A Comparison of Oral and Intravenous Alfacalcidol in the Treatment of U Rem Ic Hyperpa Rathyroid

A Comparison of Oral and Intravenous Alfacalcidol in the Treatment of U rem ic Hyperpa rathyroid

Wan Tin Lee, Kashi Padayachi, John F. Collins and Tim Cundy2

H yperparathyroidism is a common complication W.T. Lee, J.F. Collins, Division of Renal Medicine, De- of end-stage chronic renal failure and an impor- partment of Medicine. Auckland Hospital, Auckland, tant cause of morbidity in patients on maintenance New Zealand dialysis. The main cause of hyperparathyroidism is K. Padayachi, T. Cundy, Division of Endocrinology, loss of activity ofthe renal 1 a hydroxylase enzyme and impaired production of calcitriol (1 ,25fOH12D) from its Department of Medicine. Auckland Hospital. precursor, calcidiol (25 OH D). Uremic hyperparathy- Auckland, New Zealand roidism is usually treated with derivatives ofvitamln D (J. Am. Soc. Nephrol. 1994; 5:1344-1348) which are already la hydroxylated, such as calcitriol itself or a.lfacalcidol (1 a OH D, which is rapidly con- verted in vivo to calcitriol) (1). Calcitriol can suppress ABSTRACT parathyroid hormone (Fri-I) secretion by two mecha- The i.v. bolus administration of la hydroxylated vita- nisms: indirectly through the stimulation of intestinal mm D derivatives is effective in the treatment of ure- calcium absorption and raising plasma calcium (2) mic hyperparathyroidism. However, few of the pub- and directly through actions on FF1-I gene transcrip- lished studies of this mode of treatment have been tion (3). In practice, the effectiveness of the la hy- adequately controlled, and recent reports have sug- droxylated vitamin D derivatives is limited by the gested that p.o. bolus administration may be Just as degree to which plasma concentrations ofcalcium can effective. In this study, 16 hemodialysis patients with safely be raised. There has been, therefore, consider- able interest in ways of maximizing the direct, noncal- mild to moderate hyperparathyroidism were as- cemic effect on PTH synthesis, particularly in the use signed, after a 4wk run-in period, to receive a 6-wk of intermittent injections of high doses of 1 a hydroxy- course of either thrice-weekly i.v. or p.o. alfacalcidol lated vitamin D derivatives. Although several reports (initial dose, 4 pg). Then, after a further control period, have attested to the efficacy of this approach (4-9), they received a second 6-wk course, with either p.o. others have suggested that intermittent high-dose p.o. or i.v. alfacalcidol (whichever was not given in the first therapy works just as well ( 1 0 - 1 5). However, none of treatment period). Plasma parathyroid hormone these studies have been adequately controlled. We (PTh) was measured weekly by the use of an intact report here a crossover study on maintenance hemo- hormone assay. Both routes of therapy resulted in a dialysis patients with mild to moderate hyperparathyroidism, comparing high-dose aLfacalcidol given either significant suppression of plasma PTH (P = 0.005) and as intermittent p.o. therapy or as intermittent i.v. an elevation in plasma ionized calcium (P = 0.01). therapy. The magnitude of the responses was similar for the two treatment phases, as was the relationship be- MATERIALS AND METHODS tween the incrementin calcium and the decrement in PTH. The most complete suppression of PTH was seen Patients in those with the greatest increment in plasma cal- Sixteen adult patients (1 1 men, 5 women) with chronic cium. The incidence of hypercalcemia and the mean renal failure and mild to moderate hyperparathyroidism were dose reductions necessary were also similar in the two studied. Their ages ranged from 24 to 78 yr (median, 54), and treatment phases. Oral bolus therapy and iv. bolus they have been on maintenance hemodialysis at a hospital- based center for periods ranging from 0.3 to 14 yr (median, therapy with alfacalcidol are equally effective in sup- 3). All received thrice-weekly hemodialysis against a dialy- pressing hyperparathyroidism. The postulated advan- sate oflow calcium content (1 .2 mmol/L). Two ofthe patients tages of i.v. over p.o. therapy with la hydroxylated were being treated with la hydroxylated vitamin D deriva- vitamin D derivatives remain to be confirmed by tives before enrollment, but therapy was withdrawn 6 wk controlled studies. before beginning this study. Three patients had subtotal parathyroldectomy 3 to 5 yr earlier but had developed recur- Key Words: Hemodialysis, vitamin 0 Therapy, adults, hyper- rent hyperparathyroidism, and three patients had returned to maintenance hemodialysis after unsuccessful renal trans- calcemia. hyperphosphatemia plantation. Patients were excluded from the study if their initial total plasma calcium exceeded 2.7 mmol/L, plasma 1 ReceIved December 13. 1993. Accepted June 10, 1993. phosphate exceeded 2.0 mmol/L. plasma aluminum cx- 2 Correipondence to Dr. 1. Cundy, DIvisIon of EndOCrinOlOgy. Auckland HOspital. ceeded 3 mol/L, or plasma V1’H was less then 10 pmol/L. Private Bag 92 024, Park Rood. Grafton, Auckland, New Zealand. After a 4-wk run-in period, patients were randomized to 1O46.6673/O5O1344SO3.OO/O receive either i.v. or p.o. allacalcidol (One Alpha’: Leo Phar- Journal of the American Society of Nephrology CopyrIght C by the American Society of Nephrology maceuticals, (Ballerup, Denmark) thrice weekly for an initial

