High-dose extended-release calcifediol successfully treated advanced secondary hyperparathyroidism in an end-stage kidney disease patient: a case report

Abstract

Background

Hemodialysis (HD) patients lose renal CYP27B1 (cytochrome P450 25-hydroxyvitamin D-1α-hydroxylase) as kidney function declines causing low serum total 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), and elevated intact parathyroid hormone (iPTH). Most require vitamin D hormone treatment which increases the risk of hypercalcemia. A recent randomized controlled trial (RCT) in HD patients showed that extended-release calcifediol (ERC) could safely raise serum 25D to high levels (≥ 50 ng/mL) and drive sufficient alternative production of 1,25D by extra-renal CYP27B1, potentially avoiding the need for hormone treatment.

Case presentation

A 41-year-old Caucasian male requiring regular HD was overdosed with 900 (rather than 300) µg/HD of ERC for 10 weeks in the RCT referenced above. When the overdosing was recognized, serum 25D had increased 18-fold (from 19 to 339 ng/mL), 1,25D had risen 23-fold (from 6 to 137 pg/mL), and iPTH had decreased 67% (from 440 to 146 pg/mL) with no impact on calcium, phosphorus or treatment-emergent adverse events noted.

Conclusions

The observations from this case report are consistent with the conclusion from the full RCT with ERC in HD patients that serum 25D repletion can control elevated iPTH in advanced chronic kidney disease by supporting adequate extra-renal 1,25D production. They also indicate that serum 25D levels required for adequate extra-renal 1,25D production and effective iPTH control are much higher than commonly used repletion targets of 20 or 30 ng/mL, and published estimates of serum 25D toxicity thresholds are probably too low for ERC. These observations, however, require substantiation in further clinical trials with ERC in end-stage kidney disease patients.

Background

More than 130,000 patients with end-stage kidney disease (ESKD) initiate dialysis each year in the United States (US), 82% of whom receive in-center hemodialysis (HD) three times per week [1]. All of them have experienced progressive loss of renal CYP27B1 (cytochrome P450 25-hydroxyvitamin D-1α-hydroxylase) as kidney function declined which causes dysregulated vitamin D metabolism, a disorder characterized by low circulating concentrations of total 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), and elevated intact parathyroid hormone (iPTH). Most of these patients (> 60%) receive regular vitamin D receptor activator (VDRA) treatment, usually oral calcitriol [1], which stimulates the absorption of dietary calcium (Ca) and phosphorus (P) and increases the risk of hypercalcemia and hyperphosphatemia [2].

Extended-release calcifediol (ERC) is approved as Rayaldee^® in the US and Europe for treating secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI) at daily oral doses of 30 µg escalating, as needed, to 60 µg. The active ingredient, calcifediol, is also known as calcidiol or 25-hydroxyvitamin D₃ (25D₃). ERC safely raises serum 25D to high levels (≥ 50 ng/mL) [3] and drives intracrine 1,25D production by CYP27B1 expressed in non-renal tissues, thereby normalizing circulating 1,25D concentrations [4]. ERC is currently in development for potential use in dialysis patients.

The following case report describes an ESKD patient on chronic HD with advanced SHPT who received overdoses of ERC continuing for 10 weeks in an investigational trial. It is the first report of a prolonged and significant ERC overdose and provides additional perspective on the potential safety and efficacy of gradual serum 25D repletion therapy with ERC in ESKD patients.

