Pharmacokinetic Evaluation of a Single Intramuscular High Dose versus an Oral Long-Term Supplementation of Cholecalciferol

RESEARCH ARTICLE Pharmacokinetic Evaluation of a Single Intramuscular High Dose versus an Oral LongTerm Supplementation of Cholecalciferol Katharina Wylon1☯, Gennadiy Drozdenko1☯, Alexander Krannich2, Guido Heine1, Sabine Dölle1, Margitta Worm1* 1 Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Berlin, Germany, 2 Koordinierungszentrum für Klinische Studien, Charité Universitätsmedizin Berlin, Berlin, Germany a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 ☯ These authors contributed equally to this work. * Abstract Background and Objectives OPEN ACCESS Citation: Wylon K, Drozdenko G, Krannich A, Heine G, Dölle S, Worm M (2017) Pharmacokinetic Evaluation of a Single Intramuscular High Dose versus an Oral Long-Term Supplementation of Cholecalciferol. PLoS ONE 12(1): e0169620. doi:10.1371/journal.pone.0169620 Editor: Robert K Hills, Cardiff University, UNITED KINGDOM Received: November 26, 2015 Accepted: December 16, 2016 Vitamin D deficiency is frequent during the winter and occurs throughout the year in the elderly or patients suffering from autoimmune diseases. The objective of this study was to evaluate the pharmacokinetic properties of oral supplementation versus a single intramuscular injection of cholecalciferol in healthy individuals. Research design and methods Up to 8,000 I.U. oral cholecalciferol was administered daily for 84 days in a 4 week doseescalation setting to vitamin D deficient individuals. In another cohort, a single intramuscular injection of 100,000 I.U. cholecalciferol was given. In both cohorts, individuals without vitamin D intake served as the comparison group. 25-hydroxyvitamin D (25(OH)D) concentrations were measured in all individuals at defined time points throughout the studies. Published: January 23, 2017 Copyright: © 2017 Wylon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. For more data from the study registered under controlledtrials.com ISRCTN65263333 and NCT01845142 whose authors may be contacted at Charité Universitätsmedizin, Luisenstr. 2-4, 10117 Berlin, Germany. Funding: The clinical trials were supported by the Deutsche Forschungsgemeinschaft (DFG SFB650/TP5) (oral study) and by Heyl Chemisch- Results The mean 25(OH)D serum concentration increased significantly after oral cholecalciferol intake compared to the control group (day 28: 83.4 nmol/l and 42.5 nmol/l; day 56: 127.4 nmol/l and 37.3 nmol/l; day 84: 159.7 nmol/l and 30.0 nmol/l). In individuals receiving 100,000 I.U. cholecalciferol intramuscular, the mean 25(OH)D serum concentration peaked after 4 weeks measuring 70.9 nmol/l compared to 32.7 nmol/l in the placebo group (p = 0.002). The increase of 25(OH)D serum concentrations after 28 days was comparable between both routes of administration (p = 0.264). Conclusions Oral and intramuscular cholecalciferol supplementation effectively increased serum 25(OH) D concentrations. PLOS ONE | DOI:10.1371/journal.pone.0169620 January 23, 2017 1 / 10 Vitamin D Pharmacokinetics and Different Routes of Administration Introduction pharmazeutische Fabrik GmbH & Co. KG (i.m. study). Vitamin D deficiency is a frequent medical condition, not only in the elderly but also in young adults, depending on lifestyle factors [1–3]. The major sources of vitamin D (chemical cholecalciferol) are the cutaneous synthesis upon sunlight exposure and, to a minor extent, dietary intake. The active form of vitamin D is a fat-soluble seco-steroid hormone [4]. When synthesized in the skin or provided through the diet, vitamin D is biologically inactive. It is hydroxylated twice into (a) the storage metabolite 25-hydroxyvitmamin D (25(OH)D) and (b) the biologically active metabolite 1.25-dihydroxyvitamin D (calcitriol) [5]. The 25(OH)D has a circulating half-life of 3 weeks [6] and is commonly used to determine the vitamin D status [7]. Calcitriol is known to regulate intestinal calcium absorption, serum calcium and phosphate homeostasis, bone mineralization and immune regulation [8, 9]. The optimal dosage, frequency and route of administration to reach sufficient vitamin D levels in the blood (25(OH) D > 50 nmol/l) are still controversially discussed [6]. Different administration routes are used to increase systemic vitamin D concentrations, e.g. oral and intramuscular (i.m.). The oral supplementation is the first-line vitamin D deficiency treatment. If 25(OH)D serum concentrations do not increase after adequate substitution, an i.m. injection with cholecalciferol is indicated. The possible reasons for oral vitamin D resistance include malabsorption, liver—or kidney failure and obesity [10]. Single, large vitamin D doses were studied without determining the optimal dosage, or route of administration. Until now no general recommendation is available. This study had been designed to assess peak vitamin D concentrations after a 100,000 I.U. single dose application in comparison to monthly increasing oral cholecalciferol substitution. Competing Interests: The authors have declared that no competing interests exist. Patients and Methods Oral vitamin D supplementation In the first cohort, 43 healthy subjects between the age of 18 and 60 years were enrolled in an open label study (Table 1) [11]. The exclusion criteria were a lack of consent, incompliance, scheduled sun tanning or UV exposure, a positive history of sarcoidosis, hypercalcemia, serum creatinine concentration > 1 mg/dl, nephrolithiasis, pregnancy and lactation, diseases of the cardiovascular system, cancer, malabsorption or chronic infection. Individuals of the vitamin D group (n = 25) received monthly increasing doses of 2,000 I.U. (50μg, week 1 to 4), 4,000 I. U. (100μg, week 5 to 8) and 8,000 I.U. (200μg, week 9 to 12) of cholecalciferol per day. Healthy individuals without vitamin D intake served as a control group (n = 18). Both study groups were comparable with respect to age, gender, and basal serum 25(OH)D concentrations (Table 1). Blood samples for serum analysis were drawn at baseline and after 4, 8 and 12 weeks. Serum 25(OH)D levels were measured using the serum 25(OH)D ELISA kit (IDS Hamburg, Germany). Table 1. Baseline characteristics of the patients with oral and intramuscular vitamin D supplementation. Values given as mean and standard deviation; p-values calculated using Students-T-Test, n.s. = not significant, n.a. = not applicable. Study oral oral p-value i.m. i.m. p-value Characteristics Vitamin D Placebo n.a. Vitamin D Placebo n.a. Number (n) 25 18 n.a. 12 6 n.a. Sex (f /m) 9 / 16 7 / 11 n.a. 8/4 4/2 n.a. Age (years) 33.4 ± 6.6 31.7 ± 5.2 n.s. 34.9 ± 9.1 36 ± 13 n.s. 2 (...truncated)