Journal List > Transl Clin Pharmacol > v.22(1) > 1082588

TOOLS
Choi, Kim, Kim, Noh, Lee, Lee, Bae, and Kim: Pharmacokinetic Characteristics of Ibandronate and Tolerability of DP-R206 (150 mg Ibandronate/24,000 IU Vitamin D3) Compared to the Ibandronate (150 mg) Monotherapy in Healthy Adults
Original Article

Translational and Clinical Pharmacology 2014;22(1):22-29.

Published online: 30 June 2014

DOI: https://doi.org/10.12793/tcp.2014.22.1.22

Pharmacokinetic Characteristics of Ibandronate and Tolerability of DP-R206 (150 mg Ibandronate/24,000 IU Vitamin D3) Compared to the Ibandronate (150 mg) Monotherapy in Healthy Adults

Hee Youn Choi1, 2, Mi Jo Kim1, 2, Yo Han Kim1, 2, Yook-Hwan Noh3, Jae-won Lee4, Tae-won Lee4, Kyun-Seop Bae1, 2, ∗, Min-Gul Kim5

1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul 138–736, Korea

2University of Ulsan College of Medicine, Seoul 138–736, Korea

3Department of Clinical Pharmacology and Therapeutics, Inje University Pusan Paik Hospital, Busan 614–735, Korea

4Dreampharma Corp., Seoul 100–755, Korea

5Clinical Trial Center, Biomedical Research Institute, Chonbuk National University Hospital, Chonju 361–711, Korea

∗Correspondence: K.S. Bae; Tel: +82-2-3010-4611, Fax: +82-2-3010-4623, E-mail: ksbae@amc.seoul.kr

Received 30 April 2014       Revised 17 May 2014       Accepted 17 May 2014

Copyright © 2014 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Ibandronate (a bisphosphonate) is commonly used as an treatment of osteoporosis in combination with vitamin D. Monthly DP-R206-a novel, fixed-dose combination tablet (150 mg ibandro-nate/24,000 IU vitamin D3)-was recently developed to enhance patient compliance. This open, randomized, two-period crossover study was conducted to compare the pharmacokinetics of ibandronate when administered as DP-R206 or 150 mg ibandronate to healthy adult volunteers. Each volunteer was randomly allocated to receive single-dose DP-R206 or ibandronate with a 28-day washout period between treatments. Blood samples were assessed using pharmacokinetic analysis. Plasma ibandronate concentrations were determined using liquid chromatography-tandem mass spectrometry. Safety and tolerability assessments were performed throughout the study. In total, 103 participants received the study drugs and 72 participants completed the study. The geometric mean ratios (DP-R206/ibandronate) of the maximum concentration (Cmax) and the area under the plasma concentration time curve from time zero to the last concentration (AUClast) values were 0.959 (90% CI: 0.820–1.120) and 0.924 (90% CI: 0.805–1.060), respectively. The frequencies of adverse events (AEs) and drug reactions were similar between treatment groups, and all AEs were recovered without sequalae. Ibandronate pharmacokinetics, tolerability, and safety are comparable when administered to healthy individuals, regardless if administered as DP-R206 or ibandronate.