Case presentation

A 41-year-old Caucasian male requiring HD three times weekly for 5 years via a forearm arterio-venous fistula was inadvertently overdosed with 900 (rather than 300) µg/HD of ERC for 10 weeks in an investigational randomized controlled trial (RCT; NCT03602261, registered 2018-07-25; protocol #00025201 approved by Advarra Institutional Board, Columbia, MD). He met all subject selection criteria for the trial but had a history of hypertension, autonomic dysfunction, type 2 diabetes with nephrotic syndrome, hypercalcemia and hyperphosphatemia. On enrollment in the trial, he had discontinued intravenous doxercalciferol (4 µg/HD) for 8 weeks preceding initiation of ERC dosing and for study duration. Concomitant medications included metoprolol succinate, nifedipine, aspirin, enalapril, furosemide, folic acid, Ca acetate, darbepoetin alfa, iron sucrose, heparin (pork) bolus and saline. A 2.5 mEq/L Ca dialysate was used prior to and during the study. A pre-dialysis electrocardiogram (ECG) obtained before ERC dosing showed sinus rhythm with possible left arterial enlargement, left ventricular hypertrophy and non-specific ST-T wave changes.

Overdosing resulted from a misreading of the study protocol and remained undiscovered by virtual monitoring (mandated during the peak of the COVID-19 pandemic) for 10 weeks at which time the study drug supply (intended to last for the entire study) was prematurely exhausted. By then, serum total 25D and 1,25D had risen to 339 ng/mL and 137 pg/mL, respectively, from 19 and 6 at pre-treatment baseline and plasma iPTH had fallen 67% from 440 to 146 pg/mL. Serum P and corrected Ca remained unchanged and well within the normal range at 3.7 and 9.1 mg/dL, respectively. Pre-dialysis blood pressure of 237/132 mmHg decreased to 170/92 by one hour into HD, a pattern that was typical prior to study participation. The subject was asymptomatic and had not experienced any treatment-emergent adverse events (TEAEs). A physical exam was unremarkable.

On discovery of overdosing, ERC was suspended and full clinical chemistries assessed 5 days later: serum 25D and 1,25D had declined to 304 ng/mL and 115 pg/mL, iPTH had risen to 200 pg/mL, and Ca and P remained stable. A repeat ECG was unchanged from the one obtained at pretreatment baseline. Dosing with ERC resumed after a 12-day hiatus at the correct level of 300 µg/HD but was reduced two weeks later to 300 µg twice weekly when iPTH was again confirmed below 150 pg/mL, the prespecified dose reduction threshold. Thereafter, the dose remained unchanged for the remaining 12 weeks of the 26-week treatment period. Plasma iPTH stabilized within the range of 200–250 pg/mL and serum 25D and 1,25D gradually declined to stable levels of about 165 ng/mL and 60 pg/mL, respectively. At the end of dosing in the study, iPTH rose markedly as serum 25D declined to nearly 50 ng/mL. Determinations of serum total 25D by liquid chromatography tandem mass spectrometry (LC-MS/MS) and 1,25D by chemiluminescence (DiaSorin Liaison) were consistent with parallel and much more specific LC-MS/MS analyses for serum calcifediol (25D₃) and calcitriol (1,25-dihydroxyvitamin D₃), addressing concerns that the observed increases merely reflected assay interferences. Serum Ca and P remained unchanged. Time courses of these five parameters are displayed in Fig. 1. No TEAEs were reported through the end of the study. The subject has been doing well and has remained on stable HD during more than four years since study participation.

Fig. 1.

Time courses of key biomarkers and weekly dosing rates with extended-release calcifediol in an end-stage kidney disease patient receiving hemodialysis three times per week. Time courses of serum total 25-hydroxyvitamin D (25D), serum total 1,25-dihydroxyvitamin D (1,25D) and plasma intact parathyroid hormone (iPTH) are displayed in the top panel, and corrected serum calcium (Ca) and serum phosphorus (P) are displayed in the bottom panel before and after initiation of oral dosing (three times per week during HD) on Day 1 with extended-release calcifediol (ERC). Weekly rates of ERC dosing during the 26-week treatment period are displayed in the middle panel, beginning with 2,700 µg/week (900 µg/HD) instead of the intended 900 µg/week. ERC administration was suspended after 10 weeks when the overdosing was discovered, restarted at the correct dose 12 days later, and subsequently adjusted downward to 600 µg/week (300 µg during each of two HD sessions per week) because iPTH was confirmed below 150 pg/mL (a pre-specified dose reduction threshold). Prior administration of intravenous doxercalciferol (4 µg/HD) was suspended at enrollment and until the end of the study. ERC dosing was discontinued during the final 6-week follow-up period

