a thrice-weekly or daily basis.3 Also, suppression of iPTH by 1␣D2 was accompanied by a low frequency of hypercalcemia.1,2 Intermittent intravenous dosing of the vitamin D sterols, calcitriol or paricalcitol, is widely used in the United States, and there are advantages in terms of good patient compliance and a favorable reimbursement policy. After the introduction of intermittent intravenous calcitriol therapy,4 several studies compared the intermittent oral route of administration with either intravenous5-12 or intra-
O
American Journal of Kidney Diseases, Vol 37, No 3 (March), 2001: pp 532-543
INTRAVENOUS VERSUS ORAL 1␣D2
peritoneal13 treatment. Most reports detected no difference between oral and intravenous administration,5,7,8,10-12 but two reports described greater effects of parenteral over oral calcitriol to increase serum calcium levels and reduce iPTH levels.9,13 The present study was undertaken to evaluate the effectiveness and safety of intravenous 1␣D2 and compare the effect of intermittent oral 1␣D2 with intravenous 1␣D2, with the same patients administered the sterol by both routes. Patients administered oral 1␣D2 in an earlier trial2 later entered onto a trial with intravenous 1␣D2. The two trials were separated by a variable interval free of 1␣D2 therapy, and identical 8-week washout periods preceded each trial. The results show similar suppression of plasma iPTH levels; however, increments in both serum calcium and serum phosphorus levels were significantly less during intermittent intravenous 1␣D2 compared with earlier intermittent oral treatment. MATERIALS AND METHODS
Patients This multicenter open-label study compares intravenous 1␣D2 with oral 1␣D2 therapy, each administered to the same hemodialysis patients with secondary hyperparathyroidism. 1␣D2 was administered thrice weekly at the end of the dialysis procedure. The initial trial with oral 1␣D2 consisted of 8 weeks of washout, 16 weeks of open-label treatment with oral 1␣D2, and 8 weeks of double-blinded controlled
533
treatment with either continued 1␣D2 or placebo.2 All patients who completed 16 weeks of open-label treatment with oral 1␣D2 per protocol were invited to participate in the intravenous trial with 1␣D2. The present study evaluates the efficacy and side effects of intravenous 1␣D2 therapy in patients who entered and completed 12 weeks of open-label treatment with oral 1␣D2 and compares the efficacy and side effects of the two trials. The oral 1␣D2 trial enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism; these patients underwent treatment with hemodialysis in 18 hemodialysis units in southern California and western Tennessee/eastern Arkansas/Mississippi. Of the 138 patients who completed the washout period and began oral treatment, 107 patients finished 16 weeks of open-label treatment per protocol and were recruited for the intravenous trial. Ninety-seven of these patients consented to enter, and 70 patients qualified for treatment in the open-label trial with intravenous 1␣D2. The studies are shown in Fig 1. Inclusion criteria for entry onto the washout period were: (1) age, 20 to 75 years; (2) hemodialysis duration greater than 4 months; (3) historical iPTH value greater than 400 pg/mL when calcitriol therapy was not administered; (4) serum albumin level greater than 3.3 g/dL; (5) average serum phosphorus level between 2.5 and 6.9 mg/dL during 2 recent months; and (5) no intake of aluminum-containing phosphate binders for at least 12 months combined with a serum aluminum level less than 40 g/L. Patients were eligible to enter washout for the trial with intravenous 1␣D2 if they satisfied these same entry criteria. Exclusion criteria, similar for the intravenous and oral trials, were: (1) patients not meeting the inclusion criteria, (2) partial or total parathyroidectomy during the last 12 months, (3) malignancy requiring ongoing medical treatment, and (4) malabsorption syndrome or impairment of hepatic function. Patients were excluded from entering open-label treatment if during the first 7 weeks of washout they failed to show: (1) an average
Fig 1. Schema of the two trials with 1␣D2. (Left) The oral trial included an initial washout of 8 weeks, followed by 16 weeks of oral treatment with 1␣D2, with 138 patients qualified for entry onto this treatment period. After 16 weeks of open-label treatment, patients were randomly assigned to double-blinded treatment with either continued 1␣D2 or placebo. During the first 12 weeks of oral treatment, which were used for comparison with the later intravenous trial, 107 patients followed the treatment per protocol. Of this group, 97 patients consented later to enter (right) the intravenous protocol; 70 patients qualified for entry onto the 12-week treatment phase, and 64 patients completed the intravenous trial per protocol. *Between the two trials, 1 to 30 weeks elapsed before the washout for the second trial. B, time of baseline measurements for two trials.
534
predialysis serum phosphorus level of 2.5 to 6.9 mg/dL, (2) an average predialysis serum calcium level less than 10.6 mg/dL, (3) an average calcium X phosphorus (Ca X P) product of 70 or less, and (4) at least one plasma iPTH value greater than 400 pg/mL at enrollment or a mean iPTH value greater than 350 pg/mL during washout. The institutional review board at each institution approved the protocols and consent forms for the oral and intravenous trials; informed consents for the two protocols were obtained from each patient.