Keywords: ibandronic acid, Vitamin D, Drug combination, Pharmacokinetics

References

1. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998; 13:581–589.
crossref
2. Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmacody-namics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet. 2005; 44:551–570.
3. Clinician's guide to prevention and treatment of osteoporosis. 2014. http://nof.org/hcp/clinicians-guide/Accessed17Feb.
4. Penning-van Beest FJ, Goettsch WG, Erkens JA, Herings RM. Determinants of persistence with bisphosphonates: a study in women with postmenopausal osteoporosis. Clin Ther. 2006; 28:236–242.
crossref
5. Mühlbauer RC, Bauss F, Schenk R, Janner M, Bosies E, Strein K, et al. BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J Bone Miner Res. 1991; 6:1003–1011.
crossref
6. Lewiecki EM, Babbitt AM, Piziak VK, Ozturk ZE, Bone HG. Adherence to and gastrointestinal tolerability of monthly oral or quarterly intravenous ibandronate therapy in women with previous intolerance to oral bisphosphonates: a 12-month, open-label, prospective evaluation. Clin Ther. 2008; 30:605–621.
crossref
7. Reginster JY, Felsenberg D, Cooper C, Stakkestad JA, Miller PD, Kendler DL, et al. A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate. Osteoporos Int. 2006; 17:159–166.
crossref
8. Busse B, Bale HA, Zimmermann EA, Panganiban B, Barth HD, Carriero A, et al. Vitamin D deficiency induces early signs of aging in human bone, increasing the risk of fracture. Sci Transl Med. 2013; 5:193ra88. doi: 10.1126/scitranslmed.3006286.
crossref
9. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons RA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012; 367:40–49. doi: 10.1056/NEJMoa1109617.
crossref
10. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. 2012; 97:1153–1158. doi: 10.1210/jc.2011-2601.
crossref
11. Sohl E, van Schoor NM, de Jongh RT, Visser M, Deeg DJ, Lips P. Vitamin D status is associated with functional limitations and functional decline in older individuals. J Clin Endocrinol Metab. 2013; 98:E1483–E1490. doi: 10.1210/jc.2013-1698.
crossref
12. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et al. Fall prevention with supplemental and active forms of vitamin D: a metaanalysis of randomised controlled trials. BMJ. 2009; 339:b3692. doi: 10.1136/bmj.b3692.
crossref
13. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985; 76:1536–1538.
crossref
14. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet. 1989; 2:1104–1105.
crossref
15. Mosali P, Bernard L, Wajed J, Mohamed Z, Ewang M, Moore A, et al. Vitamin D status and parathyroid hormone concentrations influence the skeletal response to zoledronate and denosumab. Calcif Tissue Int. 2014; 94:553–559. doi: 10.1007/s00223-014-9840-0.
crossref
16. Deane A, Constancio L, Fogelman I, Hampson G. The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following longterm use in postmenopausal osteoporosis. BMC Musculoskelet Disord. 2007; 8:3.
crossref
17. Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone. 2006; 38(2 Suppl 1):S4–S9.
crossref
18. Choi HJ, Shin CS, Ha YC, Jang S, Jang S, Park C, et al. Burden of osteoporosis in adults in Korea: a national health insurance database study. J Bone Miner Metab. 2012; 30:54–58. doi: 10.1007/s00774-011-0280-x.
crossref
19. Bonviva (ibandronate sodium) tablets. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021455s001lbl.pdf. Accessed 17 Feb. 2014.
20. Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res. 2005; 20:1315–1322.
crossref
21. Miller PD, Epstein S, Sedarati F, Reginster JY. Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. Curr Med Res Opin. 2008; 24:207–213.
crossref
22. Barrett J, Worth E, Bauss F, Epstein S. Ibandronate: a clinical pharmacological and pharmacokinetic update. J Clin Pharmacol. 2004; 44:951–965.
crossref
23. Diletti E, Hauschke D, Steinijans VW. Sample size determination for bioequivalence assessment by means of confidence intervals. Int J Clin Pharmacol Ther Toxicol. 1991; 29:1–8.
24. Jeon JY, Lee SY, Im YJ, Kim EY, Kim Y, Park TS, et al. Comparison of the pharmacokinetics, safety, and tolerability of vitamin D3 in DP-R206 (150-mg ibandronate/24,000-IU vitamin D3 tablet) and as monotherapy (24,000 IU) in healthy male Korean adults. Clin Ther. 2014; 36:48–57. doi: 10.1016/j. clinthera.2013.12.001.
crossref
25. Papapetrou PD. Bisphosphonate-associated adverse events. Hormones (Athens). 2009; 8:96–110.
crossref

Figure 1.
Allocation of the subjects to study groups
tcp-22-22f1.tif
Figure 2.
Mean plasma ibandronate concentration-time curves (semilog (upper) and linear (lower) scale)
tcp-22-22f2.tif
Table 1.
Demographic characteristics of the enrolled subjects
    RT (n=49) TR (n=54) Total (n=103) p
Age (yr)   24.71±2.75 24.70±3.49 24.71±3.15 0.694∗
Weight (kg)   70.24±8.73 71.71±8.03 71.01±8.37 0.579†
Height (cm)   174.62±4.92 175.15±4.59 174.90±4.73 0.376†
Drinking‡ Yes 63.3% (31) 61.1% (33) 62.1% (64) 0.822§
No 36.7% (18) 38.9% (21) 37.9% (39)
Smoking‡ Yes 38.8% (19) 33.3% (18) 35.9% (37) 0.565§
No 61.2% (30) 66.7% (36) 64.1% (66)
Caffeine‡ Yes 61.2% (30) 55.6% (30) 58.3% (60) 0.560§
No 38.8% (19) 44.4% (24) 41.7% (43)
Subjects who administered the study drug at least once were included in this analysis.

