Clinical Therapeutics/Volume 36, Number 1, 2014

Comparison of the Pharmacokinetics, Safety, and Tolerabilityof Vitamin D3 in DP-R206 (150-mg Ibandronate/24,000-IUVitamin D3 Tablet) and as Monotherapy (24,000 IU) inHealthy Male Korean Adults

Ji-Young Jeon, MS1,*; Sun Young Lee, MD, PhD1,2,*; Yong-Jin Im, MS1; Eun-Young Kim, MS1;Yunjeong Kim, MS1; Tae Sun Park, MD, PhD1,3; Soo-Wan Chae, MD, PhD1;Jae Won Lee, PhD4; Hun Jun, MS4; Tae Won Lee, MS4; and Min-Gul Kim, MD1

1Clinical Trial Center and Biomedical Research Institute, Chonbuk National University Hospital, Jeonju,Republic of Korea; 2Department of Radiation Oncology, Chonbuk National University, Jeonju, Republic ofKorea; 3Department of Endocrinology and Metabolism, Chonbuk National University, Jeonju, Republic ofKorea; and 4Research and Development Center, DreamPharma Corp, Seoul, Republic of Korea

Accepted for publication December 3, 2013.

ABSTRACT

Background: Combined treatment with a bi-sphosphonate and vitamin D has been proposed forpostmenopausal osteoporosis. A new, fixed-dose com-bination tablet of ibandronate plus vitamin D3 hasbeen developed for monthly administration to treatpostmenopausal osteoporosis.

Objectives: The main objective of the present studywas to compare the pharmacokinetics of vitamin D3

administered in 2 forms: a newly developed ibandro-nate 150-mg/vitamin D3 24,000-IU tablet (DP-R206,test drug) and a stand-alone vitamin D3 24,000-IUtablet (reference drug). A secondary objective was toevaluate the safety and tolerability of DP-R206 inhealthy adult male Korean volunteers.

Methods: This study was a single-dose, open-label,randomized-sequence, 2-treatment, 2-way crossovertrial. Blood samples were collected from 24 hours’predose to 120 hours’ postdose. The plasma concen-trations of vitamin D3 were analyzed by using avalidated HPLC-MS/MS method. Pharmacokinetic pa-rameters were calculated, and the 90% CIs of the ratiosof the geometric means of the parameters were deter-mined from the logarithmically transformed data byusing ANOVA.

Results: Thirty-sex healthy adult male Korean volun-teers with a mean (SD) age of 25.8 (2.7) years, a meanheight of 174.0 (5.9) cm, and a mean weight of 69.1 (6.2)kg were enrolled; 29 participants completed the study.

*These authors contributed equally to this work.

48

The 90% CIs of the ratios of the geometric means (testdrug/reference drug) of the baseline-corrected Cmax,AUC0–last, and AUC0–1 values were 0.93 to 1.24, 0.89to 1.19, and 0.87 to 1.18, respectively. The 90% CIs ofthe ratios of the geometric means (test drug/referencedrug) of the baseline-uncorrected Cmax, AUC0–last, andAUC0–1 values were 0.93 to 1.24, 0.88 to 1.19, and 0.87to 1.18, respectively. Eighty-four adverse events (AEs)were reported in 24 of 32 subjects receiving DP-R206,and 14 AEs were reported in 8 of 29 subjects receivingthe vitamin D3 24,000-IU tablet. All of the subjects whoexperienced AEs recovered without sequelae, and noserious AEs were observed.

Conclusions: The vitamin D3 pharmacokinetics weresimilar for DP-R206 and the 24,000-IU vitamin D3

tablet. DP-R206 was well tolerated. ClinicalTrials.govidentifier: NCT01577849. (Clin Ther. 2014;36:48–57)& 2014 Elsevier HS Journals, Inc. All rights reserved.

Key words: ibandronate, osteoporosis, pharmaco-kinetics, vitamin D3.

INTRODUCTIONOsteoporosis is a common bone disease characterized bylow bone mass and the structural deterioration of bonetissue, which lead to bone fragility and an increased risk

http://dx.doi.org/10.1016/j.clinthera.2013.12.0010149-2918/$ - see front matter

& 2014 Elsevier HS Journals, Inc. All rights reserved.