Study Design For the purpose of this evaluation and comparison, the oral and intravenous trials of 1␣D2 consisted of 8 weeks of washout followed by 12 weeks of open-label treatment. During the oral trial, patients initially were administered 10 g of 1␣D2 after each dialysis session (30 g/wk). During the intravenous trial, the same patients were administered 4.0 g of 1␣D2 intravenously at the end of each hemodialysis session (12 g/wk). This dosing ratio was chosen because an earlier study of single-dose pharmacokinetics in healthy subjects showed that the bioavailability of oral 1␣D2, based on serum levels of 1␣,25-dihydroxyvitamin D2 [1␣,25-(OH)2D2], was approximately 40% of intravenous 1␣D2. During both the oral and intravenous trials, doses of 1␣D2 were adjusted, as described later, to bring plasma iPTH levels into a target range of 150 to 300 pg/mL, values associated with normal or near-normal bone formation and minimal features of secondary hyperparathyroidism among hemodialysis patients.14,15 The efficacy of 1␣D2 was evaluated from suppression of plasma iPTH levels, and the side effects were assessed for both increases in serum calcium and phosphorus levels and incidence of significant hypercalcemia and hyperphosphatemia. The trials were not designed or conducted as an integrated crossover study of oral and intravenous 1␣D2. During both trials, an effort was made to maintain serum phosphorus levels between 4.0 and 6.0 mg/dL with the use of calcium carbonate and/or calcium acetate; no aluminumbased phosphate binders were used. Each patient underwent hemodialysis thrice weekly for 3 to 4 hours. During the oral trial with 1␣D2, 69.0% of the patients underwent dialysis using dialysate with a calcium concentration of 2.5 mEq/L; 15.5%, 3.0 mEq/L; 10.8%, 2.0 mEq/L; and 4.7%, 3.5 mEq/L. During the intravenous study, 57 of the 64 patients used the same dialysate calcium concentration as in the oral trial. Of the 7 patients for whom the dialysate calcium concentration was changed, 5 patients used a higher dialysate calcium concentration during the intravenous than oral trial, and 2 patients used a lower dialysate calcium concentration during the intravenous than oral trial.
Dose Adjustments Doses of 1␣D2 were adjusted based on the weekly results of plasma iPTH and serum calcium and phosphorus measurements. The drug was discontinued if the iPTH level decreased to less than 150 pg/mL. One week later, 1␣D2 was resumed at a dose reduced by either 1.0 or 2.5 g from the previous dose for the intravenous or oral forms, respectively, according to the dosage schedule listed in Table 1. In both
MAUNG ET AL Table 1.
Dosage Schedules for Oral and Intravenous 1␣D2 Trials Oral
Dosage Level
A B* C D E
Intravenous
Regimen (g post-HD)
Weekly Dose (g)
Regimen (g post-HD)
Weekly Dose (g)
15.0 10.0 7.5 5.0 2.5
45.0 30.0 22.5 15.0 7.5
5.0 4.0 3.0 2.0 1.0
15.0 12.0 9.0 6.0 3.0
Abbreviation: HD, hemodialysis. *Initial doses.
trials, the drug was temporarily withheld for safety reasons with the development of significant hypercalcemia (serum calcium ⬎11.2 mg/dL), confirmed marked hyperphosphatemia (serum phosphorus ⬎8.0 mg/dL), or a persistent Ca X P product greater than 75. When patients developed one of these side effects, blood calcium and phosphorus levels were monitored before each dialysis session until the serum calcium level decreased to 10.5 mg/dL or less, serum phosphorus level reached 6.9 mg/dL or less, or the Ca X P product was 70 or less. Treatment with 1␣D2 was then resumed at a dosage reduced by one step, as described previously. The dose of calcium-based phosphate binders was adjusted upward or downward based on serum calcium and phosphorus levels. If levels of both serum calcium and phosphorus were persistently greater, in addition to decreasing the dose of 1␣D2, attention was given to other factors, such as dietary indiscretion and/or compliance with the proper ingestion of calcium-based phosphate binders. During both the oral and intravenous trials, doses of 1␣D2 could be increased after week 8 at the discretion of the individual investigator if the iPTH level was not within the target range of 150 to 300 pg/mL and was not suppressed by 50% less than the baseline value.
Biochemical Measurements Baseline values for iPTH, calcium, and phosphorus are defined as the mean of the last three determinations during washout (weeks –2, –1, and 0). Plasma iPTH and serum calcium and phosphorus levels were measured weekly throughout both washout and open-label treatment. Additional blood samples were obtained week 0 and at 4-week intervals for a chemistry profile that included total alkaline phosphatase and serum albumin. Plasma levels of 1␣,25(OH)2D2 and 1␣,25-(OH)2D3 were measured at baseline and weeks 4 and 12 in the oral trial and at baseline and weeks 4, 8, and 12 in the intravenous trial. Levels of plasma iPTH and serum calcium and phosphorus were measured at the same central laboratory (Lifechem Laboratories, Woodland Hills, CA). Plasma iPTH was determined by an immunoradiometric method using the Nichols Institute Kit (Corning-Nichols Laboratories, San Juan Capistrano, CA), and albumin was measured with a Hitachi 736 analyzer (Hitachi, Indianapolis, IN). Plasma 1␣,25-(OH)2D2 and 1␣,25-(OH)2D3 levels were
INTRAVENOUS VERSUS ORAL 1␣D2
determined at Bone Care International (Madison, WI) by means of a radioreceptor assay after high-performance liquid chromatography.16,17 The detection limits of quantitation were 5.0 pg/mL for 1␣,25-(OH)2D2 and 10 pg/mL for 1␣,25-(OH)2D3. For the calculation of mean concentrations, levels of 1␣,25-(OH)2D2 and 1␣,25-(OH)2D3 that were less than the limits of quantitation were arbitrarily assigned values of 5.0 and 10 pg/mL, respectively.
