Tac Babe

CLINIGENE
STUDY REPORT
SPONSOR: Biocon Limited
Study No.: BA/BE:067/08
Tacrolimus 5 mg Capsule
Status: Draft, Version: 1.00
STUDY REPORT
STUDY NO.: BA/BE:067/08
A RANDOMIZED, OPEN LABEL, TWO TREATMENT, TWO PERIOD, TWO SEQUENCE,
CROSSOVER COMPARATIVE BIOAVAILABILITY STUDY OF SINGLE DOSE TACROLIMUS 5
MG CAPSULES MANUFACTURED BY BIOCON LIMITED, INDIA WITH SINGLE DOSE OF
PROGRAF 5 MG CAPSULES OF FUJISAWA PHARMACEUTICALS CO. LTD. AND HIKMA
PHARMACEUTICALS, AMMAN-JORDAN, IN HEALTHY, ADULT HUMAN MALE SUBJECTS
UNDER FASTING CONDITIONS
Test Drug [T]
Tacrolimus 5 mg capsules manufactured by Biocon Limited, India
Reference Drug [R]
Prograf 5 mg capsules of Fujisawa Pharmaceutical Co. Ltd. and

Hikma Pharmaceuticals, Amman-Jordan
Protocol Identification
Study No.: BA/BE:067/08, Status: Final, Version: 1.0,

Dated: 24/05/2008
Clinical Study Initiation Date
04/06/2008
Clinical Study Completion Date :
01/07/2008
Study Report Date
31/07/2008
Principal Investigator
Dr. Anil K., MBBS, MD

Human Pharmacology Unit,
Clinigene International Limited,
Clinigene House, Tower - I, Semicon Park,
Electronics City Phase - II,
Bangalore - 560100. India.
Phone No.: +91 80 2808 2771; Fax: +91-80-2808 2835
Clinical Investigator
Dr. Anil Kumar Anand, MBBS, MD

Phone No.: +91-80-2808 2818, Fax: +91-80-2808 2835
Study Coordinator
Dr. Shrinivas Savale, M.Pharm., Ph.D.

Phone No.: +91 80 2808 2739; Fax: +91-80-28082722
Sponsor
Biocon Limited,
20th KM, Hosur Road,
Bangalore 560 100. India.
Phone: +91-80 -2808 2808, Fax: +91-080- 2852 3423
Clinigene Intl. Ltd.
Confidential
Page 1 of 8
CLINIGENE
STUDY REPORT

APPROVAL: STUDY REPORT
A RANDOMIZED, OPEN LABEL, TWO TREATMENT, TWO PERIOD, TWO SEQUENCE,

CROSSOVER COMPARATIVE BIOAVAILABILITY STUDY OF SINGLE DOSE TACROLIMUS 5
MG CAPSULES MANUFACTURED BY BIOCON LIMITED, INDIA WITH SINGLE DOSE OF
PROGRAF 5 MG CAPSULES OF FUJISAWA PHARMACEUTICALS CO. LTD. AND HIKMA
PHARMACEUTICALS, AMMAN-JORDAN, IN HEALTHY, ADULT HUMAN MALE SUBJECTS
UNDER FASTING CONDITIONS
STUDY NO.: BA/BE:067/08
I hereby declare that I have reviewed this study report and that I approve its contents.
__________________________________________________________________________________
Dr. Anil K MBBS., MD.
Date
Principal Investigator,

Phone No.: +91 80 2808 2771, Fax: +91-80-2808 2835
Confidential
Page 2 of 8
CLINIGENE
1.0
STUDY REPORT