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J.-Y. Jeon et al.

of fracture.1 Vitamin D is an essential nutrient that isrequired for the maintenance of bone health.2 Itregulates intestinal calcium absorption and thestimulation of bone resorption, leading to themaintenance of serum calcium concentrations.3 Therecommended daily intake of vitamin D for adultsaged Z50 years is 800 to 1000 IU.4 The Institute ofMedicine’s Dietary Reference Intake values for vitaminD are 600 IU/d until age 70 years and 800 IU/d foradults aged Z71 years.5 Vitamin D deficiency results inimpaired bone mineralization, which can lead to diseasessuch as hypoparathyroidism, hypophosphatemia, andosteomalacia and may exacerbate osteoporosis in theelderly.6,7

Bisphosphonates are the most widely used class ofprescription medications for the treatment and pre-vention of osteoporosis. Ibandronate sodium, a highlypotent, third-generation, nitrogen atom–containingbisphosphonate drug, is administered as 1 tablet onceper month. Ibandronate exhibits high antiresorptivepotency and gastrointestinal tolerability, and compli-ance has significantly improved as a result of the lessfrequent administration that it requires.8–10 Therapywith once-monthly oral ibandronate 150 mg has beenapproved and marketed worldwide, including in theUnited States, Europe, and Asia.

Combination therapy involving a bisphosphonateand vitamin D has been proposed for the treatmentof postmenopausal osteoporosis. The beneficial effectsof vitamin D on muscles and the reduction infalls should increase interest in combination therapy,and the reduction in falls associated with vitaminD administration may improve the antifracture effi-cacy of bisphosphonates.11 Based on these hypotheses,DP-R206 was developed; this tablet contains 150 mgof ibandronate sodium and 24,000 IU of vitaminD3 and is administered once per month. DP-R206is expected to increase the overall efficacy of bi-sphosphonate treatment, as well as to improve intakecompliance among postmenopausal osteoporosispatients.

The purpose of the present study was to comparethe pharmacokinetics of vitamin D3 administered asDP-R206 (a 150-mg ibandronate/24,000-IU vitaminD3 tablet) with those administered as a 24,000-IUvitamin D3 tablet in healthy adult volunteers underfasting conditions. A secondary objective was toevaluate the safety and tolerability of DP-R206 inhealthy adult male Korean volunteers.

January 2014

SUBJECTS AND METHODSThis study was approved by the Ministry of Food andDrug Safety and the Institutional Review Board ofChonbuk National University Hospital (Jeonju, Re-public of Korea; institutional review board numberCUH 2012-03-002), and it was conducted accordingto the Ethical Principles for Medical Research Involv-ing Human Subjects outlined in the Declaration ofHelsinki and according to the Good Clinical PracticeGuideline. Written informed consent was obtainedfrom all participants before screening, and a detailedexplanation of the study was provided.

SubjectsHealthy male adult volunteers aged 20 to 55 years

with body mass indices ranging from 19 to 26 kg/m2

were enrolled in the study. Each subject’s health wasconfirmed via physical examinations, measurements ofvital signs, 12-lead ECG, and clinical laboratory assess-ments (ie, hematology, biochemistry, serology, urinaly-sis, urine drug screening) performed 11 to 42 daysbefore the first administration of the investigationalproduct. Subjects were enrolled if their vital signs werein the following ranges: systolic blood pressure, 90 to150 mm Hg; diastolic blood pressure, 50 to 100 mmHg; and pulse rate, 40 to 100 beats/min. The subjectswere asked to limit their sun exposure by wearingclothing that covered much of the skin, a hat, andsunscreen (SPF Z30) when performing activities thatexposed them to sunlight for Z1 hour per day, begin-ning a minimum of 10 days before the first date ofadministration of the investigational product and con-tinuing for the duration of the study. The subjects wereasked to abstain from foods with high vitamin Dcontents (eg, cod liver oil, salmon, tuna, catfish, mack-erel, sardines, eel), vitamin D–fortified foods (eg, vitaminD–fortified dairy products, including milk and cheese),and vitamin D supplements for a minimum of 10 daysbefore the first administration of the investigationalproduct. Subjects were excluded if they had consumedherbal medications within the previous 30 days, hadtaken any prescription medications within the previous14 days, or had used over-the-counter drugs within 7days before the first administration of the investigationalproduct.