Statistical Analysis Data from 64 patients who completed 12 weeks of treatment in both the oral and intravenous trials per protocol were included in the efficacy analysis based on suppression of plasma iPTH. Data from all 70 intent-to-treat (ITT) patients who entered open-label treatment were analyzed for the side effects of hypercalcemia and hyperphosphatemia. For comparison of changes in serum calcium and phosphorus levels from baseline during the oral and intravenous treatments, two patients with low dose compliance during the intravenous trial were excluded from the ITT analysis. The degree of iPTH suppression and changes in serum calcium and phosphorus levels observed during the intravenous and oral 1␣D2 treatments were compared over 12 weeks of openlabel treatment. All data are expressed as mean ⫾ SE unless stated otherwise. At each week during treatment, the significance of change from baseline was determined by using either paired t-test or Wilcoxon’s one-sample test, as appropriate. The differences in changes in various parameters with the oral and intravenous 1␣D2 therapies were compared using two-tailed t-test. The same test was also used to evaluate whether the administration of intravenous calcitriol between the completion of the oral trial and the beginning of washout for the intravenous treatment had an effect on the response to intravenous 1␣D2 treatment. For comparison of multiple subsets of data, analysis of variance was applied using the Neuman-Keuls correction. All computations were performed using the Statistical Analysis System (SAS Institute, Cary, NC). P less than 0.05 is considered statistically significant.
RESULTS
Among the patients who completed 16 weeks of open-label treatment with oral 1␣D2, 107 patients qualified for entry onto the washout for the intravenous treatment; 97 of these patients entered the intravenous trial. Twenty-seven of the 97 patients were disqualified during washout for the intravenous trial for reasons listed in Table 2. Fifteen patients were excluded because of inadequate elevations in iPTH levels, and 3 patients, because of excessive elevations in serum phosphorus levels (mean, ⱖ6.9 mg/dL). Other reasons for failure to enter into the intravenous treatment with 1␣D2 included death of 4 patients during washout from unrelated causes, failure to identify 2 patients who were disqualified for the per-protocol analysis for the 16
535 Table 2. Reasons for Failure to Qualify for Entry Onto Intravenous Treatment or to Complete Study Per Protocol
Reason
Failure to qualify for entry onto IV treatment Low PTH High serum phosphorus Low serum phosphorus IV calcitriol treatment Aluminum hydroxide ingestion Died during washout Protocol violations IV calcitriol treatment Mean serum phosphorus ⱖ 6.9 mg/dL Prolonged hospitalization Change in dialysis modality Total
No. of Patients
15 5* 1 1 1 4 1 2 2† 1 33
Abbreviation: IV, intravenous. *Includes two enrollment errors. †Low dose compliance.
weeks of open-label treatment in the oral trial, and 1 patient each for the following reasons: mean serum phosphorus level less than 2.5 mg/ dL, ingestion of aluminum gels, and inadvertent treatment with intravenous calcitriol. Of the 70 patients who entered onto the intravenous trial, 64 patients completed the treatment per protocol. Reasons for failure to complete the intravenous trial per protocol included: excessive elevation of serum phosphorus levels, 2 patients; low compliance to the prescribed dosage of 1␣D2 because of prolonged hospitalization, 2 patients; and 1 patient each for the mistaken administration of intravenous calcitriol or a change in hemodialysis modality to twice weekly. Of the 70 patients in the ITT analysis, 38 patients were administered placebo and 32 patients were administered 1␣D2 during the 8-week double-blinded period that followed oral openlabel treatment (P ⫽ not significant [NS]). The interval between completion of the oral trial and entry into washout for the intravenous trial ranged from 2 to 208 days (median, 35 days). During this interval between the studies, 33 patients were prescribed intravenous calcitriol at various doses by their local nephrologist. Among the 37 patients not administered intravenous calcitriol between the two studies, the interval free of vitamin D treatment between the completion of
536
MAUNG ET AL
Table 3. Baseline Data for Patients Completing Both Oral and Intravenous Trials With 1␣D2 Per Protocol Intravenous Study
Serum calcium (mg/dL) Serum phosphorus (mg/dL) PTH (pg/mL)
Oral Study
9.06 ⫾ 0.08
9.01 ⫾ 0.08
4.83 ⫾ 0.14 748 ⫾ 49.5
4.72 ⫾ 0.11 950 ⫾ 67.2*
NOTE. Values expressed as mean ⫾ SE. *P ⬍ 0.05.
