1. Effect of omeprazole on the pharmacokinetics of cefixime in healthy volunteers
Win Nandar Aye1, Latt Latt Win2,  Khin Hnin Pwint3,  Shwe Su Mon4 
1Department of Pharmacognosy, University of Pharmacy, Yangon 2University of Medicine, Taunggyi 3Department of Medical Reserach 4University of Medicine (1), Yangon

2. Contents Introduction Aim and Objectives Materials and Methods Results
Discussion
Limitations
Conclusion
Acknowledgement
References
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3. INTRODUCTION For some bacterial infections
cefixime - to eliminate bacteria,
non steroidal anti-inflammatory drugs (NSAIDs) - to relieve fever and pain
omeprazole - to prevent the untoward effects of NSAIDs
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4. INTRODUCTION (Cont.) Cefixime third generation cephalosporin
orally for respiratory tract infections; chronic bronchitis, pharyngitis, otitis, gonorrhoea, urinary-tract infections (Arunkumar et al., 2013)
MIC - between μg/mL (Guay, 2010)
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5. INTRODUCTION (Cont.) Cefixime
Acidic drug, only 40 % to 50 % of an oral dose; absorbed from the gastrointestinal tract whether taken before or after meals
The rate of absorption may be decreased in the presence of food (Sweetman, 2009).
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6. INTRODUCTION (Cont.) Omeprazole proton pump inhibitor
inhibits H+/K+ ATPase enzyme system
suppresses acid secretion from the secretory surface of the gastric parietal cell (McQuaid, 2015)
The increasing gastric pH may affect the ionization of cefixime which is acidic in nature, thus the absorption of cefixime may decrease.
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7. INTRODUCTION (Cont.)
Khan, 2012 found that the total bioavailability of cefixime with simultaneous administration of cefixime and omeprazole decreased to 66.4 %.
The decreased in bioavailability can cause drug resistance.
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8. INTRODUCTION (Cont.)
To evaluate Cmax of cefixime in twelve healthy volunteers by using HPLC-UV method and
To determine whether dosage adjustment of cefixime may be required or not to achieve the therapeutic goal of cefixime when cefixime is simultaneously administered with omeprazole.
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9. AIM AND OBJECTIVES
AIM
To study the effect of omeprazole on the pharmacokinetic parameters of cefixime in healthy volunteers
OBJECTIVES
To determine the pharmacokinetic parameters of single oral dose of cefixime
To determine the pharmacokinetic parameters of cefixime after concurrent administration of cefixime and omeprazole
To compare the pharmacokinetic parameters of single oral dose of cefixime with and without omeprazole
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10. Study plan Contents assay of the studied drugs Recruitment of subjects
Drugs administration
Measurement of plasma cefixime concentrations
Comparison of pharmacokinetic parameters of cefixime
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11. MATERIALS AND METHODS (Cont.)
Type of study- Laboratory based comparative study
Participant Selection
Inclusion criteria
Both sex
Age of 18 to 50 years
No abnormality detected after laboratory investigations such as liver function tests, renal function tests and physical examination
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12. MATERIALS AND METHODS (Cont.)
Exclusion criteria
Participants with presence of clinically apparent infection
Participants who had history of drug allergy to cephalosporin
Participants who were heavy alcoholic and smoker
Participants who had medical history of liver disease, renal disease, heart disease and subjects who were taking nifedipine and clopidogrel regularly
Pregnancy and lactation
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13. MATERIALS AND METHODS (Cont.)
Withdrawal criteria
Occurrence of any adverse effect to the test drugs
Any infection during wash out period
Participant’s request
Non-compliance
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14. MATERIALS AND METHODS (Cont.)
The sample size was calculated by using the following formula (Daniel, 2013).
n = required sample size
= reliability coefficient at 95% confidence level (1.96 for α = 0.05)
= Standard normal deviation from β = (power 90%)
= Standard deviation of pharmacokinetic parameter (Cmax) of cefixime (0.55, Khan, 2012)
µ1 = mean Cmax of cefixime when giving alone (3.545 µg.mL -1 , Khan, 2012)
µ2 = mean Cmax of cefixime with concurrent administration of omeprazole (2.648 µg.mL -1 , Khan, 2012)
= the difference between two means of Cmax = 0.89
n = 5 (for each group)
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15. MATERIALS AND METHODS (Cont.)
Description
Afix
(Cefixime BP 200 mg) Capsule
Omez 20 (Omeprazole 20 mg) Capsule
Manufacturer .
ARISTOPHARMA, Bangladesh
Dr. REDDY’S LABORATORIES LTD, Ind
Myanmar Registration No
R1803 AA 355
R2107A1897
Batch No.
17J13
B701937
Manufactured Date
Expired Date
7.2019
Price
400 Myanmar Kyats per capsule
130 Myanmar Kyats per capsule
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16. MATERIALS AND METHODS (Cont.)
Drugs
Tests
Method
Omez 20
Identified and Assay content
UV-Vis Spectroscopy
Afix
Identified
Assay content
HPLC-UV
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17. MATERIALS AND METHODS (Cont.)
The chromatographic condition of established method by Choi and Burm, 2007 was optimized.
Column
Reverse phase C18 column
Mobile phase
Acetonitrile : Potassium phosphate buffer with pH 2.8 (10 : 90 v/v)
Column temperature
30 ºC
Flow rate
1 mL/min
Injected volume
20 µL
Wavelength
286 nm
Running time
9 minutes
Method was validated over the concentration range of 0.5 µg/mL to 5 µg/mL
linearity, accuracy, precision, recovery, limit of detection and quantitation.