Study DesignThis study was conducted as an open-label, random-

ized-sequence, 2-period, 2-treatment, single-dose, 2-way

49

Clinical Therapeutics

crossover trial at the Clinical Trial Center of ChonbukNational University Hospital, Jeonju, Republic ofKorea. All of the subjects were randomly assigned to1 of 2 sequences of treatments. The test drug wasDP-R206 (a 150-mg ibandronate/24,000-IU vitaminD3 tablet), and the reference drug was a 24,000-IUvitamin D3 tablet. Each sequence group consisted of18 subjects.

All of the subjects visited the facility 10 days beforethe first administration of the investigational product,and explanations were provided regarding the impor-tance of shielding themselves from sunlight. Light-protection and nutrition diaries were given to thesubjects, and these records were checked at the time ofhospital admission.

The subjects were hospitalized at the clinical trialcenter on day –1 (Figure 1). On day 1, each subjectreceived the investigational product assigned to hissequence group: a 24,000-IU vitamin D3 tablet or aDP-R206 tablet (150 mg ibandronate/24,000-IU vita-min D3) orally administered with 240 mL of waterafter an overnight fast of at least 10 hours.The subjects were maintained in a fasting state until

DP-R206 (150-mibandronate/24,00

vitamin D3 tablet24,000 IU of vitam

Limit sun exposure and vitamin

Limit sun exposure and vitami

Period 1

Period 2

Washout period:28 days

Day –10 ~ Day –1 Day –1 Day 1

Day –19 ~ Day 28

Hospitalization

Hospitalization

Day 28 Day 2

DP-R206 (150-mibandronate/24,00

vitamin D3 tablet24,000 IU of vitam

B

Figure 1. Study design evaluating the pharmacokineticsvolunteers.

50

4 hours after drug administration, with the exceptionof water consumption 2 hours after dosing.

The most common acute adverse event (AE) aftertreatment with bisphosphonates is influenza-like ill-ness.12 The symptoms (eg, fever, chills, myalgia) areusually easily managed with pain medications such asacetaminophen. In the present study, the recommendedadult dosage (1300 mg) of extended-release acetami-nophen was prophylactically administered to all sub-jects (based on a decision by the investigator) 14, 24,and 32 hours after the administration of the investiga-tional product. The subjects were discharged on themorning of day 6. The washout period was 28 days,and the second study period was conducted on thesame schedule as the first study period, with theexception of the assignment of the investigationalproduct to be administered to each group.

Pharmacokinetic AssessmentsBlood samples (6 mL) were collected before dosing

(–24, –18, –12, –6, and 0 hours) and 1, 4, 6, 8, 10, 16,24, 36, 48, 72, 96, and 120 hours after drug admin-istration. The blood samples were immediately

g0-IU

) orin D3

D–rich foods

n D–rich foods

Day 2 Day 3 Day 4 Day 5 Day 6

Discharge

Discharge

9 Day 30 Day 31 Day 32 Day 33 Day 34

g0-IU

) orin D3

lood sampling: from 24 hours' predose to 120

hours' postdose

Blood sampling: from 24 hours' predose to 120

hours' postdose

of a single dose of vitamin D3 in healthy adult male

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J.-Y. Jeon et al.

centrifuged at 1800 � g at 41C for 8 minutes, and theplasma was stored at –701C before analysis. Theconcentrations of vitamin D3 in the plasma sampleswere determined by using a validated HPLC-MS/MSmethod. A calibration curve covering the range of 0.5to 80 ng/mL was constructed. The calibration curveswere linear over the calibration concentration range(r Z 0.9900).

The individual pharmacokinetic parameters weredetermined by noncompartmental methods usingPhoenix WinNonlin version 6.3 (Pharsight Corpora-tion, Sunnyvale, California). Cmax and Tmax weredetermined directly from the observed values.AUC0–last was calculated by using the linear-up/log-down trapezoidal rule. The ke describes the rateof decrease in concentration per unit time, which isestimated from the log-linear terminal part of theconcentration–time curve as the slope of the naturallogarithm of concentration against time. AUC0–1was calculated by using the equation AUC0–last þ(C0–last/ke), where C0–last is the last measureableconcentration. The elimination t½ of a substance,the time required for the blood plasma concentra-tion to be reduced by one half, was calculated asln 2/ke.