COMPLIANCE STATEMENT
We attest to the fact that the data presented here is accurate and reflects the raw data. The study has been
conducted as per the ICH-GCP guidelines, Amended version of Schedule Y [2005] CDSCO, India and
protocol, applicable GLP, ICMR Guidelines for Biomedical Research on Human Subjects, Declaration of
Helsinki and SOPs of Clinigene International Ltd. and we accept the responsibility for scientific correctness of
the project and the validity of the data produced in this report. We have documented significant deviations [if
any] from these requirements and have critically evaluated the report for internal consistency. All data
generated from this study including the copy of the study protocol, Informed Consent Forms [ICFs] and the
study report will be archived for a period of 15 years after the issuance of the audited reports at Clinigene.
__________________________________________________________________________________
Dr. Anil Kumar Anand, MBBS, MD
Clinical Investigator,
Phone No.: +91-80-2808 2818, Fax: +91-80-2808 2835
Date
__________________________________________________________________________________
Dr. Shrinivas Savale M.Pharm., Ph.D.
Date
Study Coordinator,
Bioanalytical Research Laboratory,
Phone No.: +91 80 2808 2739, Fax: +91-80-2808 2722
__________________________________________________________________________________
Mr. Ramsathish , M.Sc., M.Phil.
Biostatistician,
Phone No: +91 80 2808 2738
Date
Confidential
Page 3 of 8
CLINIGENE
STUDY REPORT

QUALITY ASSURANCE STATEMENT
This is to certify that periodic audits were conducted during the various phases of the study to assess
compliance of the study conduct with the protocol, SOPs GCP and GLP guidelines and that, to the best of our
knowledge, this final report accurately describes the study methods and procedures used and the results
reported herein reflect the raw data.
__________________________________________________________________________________
Dr. Sudheendra Kulkarni, M.Sc., Ph.D.
Quality Assurance Department,
Phone No.: +91 80 2808 2770, Fax: +91-80-2808 2835
Date
__________________________________________________________________________________
Mr. G. Sundar, M.Sc.
Quality Assurance Department,
Phone No.: +91 80 2852 2779, Fax: +91-80-2808 2722
Confidential
Date
Page 4 of 8
CLINIGENE
2.0
STUDY REPORT
SYNOPSIS
Name of Sponsor
Name of the
Finished Product
Name of the
Active Ingredient
Title of the Study
Investigators
Study Center
a] Clinical study
b] Bioanalytical
study
c] Central
Laboratory
Study Period
Study objective
Methodology
Number of
subjects
Inclusion criteria
Biocon Limited, Bangalore, India

Tacrolimus 5 mg capsules
Tacrolimus
A randomized, open label, two treatment, two period, two sequence, crossover comparative
bioavailability study of single dose Tacrolimus 5 mg capsules manufactured by Biocon Limited,
India, with single dose of Prograf 5 mg capsules of Fujisawa Pharmaceuticals Co. Ltd. and
Hikma Pharmaceuticals, Amman-Jordan, in healthy, adult human male subjects under fasting
conditions.
Principal Investigator
: Dr. Anil K., MBBS, MD
Clinical Investigator
: Dr. Anil Kumar Anand, MBBS, MD
Tel: +91-80-2808 2771, Fax: +91-80-2808 2835
Bioanalytical Research Laboratory,
Tel: +91-80-2808 2739; Fax: +91-80-2808 2722
Central Laboratory
Tel: +91-80-2808 2702. Fax:+91-80-2808 2722
All the subjects were housed together and dosed on the next day in both the study periods.
Clinical Phase
04/06/2008 to 01/07/2008
Activity
Period One
Period Two
Check-in
04/06/2008
25/06/2008
Dosing
05/06/2008
26/06/2008
Check-out
06/06/2008
27/06/2008
Ambulatory Visits
07/06/2008 to 10/06/2008
28/06/2008 to 01/07/2008
To compare the bioavailability of single dose Tacrolimus 5 mg capsules manufactured by Biocon
Limited, India, with single dose of Prograf 5 mg capsules of Fujisawa Pharmaceuticals Co. Ltd.
and Hikma Pharmaceuticals, Amman-Jordan, in healthy adult male human subjects under fasting
conditions.
A randomized, open label, two treatment, two periods, two sequence, crossover single dose study
under fasting conditions.
Planned and Enrolled
26
Withdrawn/Drop-out
0
Completed
26
Analyzed
24
Healthy male within the age range of 18 to 45 years.
Weight within 10% of ideal body weight. [Life Insurance Corporation of India Weight
chart for non-medical cases] with minimum of 50 kg.
Willingness to provide written informed consent to participate in the study.
Free of significant diseases or clinically significant abnormal findings during screening,
medical history, physical examination, laboratory evaluations, 12-lead ECG, chest X-ray [PA
view].
Absence of disease markers of HIV 1 and 2, Hepatitis B and C, Syphilis.
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CLINIGENE
Exclusion criteria
Screening
Test product (T)
Reference product
(R)
Dose
administration
Diet
Sampling schedule
STUDY REPORT
History or presence of significant: Cardiovascular, pulmonary, hepatic, renal, hematological,