oral treatment with 1␣D2 and the baseline for the intravenous trial ranged from 45 to 245 days, with a median of 54 days. Baseline values for plasma iPTH and serum calcium and phosphorus are listed in Table 3. Baseline serum calcium and phosphorus levels did not differ before the two trials, but mean plasma iPTH levels were slightly but significantly less at baseline before intravenous 1␣D2 therapy compared with the oral trial (P ⬍ 0.05). Serial iPTH values, shown as both absolute levels and percentages of baseline during the oral and intravenous trials, are shown in Fig 2. After baseline, mean iPTH levels did not differ between the oral and intravenous treatment groups. After 2 weeks of treatment, mean iPTH values decreased significantly and reached values that were 69.6% ⫾ 3.8% and 65.6% ⫾ 3.9% of baseline for the oral and intravenous trials, respectively (both P ⬍ 0.01 from baseline). In both trials, there was progressive suppression of iPTH levels during treatment, reaching 42.9% ⫾ 3.5% and 57.4% ⫾ 4.4% of baseline at week 12 for the oral and intravenous trials, respectively. The degree of suppression of iPTH was similar with the two routes of treatment except at week 12, when there was greater iPTH suppression with oral than intravenous therapy (P ⬍ 0.05). At the nadir of iPTH suppression, there were reductions to 42.9% ⫾ 3.5% of baseline at week 12 of the oral trial and to 50.5% ⫾ 2.8% of baseline at week 10 in the intravenous trial (P ⫽ NS). iPTH levels were suppressed by at least 30% from baseline in 95% and 94% of patients during the oral and intravenous trials, respectively. iPTH was suppressed to less than 50% of baseline in 89% and 78% of patients during the oral and intravenous treatments, respectively. During the intravenous trial, iPTH level decreased to less than the target
range (⬍150 pg/mL) in 53% of patients compared with 59% with a value less than this level during the oral trial (P ⫽ NS). Among the 751 and 744 iPTH measurements made during the oral and intravenous trials, 13.4% and 12.7% of values were less than the target range, respectively. Changes in serum calcium levels, expressed as both absolute values and percentage of change from baseline, are shown in Fig 3 for the oral and intravenous trials. Mean baseline serum calcium values did not differ between the trials. With treatment, serum calcium levels increased slightly in both trials, with mean calcium values greater during the oral than intravenous trial at weeks 3 and 5 (P ⬍ 0.05). The increment in serum calcium change from baseline became significant by the second week of treatment during both trials, and the percentage of increase in serum calcium levels was greater during oral than intravenous treatment at week 3. Highest mean serum calcium levels during the oral and intravenous treatments were 9.82 ⫾ 0.14 mg/dL at week 5 and 9.67 ⫾ 0.11 mg/dL at week 12, respectively. The average overall increase in serum calcium level to greater than baseline, calculated over the 12 treatment weeks for each individual patient, was significantly greater during oral than intravenous 1␣D2 therapy (0.50 ⫾ 0.056 versus 0.30 ⫾ 0.059 mg/dL; P ⬍ 0.02). In a comparison of
Fig 2. Plasma iPTH values, shown as both (top) absolute concentrations and (bottom) percentage of baseline in 64 per-protocol patients. Data expressed as mean ⴞ SE. *P < 0.05. **P < 0.01 for comparison of oral and intravenous trials.
INTRAVENOUS VERSUS ORAL 1␣D2
Fig 3. Serum calcium values shown as (top) measured levels and (bottom) percentage of change from baseline in 70 ITT patients. Data expressed as mean ⴞ SE. *P < 0.05. **P < 0.01 for comparison of oral and intravenous trials.
changes in serum calcium from baseline values in individual patients during the two treatment trials, 19 patients showed significantly greater increments during oral than intravenous administration, whereas 8 patients showed greater increments with intravenous than oral treatment (P ⫽ 0.032). Serum phosphorus levels, expressed as both absolute values and percentage of change from baseline, for the oral and intravenous trials are shown in Fig 4. Mean baseline serum phosphorus levels did not differ for the two trials. Serum phosphorus levels increased significantly by week 1 of the oral trial and week 3 of the intravenous trial. The percentage of increase in serum phosphorus to greater than baseline values was greater with oral 1␣D2 than intravenous treatment at weeks 2, 3, 4, 9, and 10 (P ⬍ 0.05). Highest mean serum phosphorus levels observed during the oral and intravenous trials were 5.82 ⫾ 0.21 mg/dL at week 4 and 5.60 ⫾ 0.21 mg/dL at week 12, respectively. Average overall increments in serum phosphorus levels for individual patients greater than their respective baseline values were greater during oral than intravenous 1␣D2 therapy (0.89 ⫾ 0.12 and 0.50 ⫾ 0.097 mg/dL; P ⬍ 0.02). When average increments in serum phos-
537
phorus levels during the 12 weeks of oral and intravenous therapy were compared in individual patients, 21 of the ITT patients had significantly greater increments during oral than intravenous treatment compared with 9 patients with greater increases during intravenous than oral therapy (P ⫽ 0.023). Plasma 1␣,25-(OH)2D2 levels from patients administered 30 g/wk of oral 1␣D2 during the week before blood sampling were compared with those of patients administered intravenous 1␣D2, 12 g/wk, during the week before the blood sampling. 1␣,25-(OH)2D2 levels from patients administered oral 1␣D2 averaged 45.7 ⫾ 3.5 pg/mL (n ⫽ 56) compared with 19.7 ⫾ 1.4 pg/mL (n ⫽ 45) after intravenous therapy (P ⬍ 0.0001). Average 1␣,25-(OH)2D2 levels at all doses of both oral and intravenous 1␣D2 are shown in Fig 5; mean blood levels of 1␣,25(OH)2D2 were remarkably similar at each weekly dose, administered either orally or intravenously. In a comparison of plasma 1␣,25-(OH)2D2 levels according to duration of treatment with the same dose of 1␣D2, values were 21.6 ⫾ 1.2 and 17.9 ⫾ 1.6 pg/mL after 4 and 8 weeks of intravenous 1␣D2, 12 g/wk (P ⫽ NS), respectively. These observations are similar to the findings of
Fig 4. Serum phosphorus values shown as (top) measured levels and (bottom) percentage of change from baseline in 70 ITT patients. Data expressed as mean ⴞ SE. *P < 0.05 for comparison of oral and intravenous trials.