As the baseline, the arithmetic means of the plasmaconcentration of vitamin D3 at –24, –18, –12, –6, and0 hours (predose) were calculated for each dosingperiod. Baseline correction was performed by sub-tracting the mean individual predose concentrationfrom the mean individual postdose values.13 If thebaseline correction produced a negative plasmaconcentration value, this value was set to 0 beforecalculating the baseline-corrected AUC.

Safety and Tolerability AssessmentsSafety and tolerability were assessed by evaluation

of AEs, physical examinations, 12-lead ECGs, labo-ratory assessments, and vital sign measurements. AEswere identified by asking the subjects general health-related questions before dosing (–24 and 0 hours) and4, 8, 12, 24, 48, 72, 96, and 120 hours after theadministration of the dose, as well as via subject self-reporting during the study period. The severity (eg,mild, moderate, severe) of AEs was assessed by theinvestigator. Physical examinations were performedbefore dosing (–24 and 0 hours); 24, 48, 72, 96, and120 hours after the administration of the dose; and atthe follow-up visit. ECGs were performed predose

January 2014

(–24 hours), 24 and 120 hours after the administra-tion of the dose, and at the follow-up visit. Laboratoryassessments (eg, hematology, biochemistry, urinalysis)were performed before dosing (–24 and 0 hours); 24,72, and 120 hours after the administration of thedose; and at the follow-up visit. Vital signs (eg, bloodpressure, heart rate, temperature) were measuredbefore dosing (–24 and 0 hours); 4, 8, 24, 48, 72,96, and 120 hours after the administration of thedose; and at the follow-up visit.

Statistical AnalysesStatistical analyses were performed by using SAS

version 9.3 (SAS Institute, Inc, Cary, North Carolina).Descriptive statistics, including mean (SD), were usedto summarize the baseline-corrected and baseline-uncorrected pharmacokinetic vitamin D3 data for the2 treatments. ANOVA with a mixed-effects model at a5% significance level was used to compare thepharmacokinetic parameters of the test and referencedrugs. The point estimates and 90% CIs of the ratiosof the geometric means (test drug/reference drug) ofthe log-transformed Cmax, AUC0–last, and AUC0–1 forboth the baseline-corrected and baseline-uncorrecteddata were compared. Treatment, sequence, and periodwere treated as fixed effects, and the subject nestedwithin the sequence was treated as a random effect.

RESULTSSubject Population

The 36 male subjects (with a mean [SD] age of 25.8[2.7] years, a mean height of 174.0 [5.9] cm, and amean weight of 69.1 [6.2] kg) who were determined tobe eligible for the study were assigned to the relevantsequence group by using a randomization process.There were no significant differences in demographiccharacteristics between the sequence groups (Table I).Before hospitalization during period 1, three subjectswithdrew their informed consent and one subject waswithdrawn from the study due to the use of prescrip-tion medications. Thus, 32 subjects were hospitalized.Their light-protection and nutrition diaries were exa-mined, and the investigational product was admini-stered. Two subjects withdrew their informed consentafter period 1, and 1 subject was removed from thestudy because he could not be contacted. As a result,29 subjects completed the study according to the pro-tocol (Figure 2).

51

Table I. Demographic characteristics of study subjects. Values are given as mean (SD) or number.

Sequence Group

Parameter RT (n ¼ 18) TR (n ¼ 18) Total (N ¼ 36) P

Age, y 25.61 (2.15) 26.06 (3.28) 25.83 (2.74) 0.873*

Height, cm 174.67 (6.40) 173.29 (5.51) 173.98 (5.93) 0.494†

Weight, kg 69.47 (6.43) 68.79 ( 6.21) 69.13 (6.24) 0.747†

Body mass index, kg/m2 22.73 (1.27) 22.91 (1.79) 22.82 (1.53) 0.733†

Male sex 18 18 36 –Smoke (yes/no) 11/7 8/10 19/17 0.317‡

Alcohol (yes/no) 14/4 11/7 25/11 0.278‡

Caffeine (yes/no) 9/9 11/7 20/16 0.502‡

For testing normality: Kolmogorov-Smirnov test, reference, then test (RT) group, P ¼ 0.1500; test, then reference (TR) group,P ¼ 0.0137.*Wilcoxon rank-sum test.†Independent t test.‡χ2 test.

Clinical Therapeutics

Pharmacokinetic ResultsThe pharmacokinetic parameters of vitamin D3

were evaluated and are summarized in Table II. Themean plasma concentration–time profiles are presen-ted in Figure 3.