1344 Volume 5 - Number 6 ‘ 1994 Lee et al

treatment period of 6 wk. This was followed by an 8-wk ples. Correlations were calculated by the Pearson method. period of observation off alfacalcidol, before a second treat- The results are expressed as the mean. with 95% confidence ment period of 6 wk. During the second period. those eight intervals, unless otherwise stated. FF1-I concentrations were patients initially randomized to thrice-weekly I.v. alfacalcidol not normally distributed: therefore, they were log10 trans- were treated with thrice-weekly p.o. alfacalcidol, and vice formed before analysis, and the results were transformed verse.. After the second treatment period, there was a final back for presentation. 4-wk observation period. The whole study thus lasted 28 wk, during which time, plasma concentrations of total and ion- RESULTS izeci calcium, phosphate, and I’TH were measured on plasma samples drawn immediately before the first dialysis treat- Both i.v. and p.o. alfacalcidol produced significant ment of each week. Intravenous alfacalcidol was adminis- increases in plasma total and ionized calcium (Table tered at the end of each hemodialysis treatment, as was p.o. 1 ; Figure 1). The mean increment in plasma calcium alfacalcidol. The initial dosages. 4 g thrice weekly. were the was greater in the p.o. alfacalcidol phase than in the same. If hypercalcemia (total calcium 3.0 mmol/L) oc- i.v. phase, but this difference was not statistically curred or if the calcium X phosphate product exceeded 6. significant. In the i.v. phase, nine patients developed then the two subsequent doses of alfacalcidol were omitted modest hypercalcemia (2.65 to 2.99 mmol/L) and, 3 and alfacalcidol was restarted at a dose of 1 g lower than previously. developed severe hypercalcemia (3.0 mmol/L). For All 16 subjects were receiving some form of phosphate the p.o. phase, the numbers were five and three, binder therapy, either with aluminum hydroxide (Alutabs’: respectively. In both phases oftreatment, plasma PTH 3M Pharmaceuticals, St. Paul, MN; 600 mg per tablet, two to concentrations decreased significantly (Fable 1 ; Fig- seven tablets per day, 14 subjects) and/or with calcium ure 1). The mean decrement in plasma PTH was carbonate (Oscal’: Marion Merrell Dow, Kansas City, MO; greater in the p.o. phase, but this difference again 1.25 g per tablet, two to nine tablets per day. 14 subjects). failed to reach statistical significance. Suppression of During the study, phosphate binder therapy was adjusted to PTH to the normal range (5 pmol/L) was achieved in try and maintain predialysis plasma phosphate concentra- 8 of 16 subjects during the i.v. phase and 6 of 16 tions at 2.0 mmol/L. The study was approved by the local Research Ethics Committee, and written informed consent during the p.o. phase. was obtained from all subjects. In each individual, the correlation between the plasma VFH and ionized calcium concentrations in Methods each run-in period and treatment period was calcu- Plasma I7TH concentrations were measured by an intact lated for both p.o. and i.v. phases. In 1 1 of the 16 hormone radioimmunometric assay (Nichols Institute. San subjects in the i.v. phase and 10 of 16 in the p.o. Juan Capistrano, CA) with a normal range of 1 to 5 pmol/L. phase, clear correlations were present (r values rang- Ionized calcium concentrations were measured by an Ion- ing from -0.63 to -0.98). The mean values for the specific electrode, with a normal range of 1. 17 to 1.29 slope and intercept of these regression lines were mmol/L. Plasma total calcium and phosphate were mea- calculated for both treatment phases and in neither sured on a Hitachi 737 autoanalyzer (Tokyo, Japan: normal case differed between groups (slope: i.v., 0.29 (0.23 to ranges: total calcium. 2.2 to 2.6 mmol/L: phosphate. 0.8 to 0.351 versus oral, 0.29 10.24 to 0.341; intercept: i.v., 1 .4 mmol/L). Plasma calcitriol concentrations (measured 44 h postdose, once per patient in each treatment period) were 4.61 (3.94 to 5.281 versus oral, 4.78 (4.25 to 5.311), measured by a competitive protein binding assay (Nichols indicating that the relationship between ionized cal- Institute) with a normal range of 18 to 62 ng/L. cium and FF1-I did not differ between the treatment phases. Ths is also ifiustrated in Figure 2, which Statistical Analysis shows the relationship between the percentage Differences between control and treatment periods and change in ionized calcium and the percentage change between treatments were assessed by t test for paired sam- in PT’!-!. A distinct curvilinear relationship is evident,