gastro-intestinal, endocrine, immunologic, dermatologic, neurological and psychiatric
diseases.
History or presence of significant:
Alcohol dependence, alcohol abuse or drug abuse during past one year.
Smoking, of more than 5 cigarettes per day or consumption of other forms of tobacco
containing products.
Asthma, urticaria or other allergic type reactions after taking aspirin or any other drug.
Ulceration or history of gastric and/or duodenal ulcer.
Jaundice in the past 6 months.
Bleeding disorders.
Allergy to the test drug or any drug chemically similar to the drug under Investigation.
Donation of 500 mL or more blood in the previous 8 weeks before the start of this study.
Subjects who have participated in another clinical study in the past 12 weeks of
commencement of the study.
Volunteers aged between 18 and 45 years were selected according to the inclusion and exclusion
criteria. They were assessed to be healthy according to physical examination including vital signs,
normal chest X-ray [PA view], 12-lead ECG within normal limits and laboratory test results
[hematology, serum chemistry, urinalysis] judged to be clinically normal and negative results for
HIV, Hepatitis B, Hepatitis C, RPR test for syphilis as well as negative screening for identified
drugs of abuse in urine [Marijuana [THC], Cocaine, Morphine, Benzodiazepines, Barbiturates and
Amphetamine].
Formulation
Tacrolimus capsules
Strength
5 mg
Dose
5 mg
Manufactured by
Biocon Limited, India.
Batch No.
BA070005
Mfg. Date
May 2007
Expiry Date
April 2009
Oral
Mode of Administration
Formulation
Prograf capsule
Strength
5 mg
Dose
5 mg
Manufactured by
Fujisawa Pharmaceutical Co. Ltd. and Hikma
Pharmaceuticals, Amman-Jordan.
Batch No.
4300
Mfg. Date
August 2006
Expiry Date
August 2009
Oral
Mode of Administration
In both the periods, investigational product administration was carried out under fasting
conditions. Following an overnight fast of minimum 10 h in both the periods, subjects received a
single oral dose of Tacrolimus 5 mg (Test or Reference product). Dosing for subjects started at
08:00 a.m. and was completed at 08:24 a.m.
Supervised fast of minimum 10 h overnight before dosing was observed. Lunch, snacks and
dinner were served at 4, 8 and 12 h after dosing was observed. Meal plans were identical for both
the periods. Water was permitted ad-libitum until 1 h before dosing and again starting not less
than 1 h after dosing except the water provided for drug administration.
Subjects were provided unlimited dinner during the day of check-in [Day 0]. Following an
overnight fast of minimum 10 h in both the periods, subjects were provided lunch [1027.6 Kcal],
snacks [340.7 Kcal] and dinner [1046.0 Kcal] at 4, 8 and 12 h post-dose, respectively, on dosing
day [Day 1].
In each of the 2 study periods, 22 blood samples of 6 mL each were collected in K 2EDTA via an
indwelling catheter placed in one of the forearm vein till 24 h. Heparin-lock technique was used to
prevent clotting of blood in the indwelling catheter. Ambulatory blood sampling was done by
direct venipuncture. The pre-dose blood sample of was collected within a period of 1 h before the
drug administration. The post-dose blood samples was collected at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5,
1.75, 2.0, 2.25, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 24.0, 48.0, 72.0, 96.0 and 120.0 h. Before each
blood samples up to 24 h, 0.5 mL of blood was discarded so as to purge heparin in the catheter.
Confidential
Page 6 of 8
CLINIGENE
Blood loss
Washout period
Drug analysis
Estimation of
pharmacokinetic
parameters
Criteria for
evaluation
Statistical methods
Results
STUDY REPORT