The baseline-corrected mean Cmax, AUC0–last, andAUC0–1 of vitamin D3 were 37.74 nmol/L, 1814 h ∙nmol/L, and 2138 h ∙ nmol/L, respectively, for DP-R206; these values were 37.31 nmol/L, 1857 h ∙ nmol/L,and 2213 h ∙ nmol/L for the 24,000-IU vitamin D3

tablet. The baseline-uncorrected mean Cmax, AUC0–last,and AUC0–1 of vitamin D3 were 37.93 nmol/L, 1838 h∙ nmol/L, and 2181 h ∙ nmol/L for DP-R206; thesevalues were 37.48 nmol/L, 1879 h ∙ nmol/L, and 2251 h∙ nmol/L for the 24,000-IU vitamin D3 tablet. The Tmax

and elimination t½ values of vitamin D3 were similar forthe 2 treatments.

The point estimates and 90% CIs of the ratios ofthe geometric means (test/reference) of the baseline-corrected Cmax, AUC0–last, and AUC0–1 of vitamin D3

administered as DP-R206 compared with that admin-istered as the 24,000-IU vitamin D3 tablet were 1.08(0.93–1.24), 1.03 (0.89–1.19), and 1.01 (0.87–1.18),respectively. The point estimates and 90% CIs of theratios of the geometric means (test/reference) of thebaseline-uncorrected Cmax, AUC0–last, and AUC0–1 ofvitamin D3 administered as DP-R206 compared withthat administered as the 24,000-IU vitamin D3 tablet

52

were 1.07 (0.93–1.24), 1.02 (0.88–1.19), and 1.01(0.87–1.18), respectively (Table III). The intrasubject%CV of the Cmax, AUC0–last, and AUC0–1 of vitaminD3 was �32.6% to 34.6%. The ANOVA resultsrevealed no carryover effect of any of thepharmacokinetic parameters.

Safety and TolerabilitySafety and tolerability were assessed in 32 subjects

who received the investigational product. A total of 98AEs were reported in 26 subjects (Table IV). Therewere 92 mild cases and 6 cases that were moderate inintensity. Eighty-four AEs were reported in 24 of 32subjects receiving DP-R206, and 14 AEs were re-ported in 8 of 29 subjects receiving the 24,000-IUvitamin D3 tablet. The AE incidence was significantlyhigher after DP-R206 treatment than after treatmentwith the 24,000-IU vitamin D3 tablet (P ¼ 0.0002).Eighty-three AEs were considered to be related to theinvestigational product: 74 cases with DP-R206 and 9cases with 24,000-IU vitamin D3 treatment. The mostcommonly reported AEs were diarrhea (23 cases),myalgia (16 cases), and abdominal pain (12 cases). Allof the subjects with AEs recovered without sequelae,and no serious AEs were observed. In addition, theresults of the ECGs, physical examinations, vital signmeasurements, and clinical laboratory tests indicated

Volume 36 Number 1

Assessed for eligibility(N = 50)

Excluded (n = 14)

Randomized (n = 36)

Lost to follow-up (n = 0)Discontinued intervention (n = 0)

Lost to follow-up (n = 0)Discontinued intervention (n = 3)

Analyzed (n = 17) Analyzed (n = 12)

Allocated to sequence 1 (RT) (n = 18) Allocated to sequence 2 (TR) (n = 18)

Enro

llmen

tA

lloca

tion

Follo

w-u

pA

naly

sis

• Did not meet inclusion criteria (n = 6)• Refused to participate (n = 3)

• Received allocated intervention (n = 17)• Did not receive allocated intervention (refused to participate [n = 1])

• Received allocated intervention (n = 15)• Did not receive allocated intervention (refused to participate [n = 2], other reasons [n = 1])

(declined to participate [n = 2]),could not be contacted [n = 1])

• Other reasons (n = 5)

Figure 2. Subject allocation and disposition. RT ¼ reference, test; TR ¼ test, reference.

Table II. Pharmacokinetic parameters of vitamin D3 after a single oral administration of 2 treatments. Unlessotherwise noted, values are given as mean (SD).