TABLE 1 . Plasma biochemistry

iv. Alfacalcidol p.o. Alfacalcidol

Run ma Treatment’ p Run Ina Treaimentb pC

Total Calcium (mmol/L) 2.47 2.57 0.01 1 2.43 2.57 0.005 (2.35-2.59) (2.44-2.70) (2.31-2.55) (2.44-2.70) Ionized Calcium (mmol/L) 1.21 1.28 0.010 1.19 1.29 0.001

(1 . 16-1 .26) (1 .22-1 .39) (1 . 13-1 .25) (1.22-1.36) Parathyroid hormone (pmol/L) 21 .4 11.5 0.003 26.3 12.6 0.004 (1 3.5-33.9) (5.8-22.9) (1 7.0-40.7) (6.3-25.1) Phosphate (mmol/L) 1.85 2.17 0.010 1.99 2.03 NS (1 .67-2.03) (1 .92-2.42) (1 .78-2.20) (1.73-2.33)

0 on the mean of the last five consecutive samples obtained In each subject before each treatment phase. b on the mean of the last five samples obtained in each subject dunng each treatment phase. C p values for paired t test comparing run-in and treatment phases. NS. not signIficant.

Journal of the American Society of Nephrology 1345 Oral Versus Intravenous Alfacalcidol

1.40

1.30 Ca++ (mmoVL) 1.20

1.10

1.00 1---- IV first -0- Oral first

30 PTH (pmol/L) 10

10 15 20 25 Weeks

Figure 1 . Serial measurements of ionized calcium and PTH. Closed symbols, the eight patients who received iv. therapy first; open symbols, the eight patients who were given p.o. therapy first. The two freatment phases are indicated by the shaded areas. Results are given as the mean (with SE). Note the logarithmic scale for PTH.