Discussion and conclusions

This case report recounts a prolonged and significant overdosing (2,700 µg/week for 10 weeks) with ERC by an ESKD patient requiring chronic regular HD. Serum 25D rose 18-fold in this patient to 339 ng/mL, circulating 1,25D increased 23-fold to 137 pg/mL, and iPTH decreased 67% from 440 pg/mL, yet serum Ca and P remained stable. The marked changes in 25D, 1,25D and iPTH moderated during the transient suspension of dosing and subsequent downward adjustment but serum Ca and P remained unchanged and within the normal range with continued dosing at the correct level.

The absence of severe and sustained increases in serum Ca and P with such high serum 25D exposure may have derived from a partial but as yet unidentified resistance to vitamin D therapy. This seems unlikely, however, in view of the observed biomarker changes: serum total 25D elevation confirmed ERC’s bioavailability, the rise in serum 1,25D confirmed its metabolic activation, and the iPTH reduction confirmed the expected target tissue response. It seems more likely that the published estimates for the serum 25D toxicity threshold are too low for ERC.

In 2011, the Institute of Medicine expressed safety concerns about serum 25D exposures exceeding 50 ng/mL, including heightened risks of vitamin D toxicity, all-cause mortality and cancer [5]. But, toxicity (defined as increased rates of hypercalcemia, hyperphosphatemia, hypercalciuria, elevated fibroblast growth factor 23 or TEAEs) was not apparent in this case or during up to one year of treatment with ERC in RCTs wherein serum 25D was maintained at concentrations averaging well above 50 ng/mL [3, 4]. Admittedly, much larger and longer studies with ERC will be needed to assess its impact on the rate of all-cause mortality in CKD and ESKD patients. A carcinogenicity study (required for regulatory approval of ERC) found no neoplastic changes attributable to daily subcutaneous administration of calcifediol at ≤ 33 µg/kg/day for 26 weeks to rasH2 transgenic mice (data on file). Others have postulated toxicity thresholds for serum 25D that exceed 50 ng/mL, ranging from 60 to 250 ng/mL [6–10], all of which remain unsubstantiated.

Observations from this overdosed patient suggest the possibility that sufficient serum 25D repletion may control elevated iPTH in advanced CKD and that VDRA treatment may not be needed to manage dysregulated vitamin D metabolism. The widespread belief regarding an ultimate requirement for VDRA treatment derives logically from the known decline in renal CYP27B1 (which converts 25D to 1,25D) and the long unproven efficacy of dietary vitamin D supplements (cholecalciferol or ergocalciferol) to lower elevated iPTH in progressive CKD [2, 11, 12]. Recent RCTs, however, have demonstrated that ERC effectively reduces elevated iPTH in non-dialysis CKD patients irrespective of declining kidney function [13] and normalizes serum 1,25D and halts SHPT progression in dialysis patients [4] when serum 25D concentrations are raised to ≥ 50 ng/mL.

Raising serum 25D to ≥ 50 ng/mL with ERC is effective for treating SHPT despite declining or insufficient kidney function because it gradually supplies adequate substrate to extra-renal CYP27B1 [4]. This 25D-1α-hydroxylase is broadly expressed in the body, not just in kidneys. When renal CYP27B1 declines in advancing CKD, its extra-renal counterparts can be engaged by sufficient elevation of serum 25D with ERC treatment to become major alternative sources of 1,25D, thereby restoring normal vitamin D metabolism, as demonstrated in the current case report and in the RCTs cited herein. Extra-renal CYP27B1 receives 25D substrate largely by passive diffusion which requires a high concentration gradient across cell membranes. Such production is substrate driven, increasing in proportion to rising serum 25D concentrations, and unimpeded by negative feedback mechanisms regulating renal CYP27B1 [4, 6, 14, 15]. In contrast, renal CYP27B1 can receive adequate substrate by megalin-cubulin mediated endocytosis [16] even when serum 25D concentrations are low, and its activity is down-regulated by negative feedback mechanisms as circulating 1,25D increases. It is not implausible to speculate that renal CYP27B1 provides exigent 1,25D production when circulating 25D concentrations are too low to support normal extra-renal production.