Baseline-Corrected Vitamin D3 Baseline-Uncorrected Vitamin D3

Parameter Test (n ¼ 29) Reference (n ¼ 29) Test (n ¼ 29) Reference (n ¼ 29)

Cmax, nmol/L 37.74 (8.44) 37.31 (11.58) 37.93 (8.40) 37.48 (11.52)AUC0–last, h ∙ nmol/L 1814 (382) 1857 (505) 1838 (380) 1879 (500)AUC0–1, h ∙ nmol/L 2138 (468) 2213 (614 2181 (466) 2251 (606)Tmax, h

* 16.00 (10.00–24.00) 16.00 (10.00–16.02) 16.00 (10.00–24.00) 16.00 (10.00–16.02)t½, h 43.47 (6.42) 42.97 (8.60) 44.54 (5.97) 43.71 (8.41)

*Median (minimum–maximum).

J.-Y. Jeon et al.

January 2014 53

24,000-IU vitamin D3 tablet

60A B

C D

50

40

Plas

ma

Con

cent

ratio

n (n

mol

/L)

30

20

10

0–24 –12 0 12 24 36 48

Time (h) Time (h)60 72 84 96 108 120

Plas

ma

Con

cent

ratio

n (n

mol

/L)

–240.01

0.1

1

10

100

–12 0 12 24 36 48 60 72 84 96 108 120 132

60

50

40

Plas

ma

Con

cent

ratio

n (n

mol

/L)

30

20

10

0–24 –12 0 12 24 36 48

Time (h) Time (h)60 72 84 96 108 120

Plas

ma

Con

cent

ratio

n (n

mol

/L)

–240.01

0.1

1

10

100

–12 0 12 24 36 48 60 72 84 96 108120132

DP-R206 (150-mg ibandronate/24,000-IU vitamin D3 tablet)

Figure 3. Mean (SD) plasma concentration–time profiles of (A) baseline-corrected vitamin D3 and (B) thelog-transformed values, as well as those of (C) baseline-uncorrected vitamin D3 and (D) the log-transformed values, after administration of a single oral dose of the test or reference drug tohealthy adult male volunteers (N ¼ 29).

Table III. Analysis of variance of 2 treatments of vitamin D3 after single-dose administration.

Baseline-Corrected Vitamin D3 Baseline-Uncorrected Vitamin D3

Parameter Ratio 90% CI Intrasubject %CV Ratio 90% CI Intrasubject %CV

Cmax, nmol/L 1.08 0.93–1.24 32.63 1.07 0.93–1.24 32.60AUC0–last, h ∙ nmol/L 1.03 0.89–1.19 33.27 1.02 0.88–1.19 33.44AUC0–1, h ∙ nmol/L 1.01 0.87–1.18 34.38 1.01 0.87–1.18 34.59

Clinical Therapeutics

54 Volume 36 Number 1

Table IV. Adverse events per treatment.

Test (n ¼ 32) Reference (n ¼ 29)

Related Not Related Related Not Related

Adverse Event Mild Moderate Mild Moderate Mild Moderate Mild Moderate

Gastrointestinal disordersAbdominal pain 11 (11) 1 (1)Diarrhea 19 (19) 4 (4)Dyspepsia 1 (1)Oropharyngeal pain 1 (1) 2 (2)Vomiting 1 (1)

General disorders and administrationsite conditions

Asthenia 1 (1)Catheter site erythema 1 (1)Catheter site edema 1 (1)Catheter site pain 1 (1)Chills 3 (3) 1 (1) 1 (1)Hyperhidrosis 1 (1)Pyrexia 7 (7) 1 (1) 1 (1) 1 (1)

Musculoskeletal and connective tissuedisorders

Arthralgia 1 (1) 1 (1)Bone pain 1 (1)Musculoskeletal pain 2 (3)Myalgia 10 (11) 4 (4) 1 (1)Pain in extremity 1 (1)

Nervous system disordersDizziness 1 (1)Headache 7 (8)

Respiratory, thoracic, and mediastinaldisorders

Cough 1 (1)Nasal obstruction 2 (2) 1 (1)Rhinorrhea 2 (2)

Total 23 (68) 4 (6) 6 (10) — 7 (9) — 2 (5) —

The number of individuals with events (number of events) is shown for each treatment.

J.-Y. Jeon et al.

that no clinically significant changes occurred duringthe study.