∗ Mann-Whitney U test,

† T-test,

‡ % (numbers of participants),

§ Chi-square test,

Shapiro-Wilk test for normality check were conducted. The p-value was <0.05 for age, while p-value>0.05 for weight and height parameters each.

Table 2.
Pharmacokinetic parameters
PK parameter Summary statistics Ibandronate (150 mg) DP-R206∗
Cmax (ng/mL) Arithmetic mean
SD
CV (%)		 90.64
54.72
60.4		 87.70
74.52
85.0
AUClast (ng/mL) Arithmetic mean
SD
CV (%)		 530.66
340.96
65.9		 482.80
325.34
67.4
AUCinf (ng·hr/mL) Arithmetic mean
SD
CV (%)		 549.24
366.76
66.8		 501.43
349.59
69.7
Tmax (hr) Median
Minimum
Maximum		 2.00
0.50
6.00		 2.00
0.50
6.00
t1/2 (hr) Mean
SD
CV (%)		 32.38
15.29
47.21		 30.76
16.52
53.71

∗ DP-R206: fixed-dose 150 mg ibandronate/24,000 IU vitamin D3

Table 3.
Geometric mean ratio and 90% confidence interval limits of the primary ibandronate PK parameters (DP-R206∗:150 mg tablet ibandronate)
PK parameter Geometric mean ratio 90% Confidence interval
Cmax 0.959 0.820–1.120
AUClast 0.924 0.805–1.060
AUCinf 0.923 0.801–1.062

∗ DP-R206: fixed-dose 150 mg ibandronate/24,000 IU vitamin D3

Table 4.
Adverse events
Treatment Ibandronate 150 mg (n=85) DP-R206∗ (n=90) Total
System organ class Severity Probably related Possibly related Unlikely related Definitely not related Probably related Possibly related Unlikely related Definitely not related  
Gastrointestinal disorders Mild 27 6 0 0 35 7 0 0 75
Moderate 2 1 0 0 6 2 0 0 11
Severe 1 0 0 0 3 0 0 0 4
General disorders and administration site conditions Mild 19 1 0 0 20 1 0 0 41
Moderate 7 0 0 0 6 0 0 0 13
Severe 0 0 0 0 1 0 0 0 1
Immune system disorders Mild 0 0 0 0 0 0 0 0 0
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 1 0 0 0 0 0 0 1
Infections and infestations Mild 0 1 0 0 0 0 1 0 2
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 0 0 0 0 0 0 0 0
Injury, poisoning, and procedural complications Mild 0 0 0 0 0 0 0 1 1
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 0 0 0 0 0 0 0 0
Investigations Mild 0 1 2 0 0 0 0 0 3
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 0 0 0 0 0 0 0 0
Metabolic and nutritional disorders Mild 0 0 0 0 0 1 0 0 1
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 0 0 0 0 0 0 0 0
Musculoskeletal and connective tissue disorders Mild 25 0 0 0 26 1 0 0 52
Moderate 8 0 0 0 6 0 0 0 14
Severe 0 0 0 0 0 0 0 0 0
Nervous system disorders Mild 9 7 0 0 9 3 0 1 29
Moderate 0 0 0 0 0 1 0 0 1
Severe 0 0 0 0 0 0 0 0 0
Renal and urinary disorders Mild 0 2 0 0 0 0 0 0 2
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 0 0 0 0 0 0 0 0
Respiratory, thoracic, and mediastinal disorders Mild 0 0 1 0 0 0 1 3 5
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 0 0 0 0 0 0 0 0
Dermal and subcutaneous tissue disorders Mild 1 0 0 0 0 0 0 0 1
Moderate 0 0 0 0 0 0 0 0 0
Severe 0 1 0 0 0 0 0 0 1
Total   99 21 3 0 112 16 2 5 258

∗ DP-R206: fixed-dose 150 mg ibandronate/24,000 IU vitamin D3

TOOLS
Similar articles