normal range and only modest hyperparathyroidism 50 ______[intravenous I (PTH, 15 pmol/L), and the other (Patient 15) had more 40 (ooral______I severe hyperparathyroidism (VFH, 85 pmol/L), a ris- ing alkaline phosphatase, and hypocalcemia, which 30 did not respond to the short courses of alfacalcidol. Percentage Change in lonised Calcium Patients 15 and 9, who also had severe disease (Fri-I, 20 Concentration #{149}00 79 pmol/L) and hypocalcemia, were two of the three

10 . subjects in whom no correlation between the change in Fri-I and the change in ionized calcium was evident 0 in either treatment phase. Alfacalcidol dose reduction was necessary in eight subjects. in both treatment -10 phases. The mean thrice-weekly dose ofalfacalcidol at -20 the end of the treatment phase was 3.2 pg in both the i.v. and p.o. phases. The mean number of aluminum -100 -80 -60 -40 -20 0 20 40 60 hydroxide tablets prescribed increases significantly in Percentage Change in Plasma PTH Concentration both treatment phases, from 3.0 to 3.9 in the i.v. Figure 2. RelatIonship between changes in ionized calcium phase and from 3.6 to 4.8 in the p.o. phase (both (P < and PTH. The mean ofthe five values In the run-In period and 0.05). The higher rate of aluminum hydroxide use in the final two values of each freatment period were calcu- the p.o. phase presumably explained the between- bled, and the change between the freatment and run-In groups difference in mean plasma phosphate, which periods is expressed as a percentage of the latter. The increased significantly during the i.v. phase but not degree of suppression of PTH is clearly related to the incre- during the p.o. phase (Fable 1). There was no differ- ment in ionized calcium, and the relationship between the ence between the groups in calcium carbonate usage. two was the same whether alfacalcidol was given by the Mean plasma calcitriol concentrations measured 44 h P.O. 01 the iv. route. after dosing were similar on the two treatments: 53 ng/L (32 to 74) during the p.o. phase and 44 ng/L (31 with the most profound suppression of PT!-! being to 57) during the i.v. phase. seen in those subjects with the greatest increment in DISCUSSION ionized calcium, irrespective of treatment phase. The individual data displayed in Figure 2 show that, In this study, both p.o. and i.v. alfacalcidol were in the last 2 wk of each treatment, PTH had increased effective in suppressing plasma FT’H in the majority of in three subjects. In two subjects, this occurred in these hemodialysis patients who had hyperparathy- both treatment phases. One subject (Patient 4) had an roidism of mild to moderate severity. In both treat- ionized calcium concentration at the upper end of the ment phases, the degree of suppression of plasma