DISCUSSIONThe main objective of the present study was tocompare the pharmacokinetics of vitamin D3 after

January 2014

the administration of DP-R206 (a 150-mg ibandro-nate/24,000-IU vitamin D3 tablet) and a 24,000-IUvitamin D3 tablet. The 90% CIs for both the baseline-corrected and baseline-uncorrected parameters werewithin the bioequivalence limit of 0.8 to 1.25. Thepharmacokinetic properties of vitamin D3 were not

55

Clinical Therapeutics

significantly affected by the pharmacokinetics ofibandronate, and the bioavailability of vitamin D3 inhealthy adult volunteers was similar for DP-R206 andthe 24,000-IU vitamin D3 tablet.

Vitamin D comprises 2 bioequivalent forms: vitaminD2 (ergocalciferol) is largely synthetic and is acquiredfrom fortified dietary sources, whereas vitamin D3

(cholecalciferol) is an endogenous substance that ispredominantly synthesized in the skin during exposureto sunlight. Some dietary supplements also act asprecursors for vitamin D3 synthesis.5 In the presentstudy, subjects administered the vitamin D3 24,000-IUtablet (vitamin D3 24,000 IU per month, equivalent to800 IU daily). To stabilize the predose concentrationsof vitamin D3, the subjects were required to applysunscreen and to abstain from foods with high vitaminD contents for at least 10 days before theadministration of the investigational product. All thesubjects achieved stable endogenous vitamin D3 levelsby 24 hours before treatment administration. Thesubjects continued to follow the aforementionedrestrictions at the clinical trial center from 24 hoursbefore the administration of the investigational productthrough the last pharmacokinetic sampling. Therefore,the baseline vitamin D3 concentrations did not affectthe pharmacokinetic profiles of vitamin D3.

The frequency of AEs was significantly higher aftertreatment with DP-R206 compared with 24,000 IU ofvitamin D3. The majority of the AEs were attributed tothe ibandronate component of DP-R206. These AEs,such as diarrhea (5.1%), myalgia (2.0%), and abdomi-nal pain (7.8%), have previously been reported inpatients receiving ibandronate 150 mg once a monthfor the treatment of postmenopausal osteoporosis.14–16

It is presumed that the frequency of AEs is higher withhealthy volunteers than with postmenopausal osteopo-rosis patients. No safety concerns were associated withthe 24,000-IU vitamin D3 treatment. These resultsindicate that DP-R206 was well tolerated.

Monthly dosing is associated with improved adherencecompared with daily or weekly regimens. Once-monthlyibandronate therapy has significantly improved compli-ance compared with the weekly alendronate regimen.17

Therefore, monthly combined treatment with abisphosphonate and vitamin D3 is convenient, effective,and safe for treating postmenopausal osteoporosispatients.

The subjects of this single-dose, open-label studywere all healthy and young. The biologic risk factors

56

for the development of osteoporosis are low bonemass and advanced age.1,3 Therefore, additionalstudies in postmenopausal osteoporosis patients mightbe beneficial for evaluating the safety and clinicalefficacy of DP-R206.

CONCLUSIONSThe pharmacokinetics of vitamin D3 were not alteredby the presence of ibandronate. We speculate thatother bisphosphonates would also be unlikely tointerfere with vitamin D3 pharmacokinetics. DP-R206 (a 150-mg ibandronate/24,000-IU vitamin D3

tablet) was well tolerated.

ACKNOWLEDGMENTSThis study was funded by DreamPharma Corp. Thestudy was conducted by the Clinical Trial Center atChonbuk National University Hospital.

J.-Y. Jeon and S.Y. Lee contributed to the dataanalyses and wrote the manuscript. Y.-J. Im, E.-Y.Kim and Y. Kim contributed to the data analyses andparticipated in reviewing the article. T.S. Park and S.-W. Chae contributed to the data collection as inves-tigators and participated in reviewing the article. J.W.Lee, H, Jun, and T.W. Lee managed the developmentof the test drug and reviewed the article. M.-G. Kimwas the principal investigator of this study andreviewed the manuscript.

CONFLICTS OF INTERESTDr. J.W. Lee, Mr. Jun, and Mr. T.W. Lee areemployees of DreamPharma Corp. The authors haveindicated that they have no other conflicts of interestregarding the content of this article.

The sponsor did not participate in the execution ofthe study or in the analysis of the data.

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Address correspondence to: Min-Gul Kim, MD, Clinical Trial Center andBiomedical Research Institute, Chonbuk National University Hospital,Jeonju, 561-712, Republic of Korea. E-mail: mgkim@jbnu.ac.kr

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