538
Fig 5. Plasma levels of 1␣,25-(OH)2D2 shown according to the weekly dosage of 1␣D2 during the week before the measurement. Shaded symbols, oral treatment; black symbols, intravenous treatment. Data expressed as mean ⴞ SE; dotted line shows the limit of quantitation for measuring 1␣,25-(OH)2D2 in the plasma samples (10 pg/mL).
no changes in plasma 1␣,25-(OH)2D2 levels with duration of therapy during the longer trial using oral 1␣D2.2 During both trials, plasma 1␣,25(OH)2D3 levels were low and near the limits of quantitation (10 ng/mL), and values did not differ between oral and intravenous administration of 1␣D2. The effect of severity of secondary hyperparathyroidism on the response of plasma iPTH to treatment with intravenous and oral 1␣D2 therapy was evaluated retrospectively by dividing the 64 per-protocol patients into two groups based on baseline iPTH levels less than 750 pg/mL or 750 pg/mL or greater. Group I had iPTH levels less than 750 pg/mL (oral, n ⫽ 26; intravenous, n ⫽ 41), and group II had iPTH levels of 750 pg/mL or greater (oral, n ⫽ 38; intravenous, n ⫽ 23). There were different patterns of iPTH suppression in these two groups, shown in Fig 6. In group I, plasma iPTH levels decreased quickly, reaching the target iPTH range within 4 to 5 weeks of treatment independent of the route of administration. iPTH values in group II decreased gradually over the 12 weeks and remained greater than the target range at 12 weeks. For each group, there were no differences in iPTH suppression between oral versus intravenous administration of 1␣D2. Serum calcium and phosphorus levels did not differ between groups I and II at baseline or any time during treatment. For the entire ITT population, the incidence of
MAUNG ET AL
Fig 6. Plasma iPTH values of 64 per-protocol patients divided into two groups according to baseline iPTH levels before the oral or intravenous 1␣D2 trials. Group I, iPTH less than 750 pg/mL; group II, iPTH of 750 pg/mL or greater. Dotted lines encompass the target iPTH range (150 to 300 pg/mL). Data expressed as mean ⴞ SE. Parentheses indicate number in oral trial, while brackets indicate number in intravenous trial.
hypercalcemia and hyperphosphatemia, defined either as serum calcium levels greater than 11.2 mg/dL or greater than 10.5 mg/dL and serum phosphorus values greater than 8.0 mg/dL or greater than 6.9 mg/dL, are shown in Fig 7. Among the 70 patients, hypercalcemia with serum calcium levels greater than 11.2 mg/dL was noted in 0.86% of 813 serum calcium determinations during intravenous 1␣D2 treatment compared with 3.62% of 828 measurements during
Fig 7. Prevalence of hypercalcemia and hyperphosphatemia, each defined by two separate levels, during oral and intravenous 1␣D2 treatment in 70 ITT patients. P values compare the prevalence between oral and intravenous treatment.
INTRAVENOUS VERSUS ORAL 1␣D2
oral treatment (chi-square, P ⬍ 0.001). Seven patients accounted for such hypercalcemia during intravenous treatment compared with 16 patients during the oral trial (P ⫽ NS). With hypercalcemia defined as serum calcium level greater than 10.5 mg/dL, 8.4% of the measurements showed hypercalcemia during intravenous treatment compared with 14.3% of determinations during oral treatment (chi-square, P ⬍ 0.001); 24 and 31 patients were responsible for these episodes during the intravenous and oral therapies, respectively (P ⫽ NS). Serum calcium levels exceeded 12.0 mg/dL in 0.12% and 0.60% of measurements during the intravenous and oral 1␣D2 trials, respectively (P ⫽ NS); 1 and 3 patients administered intravenous or oral 1␣D2 accounted for these elevated values, respectively. Hyperphosphatemia, defined as serum phosphorus levels greater than 8.0 mg/dL, was observed in 4.29% of the 815 phosphorus measurements during intravenous treatment and 5.54% of 830 determinations during the oral trial, with 19 and 22 patients responsible for these episodes, respectively (both P ⫽ NS). Serum phosphorus levels greater than 6.9 mg/dL were noted in 13.5% and 16.5% of these measurements, including 38 and 46 patients during intravenous and oral therapy, respectively (both P ⫽ NS). Data from 33 patients administered intravenous calcitriol during the interval between the end of the oral trial and the start of washout for the intravenous trial were compared with data from the 37 patients not administered calcitriol. Baseline values for iPTH and serum calcium and phosphorus did not differ between groups. There was no difference in serum calcium levels, either absolute values or percentage of changes between these groups. The absolute values of iPTH and the percentage of reductions in iPTH levels did not differ, except for a smaller reduction in iPTH levels at weeks 2 and 3 in those administered intravenous calcitriol during the time between the trials compared with those not administered intravenous calcitriol (P ⬍ 0.01 and P ⬍ 0.05, respectively). The doses of calcium-based phosphate-binding agents, expressed as calcium content in milligrams per day, were 1,937 ⫾ 142 mg/d at baseline and 2,076 ⫾ 152 mg/d at week 12 during the oral trial; similar values were 3,241 ⫾ 375 and 3,360 ⫾ 318 mg/d during
539
Fig 8. Weekly doses of 1␣D2 among two groups stratified according to baseline iPTH levels preceding oral and intravenous treatment. Data expressed as mean ⴞ SE. *P < 0.05. **P < 0.01 for comparison of the iPTH groups during either the oral or intravenous trials.
intravenous therapy with 1␣D2. Mean dosages did not change during either trial, but the quantities were significantly greater with the intravenous than oral trial at baseline and week 12 (P ⬍ 0.001 for both occasions). Mean weekly doses of 1␣D2 administered during oral and intravenous therapy were 28.75 ⫾ 0.42 and 11.31 ⫾ 0.21 g/wk at week 1 and 22.6 ⫾ 2.0 and 10.81 ⫾ 0.76 g/wk at week 12, respectively. For the two groups separated according to entry iPTH levels, mean dosages of 1␣D2 administered to group II, with entry iPTH levels of 750 pg/mL or greater, were significantly greater than for group I during both the oral and intravenous trials. Over the 12 weeks of treatment, the reduction in dosage was greater with oral than intravenous treatment, particularly for patients with entry iPTH levels less than 750 pg/mL (Fig 8). DISCUSSION
The present results show that oral and intravenous 1␣D2, administered for 12 weeks to the same patients, were both highly effective in suppressing iPTH levels of hemodialysis patients with moderate to severe secondary hyperparathyroidism. There were slight increments of serum calcium levels with both routes of therapy, but the degree of elevation of serum calcium level was less during intravenous therapy compared with that observed during oral treatment.
