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ORIGINAL CONTRIBUTION |
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| Year : 1996 | Volume
: 50
| Issue : 7 | Page : 234-238 |
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Bioequivalence studies of celiprolol in healthy human volunteers
EK Iyer, HP Tipnis
Bombay College of Pharmacy, Kalina, Santacruz (E), Bombay-400 098, India
Correspondence Address:
E K Iyer
Bombay College of Pharmacy, Kalina, Santacruz (E), Bombay-400 098
India
PMID: 8979541
How to cite this article:
Iyer E K, Tipnis H P. Bioequivalence studies of celiprolol in healthy human volunteers. Indian J Med Sci 1996;50:234-8 |
| ¤ Introduction | |  |
Celiprolol is a hydrophilic β1 , selective adrenoceptor _antagonist with mild selective β2 , agonist as well as weak vasodilator properties. It belongs to the third generation of cardioselective beta adrenoceptor antagonists and its profile indicates that it may lower blood pressure with less depression of cardiac output than the beta blockers devoid of agonist activity, because of its ability to lower peripheral vascular resistance and minimum effect on resting heart rate. A reduced potential to induce bronchoconstriction in asthmatic hypertensives and a possible beneficial effect on serum lipid profile are other ancillary properties that confer an advantage to it over existing beta blocker drugs. It is indicated in the treatment of patients with mild to moderate hypertension, systemic hypertension and annina pectoris. The starting dose of celiprolol is 200 mg with increase in dosage recommended upto 600 mg. Commonly reported side- effects include headache, - tiredness and fatigue. No reports of orthostatic hypertension or withdrawl sensitivity has been reported with celiprolol. [1]
| ¤ Experimental Design | | |
Drug Products : The present study included two formulations (400 mg tablets) of celiprolol. The products were coded in a double blind manner and were decoded only after the completion of the study. The two formulations were coded as A and B respectively.
Subjects : A single dose complete cross over study was carried out in twelve healthy human male volunteers in the age group of 20-30 years and weighing between 55-60 kg., satisfying the standard criteria for health. Written consent was obtained from each volunteer prior to the study. Volunteers were fasted 12 hours prior to the administration of the drug and use of other drugs and stimulants (tea, coffee and alcoholic beverages) were forbidden prior to and during the study.
Protocol : A single dose (12 x 2) complete cross over design was followed as the study design. The volunteers were fasted overnight (12 hours) prior to the study. Zero hour fasting blood sample was withdrawn early morning. The formulations were administered as per the study design. Blood samples (5 ml) were withdrawn from the antecubital vein at intervals of 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours, in the post dosing period. The blood samples were centrifuged, the plasma was separated and stored at -20°C until analysis. The volunteers refrained from strenuous activities during the course of the study. Standard breakfast and lunch was provided at 2.0 and 6.0 hours post-dosing and two consecutive runs were separated by a washout period of fifteen days.
Analysis of Celiprolol from Plasma : A RP-HPLC method developed by Buskin et al [2] was used to quantitate plasma levels of celiprolol. Spiked plasma samples were measured intermittently as external standard.
Statistical Data Analysis : The mean peak plasma levels of celiprolol (Cmax) and mean time to achieve these peak levels (Tmax) were computed directly from plasma level profiles as a measure of the rate of absorption of the drug from each product. The elimination rate constant (Kel) was calculated from the terminal elimination phase of log plasma concentration versus time plot by the method of least square regression analysis. [3]
From the slope of the regressionline, Kel was calculated as
Kel = 2.303 X slope
Biological half life (T½) was determined by the formula
½ = 0.693/Kel.
The extent of absorption for both the products in the volunteers was calculated from the area under the plasma concentration time curve from time curve 0 to 12 hours by the trapezoidal rule method. Area under the plasma concentration time curve from time zero to infinity was calculated using the relation.
AUCO-d) AUC 0-12 + C12/Kel. where C12 = drug concentration in the plasma at 12 hours.
The various pharmacokinetic parameters were subjected to ANOVA [4] (Analysis of Variance) at 95% confidence interval. The statistical significance between the products and the volunteers were also evaluated.
| ¤ Results | | |
The mean plasma levels of celiprolol alongwith the various pharmacokinetic parameters obtained following the administration of both the products are given in [Table 1]. Results of the pooled -t test and the two way ANOVA of the various pharmacokinetic parameters of celiprolol tablets are shown in [Table 2].
| ¤ Conclusion | | |
From the study it can be concluded that the two products A and B of celiprolol formulation tablets can be considered bioequivalent since there is no significant difference in various pharmacokinetic parameters between the two products.
| ¤ Summary | | |
Thus bioequivalence between the two products was established by undertaking this study. From [Table 1] it can be seen that the standard deviation at the various sampling points is high indicating varying absorption rates in individual volunteers, but this was observed in case of both the products. Also, since the study design was complete crossover this high standard deviation was not due to any study design variable. As celiprolol shows non-linear [1] dose related absorption kinetics this high value of standard deviation may be due to the intersubject variation during the absorption process. However all the pharmacokinetic parameters showed a comparable profile when statistically evaluated for any significant difference between the two products.
| ¤ Acknowledgements | | |
The authors wish to thank M/s Rhone Poulenc India Limited for supply of pure drug, formulations and financial assistance rendered for the study.
| ¤ References | | |
| 1. | Buckley MT, Miluve RJ. Drugs, 1991;41:941-969.  |
| 2. | Buskin J. N. et al. J. Chromatogr 1982;230:454-460. |
| 3. | Speigel MR. Curve Fitting, Method of Least Squares and Correlation Theory. In Schaum's Outline Series, Theory and Problems of Statistics, McGraw Hill Book Co. NY First ed. 1972;PP 217. |
| 4. | Gupta CB, Gupta V. in Analysis of Variance (ANOVA), An Introduction to Statistical Methods, Eighteenth Revised Edition Vikas Publishing House Pvt Ltd New Delhi. 1992;pp 658. |
[Table 1], [Table 2]
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