1346 Volume 5 - Number 6 - 1994 Lee et al

vrH was closely related to the increment in plasma 2 to 5 h after administration and are only about ionized calcium that was attained. There was no evi- one-fifth that seen with the equivalent dose of i.v. dence that this relationship differed between the i.v. calcitriol (16, 17). With p.o. alfacalcidol, peak calcitriol and the p.o. phases of treatment. In particular, there levels occur even later, at about 8 h, and are only was no evidence that, for a given increment in plasma about one-seventh the peak reached after the equiva- ionized calcium, the use ofi.v. therapy was associated lent dose of i.v. calcitriol (18). The apparent equiva- with a greater reduction in PTH than the use of p.o. lence of p.o. pulse calcitriol therapy with i.v. caicitriol therapy. These observations argue against the notion (10-15) would, however, argue against the idea that that i.v. alfacalcidol has significant direct actions on calcitriol pharmacokinetics are critically important to the parathyroids, independent of changes in ionized the abifity of calcitriol to suppress hyperparathyroid- calcium. ism. The pharmacokinetics of p.o. and i.v. calcitriol Although in most studies of i.v. icr hydroxylated differ markedly, with peak calcitriol values occurring vitamin D derivatives, the decrement in FF1-I obtained about 3 h later and being only one-third as high with is clearly related to the increment in plasma calcium p.o. therapy as those obtained with i.v. therapy (4-9, 13, 14), others have claimed that PT!-! may fall (16, 18). The slower metabolism of alfacalcidol means before there is any detectable rise in plasma calcium that basal plasma calcitriol concentrations tend to (4, 16). Although this could be interpreted as a direct increase long term. whereas they do not with intermit- effect of calcitriol on the parathyroids, this is not the tent calcitriol therapy (18). In our subjects, plasma only possible explanation. Bone turnover is high in calcitriol concentrations were maintained in the nor- uremic hyperparathyroidism, so the effect could occur mal range for 2 days after dosing and did not differ if there was a small increase in ionized calcium, which between the treatment phases. These relatively high inhibited FTH secretion and, thus, the activation of plasma calcitriol levels may reflect the relatively large bone resorption. In the short term, bone formation doses of alfacalcidol given for what was generally mild would remain high, so calcium would be removed from hyperparathyroidism. the plasma into bone and ionized calcium would tend Our patients were a selected group with only mild to to remain low in the initial stages of therapy, Thus, moderate hyperparathyroidism, and in this range, I7TH secretion could be suppressed without a readily plasma VFH concentrations may not reflect accurately detectable rise in plasma calcium. As bone healing the underlying bone diseases. Some of our subjects occurs and less calcium enters bone, the plasma may have had adynamic bone disease. Our conclu- calcium levels rise more markedly and reductions in sions cannot necessarily be extrapolated to patients calcitriol or alfacalcidol dosage become necessaiy. with severe disease, nor (because of the pharmacoki- Overt hypercalcemia tends to occur when FFH is fully netic differences) can these results obtained with al- suppressed (14). In our study, six subjects developed facalcidol be extrapolated to the use of caicitriol. hypercalcemia of 3.0 mmol/L or more-in five, the However, a study similar to ours in design comparing FrH concentration was fully suppressed (<5 pmol/L) intermittent i.v. and p.o. calcitriol also failed to detect and in only one did it remain elevated ( 13.3 pmol/L). any difference between the two routes of administra- Although the use of the i.v. route for calcitriol and tion (19). Hyperphosphatemia, or an increased re- alfacalcidol has been enthusiastically endorsed as a quirement for phosphate binders, was observed in our means ofmanaging uremic hyperparathyroidism, very subjects. This most probably arose from the stimula- few of the studies in which i.v. therapy has been used tion of intestinal phosphate absorption. This effect is have been adequately controlled. Indeed, several re- not unique to alfacalcidol and can be seen with i.v. cent reports of intermittent or pulse p.o. therapy, calcitriol therapy (7). given in a similar way to how we gave alfacalcidol in We conclude that intermittent i.v. therapy and in- this study, describe results that appear comparable to termittent p.o. therapy with alfacalcidol are equally those achieved with i.v. puls& therapy (10-15). This effective at suppressing FFH in hemodialysis patients raises the question as to whether it is the frequency of with mild to moderate hyperparathyroidism. Con- administration that produces the favorable response, trolled studies are required to evaluate properly the rather than the route of administration. However, relative merits of continuous p.o. , intermittent p.o., clinical trials comparing “pulseS therapy with contin- and intermittent i.v. treatment. With continuous p.o. uous treatment are also conspicuously lacking. therapy, alfacalcidol and calcitriol are entirely equiv- Intravenous therapy was developed with a view to alent (20), so any potential advantage ofcalcitriol over obtaining high peak plasma calcitriol concentrations. alfacalcidol when the i.v. route is used also needs to be The necessity for hepatic 25-hydroxylation of alfacal- tested in controlled studies. Because i.v. preparations cidol would tend to blunt the pha.rmacokinetic differ- are significantly more expensive than p.o. ones, cost is ences between the p.o. and i.v. routes, and this could also an important issue in determining the therapy of be the reason why we failed to observe any difference choice. between them in their ability to suppress hyperparathyroidism. With i.v. calcitriol, peak plasma calcitriol ACKNOWLEDGMENTS levels are reached almost immediately, whereas after We are grateful to Muir Hutchison and Leo Pharmaceuticals for their i.v. alfacalcidol, the peak plasma calcitriol levels occur support of this study.

Journal of the American Society of Nephrology 1347 Oral Versus Intravenous Alfacalcidol

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