540
Also, there were significantly more individual patients who showed greater increments in serum calcium levels during oral compared with intravenous 1␣D2 treatment. The incidence of hypercalcemia, defined as serum calcium level greater than 11.2 mg/dL, was significantly greater during the oral than intravenous trial. For serum phosphorus levels, the increment greater than baseline level was significantly greater during oral than intravenous treatment during 5 of the 12 treatment weeks. The average increment in serum phosphorus level for all patients, as well as the number of individual patients showing greater increments in serum phosphorus levels during oral compared with intravenous therapy, was significantly greater during the oral trial. On the basis of single-dose pharmacokinetics in healthy subjects, the starting intravenous dose of 1␣D2 was set at 40% of the oral dose. Because hepatic activation of the prohormone 1␣D2 provides a sustained release of 1␣,25-(OH)2D2 into the blood, the plasma half-life of 1␣,25-(OH)2D2 is 32 to 37 hours after the oral or intravenous administration of 1␣D2. However, the observed plasma levels of 1␣,25-(OH)2D2 after 4 weeks of dosing were two and one half–fold greater with 30 g/wk of oral 1␣D2 compared with 12 g/wk of intravenous 1␣D2. Over the entire range of doses given, mean plasma levels of 1␣,25(OH)2D2 were similar with the same doses of 1␣D2, administered orally or intravenously. Thus, the degree of iPTH suppression during both intravenous and oral treatment with 1␣D2 was similar despite the finding of much lower blood levels of 1␣,25-(OH)2D2 during intravenous than oral therapy. The greater blood levels of 1␣,25(OH)2D2 noted during oral treatment may have accounted for the larger increments of serum calcium and phosphorus levels and the significantly greater incidence of hypercalcemia. The present data suggest that the pharmacokinetic findings obtained after single doses in healthy subjects may not be applicable to the steady-state condition after long-term administration of 1␣D2 to patients with end-stage renal disease. One may question whether lower doses of oral 1␣D2 would be as effective as the intravenous doses used in the present study. In the initial trial with 1␣D2, Tan et al1 initiated oral treatment with 4 g administered thrice weekly in 14 patients; 6
MAUNG ET AL
of these patients required an increase in dosage to 4 g daily to produce effective suppression of iPTH. Thus, it seems unlikely that a reduction on oral dosage by 40% would have resulted in similar suppression of iPTH. In addition, in the large trial with 1␣D21 in which dosage was adjusted according to iPTH levels, dosages needed to be increased in many patients with greater iPTH levels (⬎1,200 pg/mL). It seems unlikely that all the differences causing elevations in serum calcium and phosphorus levels are explained by the different oral versus intravenous dosages, but further studies are required to answer this question. The basis for the equivalent suppression of iPTH levels during intravenous treatment despite the much lower plasma levels of 1␣,25-(OH)2D2 than with oral therapy with 1␣D2 is unknown, and any explanation must be speculative. One explanation may be the greater use of calciumbased binders during the trial with intravenous 1␣D2; this seems unlikely because the degree of elevation of serum calcium level was less during intravenous therapy. It is known that there was substantial 24-hydroxylation of vitamin D2 when large doses of vitamin D2 were administered to vitamin D-deficient humans, whereas 24-hydroxylation of vitamin D3 does not occur.18 Also, 1␣D2 is either 24-hydroxylated or 25-hydroxylated in vitro by human hepatoma cells19; at high concentrations of 1␣D2, there is much greater 24-hydroxylation compared with 25-hydroxylation, whereas the opposite occurred at low concentrations of 1␣D2. Therefore, it is possible that the transiently high serum levels of 1␣D2 that occur after intravenous administration of 1␣D2 lead to greater production of 1␣,24-(OH)2D2. At present, it is not possible to measure the levels of either 1␣D2 or 1␣,24-(OH)2D2 in vivo. The possibility that 1␣,24-(OH)2D2 may directly suppress iPTH levels independent of changes in serum calcium and phosphorus levels must await further investigation. Doses of calcium-containing phosphate-binding agents were greater during the intravenous trial than during the earlier oral treatment. The ingestion of greater amounts of phosphate binders could have contributed to the smaller increase in serum phosphorus levels noted during the intravenous trial. However, an anticipated greater increase in serum calcium
INTRAVENOUS VERSUS ORAL 1␣D2
levels with greater calcium intake did not occur during the intravenous trial; the smaller increments in serum calcium levels during intravenous 1␣D2 treatment are more impressive because they occurred with a greater calcium intake. The protocol allowed patients who completed at least 16 weeks of the oral trial with 1␣D2 per protocol to immediately enter the 8-week washout period for the trial with intravenous 1␣D2. However, a delay in the availability of the intravenous form precluded such a timely change in nearly two thirds of the patients completing the oral trial. Among the 70 patients for whom entry onto the trial with intravenous 1␣D2 was delayed, 33 patients were administered intravenous calcitriol for 2 to 29 weeks before starting the washout for the intravenous trial with 1␣D2. There were no significant differences in the degree of iPTH suppression or changes in serum calcium and phosphorus levels between the patients administered intravenous calcitriol during the interval between studies compared with those who were not. These data indicate that an interval of treatment with calcitriol did not affect the subsequent response to intravenous 1␣D2. One might question whether the results would have differed if a true crossover design had been followed, with patients randomly assigned to one route of therapy and then crossed over to the other. Our observations suggest otherwise. There was equivalent suppression of iPTH during both studies when patients were segregated according to baseline iPTH level. This suggests little difference in the ability of 1␣D2 to suppress iPTH levels according to the route of administration. Also, pretreatment baseline levels of alkaline phosphatase were lower before the intravenous trial compared with those preceding the oral trial with 1␣D2, findings consistent with lower bone turnover before the second study. Such a difference would be expected to result in greater rather than smaller increments in serum calcium levels during therapy with intravenous 1␣D2. Thus, it seems unlikely that the different increments in serum calcium and phosphorus levels are explained by the sequential treatment of all patients initially with oral 1␣D2 followed by intravenous 1␣D2. Patients with greater baseline iPTH levels required more time and greater doses of 1␣D2 to