The total volume of blood drawn including the volume necessary for the laboratory safety
assessment tests, study samples and the volume of blood discarded before blood draw was about
295 mL per subject for the entire study.
A washout period of 21 days was observed between two study periods.
Concentrations of Tacrolimus in plasma were analyzed using validated LC-MS/MS method.
Calibration curve extending over the range 0.22731 to 87.425 ng/mL with a LOQ of 0.22731
ng/mL was used in the subject sample analysis for Tacrolimus levels in plasma. The
concentrations of Tacrolimus below the LOQ were set to zero.
Using the plasma concentration-time profiles of Tacrolimus following pharmacokinetic
parameters were calculated:
Cmax, Tmax, AUC0-t, AUC0-, t1/2 and AUC% Extrapolated [Residual area].
These pharmacokinetic parameters were estimated by employing non-compartmental model of
WinNonlin Enterprise Version 5.1 software.
The following standards for bioequivalence were applied: The calculated 90% confidence interval
(CI) should fall within 80-125% for Cmax and 90-112% for AUC0-t and AUC0- for conclusion of
bioequivalence.
The statistical analyses for Tacrolimus were performed using PROC GLM of SAS Version 9.1
[SAS Institute Inc., USA].
Analysis of variance [ANOVA] for Ln-transformed data of AUC0-t, AUC0- and Cmax and
evaluation of formulation, period and subject [nested within sequence] effects at 5%
significance level and sequence effect at 10% level of significance, were performed.
Calculation of ratio and 90% confidence interval [CI] [Schuirmanns two one-sided test] based on
root mean square error obtained from ANOVA and ratio [T/R] for C max, AUC0-t and AUC0- were
also performed.
The mean pharmacokinetic parameters of Tacrolimus for Test and Reference formulations for 24
evaluable subjects, who completed the study, are summarized in following table (Table No. 1),
while the ratio of means for pharmacokinetic parameters [ln-transformed] of Tacrolimus
formulations together with CI are given in Table No. 2.
Table No. 1:
Formulation means for Tacrolimus
Mean SD (n = 24)
(Untransformed data)
Test (T)
Reference (R)
Cmax (ng/mL)
43.380 12.923 41.868 13.894
Tmax (h)
1.50* 0.65
1.50* 0.42
AUC0-t (ng.h/mL)
387.57 167.03 434.98 223.28
AUC0- (ng.h/mL)
441.18 198.85 488.58 268.31
Kel (1/h)
0.0167 0.0042 0.0184 0.0034
t1/2 (h)
44.92 15.03
38.92 7.32
AUC%_Extrap (%) 11.185 5.2752 9.8948 3.5538
*Median value was reported for T max
PK Parameter
(Units)
CV (%)
Test (T)
29.79
40.07
43.10
45.07
25.09
33.46
47.16
Reference (R)
33.18
27.28
51.33
54.92
18.42
18.81
35.92
Table No. 2:
Ratios of means and intra-subject CV for pharmacokinetic parameters (Lntransformed) of Tacrolimus formulations together with 90% CI (n=24)
90% CI
Intra-subject
Parameter
Ratio (%)
Lower
Upper
CV (%)
105.04
96.41
114.44
17.42
Cmax (ng/mL)
92.75
84.76
101.49
18.32
AUC0-t (ng.h/mL)
94.20
86.51
102.56
17.30
AUC0- (ng.h/mL)
The curves of average plasma concentrationtime profiles of Tacrolimus (n = 24) for study
formulations are given in Fig. No. 1 [a) Untransformed, b) Semilog].
Confidential
Page 7 of 8
CLINIGENE
STUDY REPORT
Figure No. 1:
Average plasma concentrationtime profiles of Tacrolimus
(a) Untransformed
Average whole blood concentration-time profile for Tacrolimus (BA/BE:067/08)
40
35
30
25
20
R
T
15
10
0
0
20
40
60
80
100
120
Scheduled_time (h)
b) Semilog
Average whole blood concentration-time profile for Tacrolimus (BA/BE:067/08)
100.0
10.0
R
T
1.0
0.1
0
20
40
60
80
100
120
Scheduled_time (h)
Safety Results
Conclusion
Adverse event monitoring in the form of vitals check and subject well being questionnaire was
done during the study. Safety parameters included physical and systemic examination was done at
the end of each period. Clinical laboratory safety assessment was done at the end of the study.
Total 28 adverse events were occurred during entire study out of which 9 adverse events were
recorded during period one, 12 adverse events were recorded during period two and 7 adverse
events were recorded during post study laboratory safety assessment. Out of 28 adverse events 26
were resolved completely and from remaining 02 adverse events, 01 is ongoing and the subject is
being followed up and 01 lost to follow up [for detail refer Sec. No.12.2].
The reported adverse events were generally of mild in intensity. No concomitant medication was
administered. At post-study examination done at the end of period two, all subjects who
completed the study were found to be healthy except for those who had adverse event during post
study laboratory safety assessment. These subjects were followed up for their adverse events.
Vital signs of all subjects showed no marked changes throughout the study. No abnormal findings
were observed during the post-study physical examination.
The 90% Cl for the ratios of means of the test (T) and Reference (R) formulations for Ln
transformed Cmax was found to be within the acceptance criteria of 80-125%.
Single dose of TACROGRAF (Tacrolimus) 5 mg capsules manufactured by Biocon Ltd, India can
be considered to be bioequivalent with single dose of Prograf 5 mg capsules manufactured by
Fujisawa Pharmaceuticals Co. Ltd and Hikama Pharmaceuticals, Amman- Jordan in Healthy
human adult male subjects.
Confidential
Page 8 of 8

