Roche trials database

Protocol number:

ML28199

Title of Study:

Prospective, randomized, single-blind, cross-over, comparative study for establishing comparative bioavailability of Copegus vs Vilona® in healthy volunteers

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

Copegus

Generic name:

ribavirin [Copegus]

Therapeutic area:

• Healthy Volunteer

Clinical study summary:

This prospective, randomized, single-blind, cross-over study was designed to compare the bioavailability of Copegus (ribavirin) administered as tablets and ribavirin administered as capsules in healthy volunteers. Volunteers were randomized to one of two sequences, Sequence 1: reference drug and then test drug; Sequence 2: test drug and then reference drug.

Study center(s):

Single center in Mexico

Phase of development:

I

Objectives:

The objective was to compare the bioavailability of two pharmaceutical formulations of ribavirin

Methodology:

After screening and signing the informed consent form, eligible healthy volunteers were enrolled in the study. On Day 1, volunteers received the ribavirin formulation they were randomized too. Blood samples were taken on Days 1 to 5. After a washout period of 14 days, volunteers received the other ribavirin formulation. Safety was monitored throughout the study.

Number of patients (planned/analyzed):

40 volunteers planned and enrolled

Diagnosis and main criteria for inclusion:

Adult healthy volunteers, 18 to 55 years of age; Clinically healthy as confirmed by medical history, physical examination, electrocardiogram, thorax teleradiography and routine clinical laboratory measurements; Body mass index between 18 and 28 kg/m2; Negative testing for drugs of abuse

Test product, dose and mode of administration or test procedure:

ribavirin (Copegus) 400 mg tablets (single oral dose)

Duration of treatment:

1 day for each sequence

Reference therapy, dose and mode of administration or reference procedure:

ribavirin (Vilona®) 400 mg capsule (single oral dose)

Criteria for evaluation (efficacy, safety):

Pharmacokinetics

C_max, T_max, AUC_0-t, AUC_0-inf, T_½, MRT_0-t, MRT_0-inf

Safety

Adverse events, physical examination, medical history, vital signs, laboratory parameters

 

Statistical methods:

For the statistical analysis, pharmacokinetic parameters were analyzed by analysis of variance (ANOVA) using a linear statistical model. To estimate the bioequivalence between the test drug and the reference drug, the pharmacokinetic parameters of C_max, AUC_0-t and AUC_0-inf were subjected to the double one-sided t test; to the Classical confidence intervals and Westlake, as well as the Anderson-Hauck test. Each parameter was determined at a value of α=0.05 and a value of β=0.20 to detect the difference between the test drug and the reference drug. Safety parameters were analyzed descriptively.

Summary (efficacy, safety, other results):

Demographics

40 male healthy volunteers were enrolled in the study. The mean age was 21.4 years (SD 3.46; CI 16.15). The mean weight was 67.89 kg (SD 9.46; CI 13.94). The mean height was 167 cm (SD 0.084, CI 5.01). The mean body mass index was 24.3 (SD 2.64, CI 10.88). The mean years of schooling was 14 (SD 2.22; CI 15.85).

Pharmacokinetics

The following pharmacokinetic parameters were obtained for the test drug Copegus and the reference drug Vilona®:

Pharmacokinetic Parameter	Vilona®	Copegus
Cmax (ng/ml)	407,34 (SD 155,573)	399,85 (SD 145,324)
Tmax (hr)	1,5 (SD 0,654)	1,5 (SD 0,651)
AUC0-t (hr*ng/ml)	5217,276 (SD 2240,032)	5649,415 (SD 2282,304)
AUC0-inf (hr*ng/ml)	7542,313 (SD 3123,818)	7649,402 (SD 2945,270)
λz (hr-1)	0,019 (SD 0,009)	0,020 (SD 0,010)
T½ (hr)	45,4 (SD 29,247)	42,9 (SD 23,037)
MRT0-t (hr)	22,82 (SD 8,156)	24,45 (SD 7,309)
MRT0-inf (hr)	59,13 (SD 36,081)	55,69 (SD 27,076)

T_max = Time in which the C_max is reached

λ_z = Slope of the lineal portion of the elimination phase value

T_½ = Half-life time of λ_z

MRT = Mean residence time

SD = Standard Deviation

 

ANOVA was performed with the pharmacokinetic parameters C_max, AUC_0-t, and AUC_0-Inf. For C_max, there was no significant effect for the sequence (p=0.8342; alpha=0.05), but for the period (p=0.0066; alpha=0.05). However, since the study used a balanced design, the difference found in the period was not considered as relevant.

For AUC_0-t, and AUC_0-Inf, there were no significant effects for the sequence (p=0.9322; alpha=0.05 and p=0.7806; alpha=0.05, respectively), or the period sequence (p=0.9307; alpha=0.05 and p=0.1205; alpha=0.05, respectively).

Confidence intervals  were between 80 to 125 and the Unilateral test, double-one-sided test and the Hauck-Anderson test showed a value of less than 0.05, all of the tests had a power equal or greater than 0.8 establishing the bioequivalence of the two ribavirin formulations.

Safety

There were 7 adverse events (AEs) in 7 patients during the study. All AEs were not considered to be related to the study drug. All patients had recovered at the end of the study.

No serious adverse events were reported.

Conclusions:

The results of the bioequivalence study confirmed that the bioavailability and the pharmacokinetics of Copegus as tablet formulation and Vilona® as capsule formulation are comparable.

Date of report:

08.11.2011

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