541
suppress iPTH than patients with lower baseline iPTH levels, but there were no differences in the magnitude of elevation in serum calcium and phosphorus levels between these groups, divided according to entry iPTH level. Not unexpectedly, these data are similar to our findings in the larger trial with oral 1␣D2 when treatment was administered up to 24 weeks. There have been several reports of comparisons of intermittent oral and intravenous calcitriol,5,6,12 and one report compared intermittent oral and intravenous alfacalcidol. Several of these studies compared parallel groups of patients treated with oral or parenteral calcitriol.7-11,13 Differences depending on the route of administration were found in only two studies: Mazzaferro et al9 noted greater increments in serum calcium levels and significant reductions in iPTH levels in six patients administered intravenous calcitriol compared with no changes in those administered intermittent oral calcitriol. Salusky et al13 compared 46 peritoneal dialysis patients randomly assigned to thrice-weekly therapy with intraperitoneal or oral calcitriol; 33 patients completed 12 months of treatment. They noted greater increments in serum calcium levels and greater reductions in iPTH levels in the group administered intraperitoneal treatment. However, these patients had significantly smaller increments in serum phosphorus levels compared with patients administered oral calcitriol. The dosages administered did not differ between the treatment groups. There are several crossover trials comparing oral and intravenous calcitriol administered to the same patient5,6,12 and one crossover trial using alfacalcidol. None of these studies found a difference between oral and intravenous treatment. The study using alfacalcidol is pertinent because this sterol, like 1␣D2, is a prohormone metabolized to an active form. In the study of Lee et al,6 the initial dose of alfacalcidol was 12.0 g/wk, with the dose reduced to 9.6 g/wk at the end of the 6-week trial, and the dosages did not differ between oral and intravenous therapy. Mean plasma calcitriol levels of 53 and 44 pg/ mL, measured 48 hours after dosing, were not different during oral and intravenous administration, respectively. The present study differs from all previous reports comparing oral and paren-
542
MAUNG ET AL
teral calcitriol5,7-13 or alfacalcidol6 in that we observed similar suppression of iPTH levels with intravenous and oral 1␣D2, but noted smaller increments in both serum calcium and phosphorus levels with intravenous compared with oral therapy. Intravenous 1␣D2 therapy might be preferable to oral therapy in patients with secondary hyperparathyroidism who are prone to hypercalcemia during vitamin D therapy. APPENDIX The following persons and institutions participated in this multicenter study: Principal investigators: Jack W. Coburn, MD, University of California at Los Angeles School of Medicine and Veterans Affairs West Los Angeles Healthcare Center, Los Angeles, CA; Russell W. Chesney, MD, College of Medicine, University of Tennessee, Memphis, TN. Co-Investigators: Jerald F. Sigala, MD, Mark Rutkowski, MD, St Joseph Hospital, Orange, CA; William G. Goodman, MD, University of California at Los Angeles Medical Center; Alex U. Tan, MD, Joa˜o Fraza˜o, MD, Barton S. Levine, MD, Veterans Affairs West Los Angeles Healthcare Center; Keith C. Norris, MD, Charles R. Drew University; Hector Rodriguez, MD, PhD, Cedars Sinai Medical Center, Los Angeles, CA; John A. Robertson, MD, California Kidney Centers, Riverside and San Bernardino, CA; Sergio R. Acchiardo, College of Medicine, University of Tennessee; B.J. Kelley, MD, Gambro Healthcare, Memphis, TN; John D. Bower, MD, University of Mississippi Medical Center, Jackson, MS. Study Coordinators and Assisting Personnel: Sally Shupien, CCRC, Gail Uyehara, RN, Venice Avila, RN, David Akin, RN, Veterans Affairs West Los Angeles Healthcare Center, Los Angeles, CA; May Marooney, RN, St Joseph Hospital, Orange, CA; Jane Bandini, RN, Lisa Burk, RN, Susan J. Smith, RN, Susan O. Smith, RD, University of Tennessee, Memphis, TN; Bernadine Trenier, RN, US Health and Welfare Laboratories (USHAWL)-Doctors and USHAWL-Cedars Sinai Towers, Los Angeles, CA; Robin Maxwell, RN, Gambro Healthcare, East Memphis, TN; Edna Curry, RN, Kidney Care Hemodialysis Centers–North and –South, Jackson, MS; Shirley Capsavage, RN, Sue Estrada, RN, Linda Mullen, RN, California Kidney Center, San Bernardino, CA; Patrice Anderson, BS, Suzanne Schweitzer, MPH, Cindy Chou, BS, Judah White, JD, Lucy Nguyen, BS, University of California at Los Angeles Medical Center, Los Angeles, CA; Anita Karst, RN, Biomedical Applications (BMA)-North Parkway Dialysis, Memphis, TN; Gwendolyn Sampson, RN, Hank Williams, Pacific Coast Dialysis Center, Inglewood, CA; Jan Crawford, MN, Sue Baughman, RN, BMA-East Arkansas, West Memphis, AR, and BMA-St Francis County Dialysis Center, Forest City, AR; Mary Reed, RN, Joan Butler, RN, BMA-Graceland, Memphis, TN; James Zarara, PhD, Curtis Johnson, Raquel Rosales, Sharon Campbell, LifeChem Laboratories, Woodland Hills, CA. Bone Care International Staff: Laura L. Douglass, RN, Thomas. L. Manley, BSN, Kathy Keehn, BA, Lisa M.