The applicable Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline supports the correction of VDI in CKD but only to implied 25D levels of 20–30 ng/mL. These levels are too low to support extra-renal 1,25D production as restoration of adequate serum 1,25D concentrations in chronic HD patients requires elevation of serum 25D concentrations to at least 50 ng/mL [4], as seen during the 6-week post-treatment follow-up in the current case.

The high ERC dosage recounted in this case report, in the absence of a rigorous safety evaluation, is uncomfortably high. However, increasing dosages of vitamin D therapies are required as SHPT progresses, indicating that effective management with lower dosages is more feasible when initiated promptly after onset of SHPT, not ESKD [17]. Additional RCTs need to be undertaken in order to further characterize the efficacy and safety of 25D repletion with ERC in ESKD patients.

In conclusion, the observations from this case report are consistent with the conclusion from the full RCT with ERC in ESKD patients [4] that serum 25D repletion can control elevated iPTH in advanced CKD by supporting adequate extra-renal 1,25D production. They also indicate that serum 25D levels required for adequate extra-renal 1,25D production and effective iPTH control are much higher than commonly used repletion targets of 20 or 30 ng/mL, and that published estimates of serum 25D toxicity thresholds are probably too low for ERC. These observations, however, require substantiation in further clinical trials with ERC in ESKD patients.

Abbreviations

1,25D

1,25-dihydroxyvitamin D

25D

25-hydroxyvitamin D

25D₃

25-hydroxyvitamin D₃, calcifediol, calcidiol

Ca

Calcium

COVID-19

Coronavirus disease 2019

CKD

Chronic kidney disease

ECG

Electrocardiogram

ERC

Extended-release calcifediol

ESKD

End-stage kidney disease

HD

Hemodialysis

iPTH

Intact parathyroid hormone

P

Phosphorus

RCT

Randomized controlled trial

SHPT

Secondary hyperparathyroidism

TEAE

Treatment-emergent adverse event

US

United States

VDI

Vitamin D insufficiency

VDRA

Vitamin D receptor activator

Author contributions

C.W.B., A.A., S.A.S., and L.L.J. designed the study. J.C. and S.A.S. carried out data analysis and preparation of the figures. C.W.B. and S.A.S. drafted the initial version of the manuscript. All authors (C.W.B., A.A., J.C., S.A.S. and L.L.J.) reviewed, edited, and approved the final version.

Funding

This study was supported by the Renal Division of OPKO Health Inc. and CSL-Vifor Pharma.

Data availability

The data that support the findings of this case report are not publicly available due to contained information that could compromise the privacy of research participants, but they are available (in redacted form, as applicable) from the corresponding author (C.W.B.) upon reasonable request.

Declarations

Ethics approval and consent to participate

The study (NCT03602261; Registration Date: 2018-07-25) was conducted in compliance with the principles of the Declaration of Helinski. The protocol was reviewed by Advarra Institutional Review Board (Columbia, MD; protocol reference number 00025201). All participants provided advance written informed consent for their participation.

Consent for publication

The participant described in this case report gave written informed consent for its publication.

Competing interests

The authors (A.A., J.C., S.T., S.A.S., L.L.J. and C.W.B.) are or have been employees, consultants or contractors of OPKO Health, Inc. and have no other conflicts of interest to disclose.