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CLINIGENE

SPONSOR: Biocon Limited

Study No.: BA/BE:067/08

Status: Draft, Version: 1.00

Tacrolimus 5 mg capsules manufactured by Biocon Limited, India

Reference Drug [R]

Prograf 5 mg capsules of Fujisawa Pharmaceutical Co. Ltd. and

Study No.: BA/BE:067/08, Status: Final, Version: 1.0,

Clinical Study Initiation Date

Clinical Study Completion Date :

Study Report Date

Dr. Anil K., MBBS, MD

Dr. Anil Kumar Anand, MBBS, MD

Dr. Shrinivas Savale, M.Pharm., Ph.D.

Clinigene Intl. Ltd.

SPONSOR: Biocon Limited

Status: Draft, Version: 1.00

APPROVAL: STUDY REPORT

A RANDOMIZED, OPEN LABEL, TWO TREATMENT, TWO PERIOD, TWO SEQUENCE,

STUDY NO.: BA/BE:067/08

Human Pharmacology Unit,

Clinigene Intl. Ltd.

SPONSOR: Biocon Limited

Status: Draft, Version: 1.00

Clinigene Intl. Ltd.

SPONSOR: Biocon Limited

Status: Draft, Version: 1.00

QUALITY ASSURANCE STATEMENT

Clinigene Intl. Ltd.

SPONSOR: Biocon Limited

Study No.: BA/BE:067/08

Clinigene Intl. Ltd.

Biocon Limited, Bangalore, India

SPONSOR: Biocon Limited

Study No.: BA/BE:067/08

Test product (T)

Clinigene Intl. Ltd.

History or presence of significant: Cardiovascular, pulmonary, hepatic, renal, hematological,

SPONSOR: Biocon Limited

Status: Draft, Version: 1.00

Clinigene Intl. Ltd.

SPONSOR: Biocon Limited

Study No.: BA/BE:067/08

Status: Draft, Version: 1.00

Clinigene Intl. Ltd.

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