DeLacy, Diane M. Pauk, GBS, Beth Griffin, BA, Naomi Fields, BA, Kathy Olson, Sheri B. Bernard, MS, Kari Brausen, Leon W. LeVan, PhD, Charles R. Valliere, BS, John T. Banach, BS, Gina M. Accola, BS, Matthew A. Carmean, BS, Anne M. Lumby, BS, Darlene M. Kyllo, RAC, and Charles W. Bishop, PhD.
REFERENCES 1. Tan AU Jr, Levine BS, Mazess RB, Kyllo DM, Bishop CW, Knutson JC, Kleinman KS, Coburn JW: Effective suppression of parathyroid hormone by 1␣-hydroxyvitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int 51:317-323, 1997 2. Fra˜za˜o JM, Elangovan L, Maung HM, Chesney RB, Acchiardo SR, Bower JD, Kelley BJ, Rodriguez HJ, Norris KC, Robertson JA, Levine BS, Goodman WG, Gentile D, Mazess RB, Kyllo DM, Douglass LL, Bishop CW, Coburn JW: Intermittent doxercalciferol (1␣-hydroxyvitamin D2) therapy for secondary hyperparathyroidism: Results of a modified, double-blinded, controlled study. Am J Kidney Dis 36:550-561, 2000 3. Fra˜za˜o JM, Levine BS, Tan AU Jr, Mazess RB, Kyllo DM, Knutson JC, Bishop CW, Coburn JW: Efficacy and safety of intermittent oral 1␣ (OH)-vitamin D2 in suppressing 2o hyperparathyroidism in hemodialysis patients. Dial Transplant 26:583-595, 1997 4. Slatopolsky E, Weerts C, Thielan J, Horst RL, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 74:21362143, 1984 5. Fischer ER, Harris DCH: Comparison of intermittent oral and intravenous calcitriol in hemodialysis patients with secondary hyperparathyroidism. Clin Nephrol 40:216-220, 1993 6. Lee WT, Padayachi K, Collins JF, Cundy T: A comparison of oral and intravenous alfacalcidol in the treatment of uremic hyperparathyroidism. J Am Soc Nephrol 5:13441348, 1994 7. Faugere M-C, Friedler RM, Malluche HH: Efficacy and limitations of pulse IV and pulse oral 1,25 vit D therapy in treatment of hyperparathyroidism in patients on long term dialysis. J Am Soc Nephrol 4:695A, 1993 (abstr) 8. Quarles LD, Yohay DA, Carroll BA, Spritzer CE, Minda SA, Bartholomay D, Lobaugh BA: Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int 45:1710-1721, 1994 9. Mazzaferro S, Pasquali M, Ballanti P, Bonucci E, Di Sanza P, Sardella D, Taggi F, Coen G: Intravenous versus oral calcitriol therapy in renal osteodystrophy: Results of a prospective, pulsed and dose-comparable study. Miner Electrolyte Metab 20:122-129, 1994 10. Levine BS, Song MM: Pharmacokinetics and efficacy of pulse oral versus intravenous calcitriol in hemodialysis patients. J Am Soc Nephrol 7:488-496, 1996 11. Bacchini G, Fabrizi F, Pontoriero G, Marcelli D, Di Filippo S, Locatelli F: ’Pulse oral’ versus intravenous calcitriol therapy in chronic hemodialysis patients: A prospective and randomized study. Nephron 77:267-272, 1997 12. Peng S-J, Yang C-S, Ferng S-H, Chen L-Y: A crossover comparison of intermittent oral and intravenous admin-
INTRAVENOUS VERSUS ORAL 1␣D2
istration of calcitriol on the parathyroid hormone concentration in hemodialysis patients. Miner Electrolyte Metab 23:1318, 1997 13. Salusky IB, Kuizon BD, Belin TR, Ramirez JA, Gales B, Segre GV, Goodman WG: Intermittent calcitriol therapy in secondary hyperparathyroidism: A comparison between oral and intraperitoneal administration. Kidney Int 54:907-914, 1998 14. Quarles LD, Lobaugh B, Murphy G: Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia. J Clin Endocrinol Metab 75:145-150, 1992 15. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure—An evolving disorder. Kidney Int 43:436-435, 1993 16. Hollis BW: Assay of circulating 1,25-dihydroxyvita-
543
min D involving a novel single-cartridge extraction and purification procedure. Clin Chem 32:2060-2063, 1986 17. Horst RL, Koszewski NJ, Reinhardt TA: 1-Alphahydroxylation of 24-hydroxyvitamin D2 represents a minor physiological pathway for the activation of vitamin D2 in mammals. Biochemistry 29:578-582, 1990 18. Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HLJ, Bishop CW, Knutson JC: Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-Hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum. J Clin Endocrinol Metab 83:2156-2166, 1998 19. Strugnell S, Byford V, Makin HLJ, Moriarty RM, Gilardi R, Levan LW, Knutson JC, Bishop CW, Jones G: The 1␣,24(S)-dihydroxy vitamin D2: A biologically active product of 1␣-OH-D2 made in the human hepatoma, Hep 3B. Biochem J 310:233-241, 1995