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18. MATERIALS AND METHODS (Cont.)
Healthy participants at overnight fasting - cefixime 200 mg.
The blood samples (5 mL) - 0 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 7 hr and 10 hr.
After two weeks, cefixime 200 mg and omeprazole 20 mg
The blood samples (5 mL) - as above procedure.
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19. Plasma extraction procedure
500 µL of plasma sample +
500 µL of 12.5 % trichloro-acetic acid
vortexed for 20 minnutes
centrifuged at 5000 rpm for 20 minutes
lower layer was separated
supernatant solution was filtered through
0.22 μm nylon syringe filter
supernatant solution (20 µL) was injected
into the HPLC system
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20. Overlay UV spectra of omeprazole standard powder in different concentrations from 2 μg/mL to 10 μg/mL
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21. Overlay UV spectra of omeprazole standard powder and Omez 20 (omeprazole 20 mg) capsule
Omez 20 (0meprazole 20 mg) capsule
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22. Overlay UV spectra of cefixime standard powder and Afix (cefixime 200 mg) capsule
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23. Overlay chromatograms of spiked plasma cefixime standard powder in different concentrations from 0.5 μg/mL to 5 μg/mL
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24. The content assay must be 90 % - 110 %.
Omeprazole
Cefixime
UV-Vis Spectroscopy
Standard curve of omeprazole standard powder (2 μg/mL - 10μg/mL) (r2) at 305 nm and at 276 nm
Identification of cefixime in Afix (cefixime 200 mg) capsule
Identification of omeprazole in Omez 20 (omeprazole 20 mg) capsule
HPLC-UV method
Standard curve of spiked plasma cefixime standard powder (0.5 μg/mL - 5μg/mL) (r2)
Content of Omez 20 (omeprazole 20 mg) capsule ± 5.6 % at 305 nm and ± 5.55 % at nm
Content of Afix (cefixime 200 mg) capsule was 92.5 ± 0.79 %.
The content assay must be 90 % %.
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25. RESULTS AND DISCUSSION
Omez 20 and Afix
affordable, most frequently used and the content assays were within the acceptance limits of 90 % %
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26. Standard Concentration (μg/mL) Coefficients of variation (% CV)
Intra-day precision of standard cefixime using HPLC for three determinations within the same day
Standard Concentration (μg/mL)
Coefficients of variation (% CV)
Recovery (%)
0.5
4.72
97.95
2.5
0.61
95.03 5
3.98
99.02
Coefficients of variation (% CV) - Level of acceptance - not greater than 15 %
Percent recovery - Level of acceptance is within 80 % to 120 % (Bioanalytical Method Validation, 2001)
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27. Standard Concentration (μg/mL) Coefficients of variation (% CV)
Inter-day precision of standard cefixime using HPLC for three determinations within the same day
Standard Concentration (μg/mL)
Coefficients of variation (% CV)
Recovery (%)
0.5
9.05
108.43
2.5
7.23
99.37 5
3.26
97.44
Coefficients of variation (% CV) - not greater than 15 %
Percent recovery - within 80 % to 120 % (Bioanalytical Method Validation, 2001)
Lowest detection level was 0.15 µg/mL
Lowest quantitation level was 0.5 µg/mL
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28. RESULTS AND DISCUSSION (Cont.)
Pharmacokinetic parameters of cefixime one compartment model, student ‘t’ test (paired t test) in Microsoft Office Excel 2010
Minimum level of significance (p value) - less than 0.05
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29. Comparison of mean plasma cefixime concentrations at different times in healthy volunteers after taking cefixime alone and cefixime with omeprazole
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30. Comparison of Cmax of taking cefixime alone and cefixime with omeprazole
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31. Comparison of Tmax of taking cefixime alone and cefixime with omeprazole
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32. RESULTS AND DISCUSSION (Cont.)
When cefixime was taken with omeprazole,
mean plasma concentration of cefixime was not significantly changed at 1 hr
The interaction of cefixime with omeprazole was not found within one hour
Cmax of cefixime was decreased from 1.40 ± µg/mL to 1.21 ± 0.44 µg/mL
Tmax was altered from 3.75 ± 0.75 hr to 4.33 ± 0.65 hr
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33. RESULTS AND DISCUSSION (Cont.)
When cefixime was taken simultaneously with omeprazole,
mean plasma drug concentrations of cefixime were significantly decreased from
0.78 ± 0.27 µg/mL to 0.59 ± 0.16 µg/mL at 2 hr,
1.20 ± 0.42 µg/mL to 0.94 ± 0.32 µg/mL at 3 hr and
1.36 ± 0.45 µg/mL to 1.09 ± 0.41 µg/mL at 4 hr (p value ≤ 0.05)
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34. RESULTS AND DISCUSSION (Cont.)
When cefixime was taken with omeprazole,
mean plasma concentrations were found to be lower at 2 hr,3 hr and 4 hr
it may be due to more ionization of cefixime in increased gastric pH caused by omeprazole which decreases the absorption of the cefixime, and hence it may take longer time to reach Cmax
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35. RESULTS AND DISCUSSION (Cont.)
When cefixime was taken with omeprazole,
the mean plasma concentrations were not altered significantly at 5 hr, 7 hr and 10 hr
theoretically the absorption of cefixime ceases approximately 6 hours after dosing (Guay, )
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36. Comparison of Kab of taking cefixime alone and cefixime with omeprazole
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37. Comparison of T1/2ab of taking cefixime alone and cefixime with omeprazole
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38. RESULTS AND DISCUSSION (Cont.)
When cefixime was taken with omeprazole,
no significant differences of Kab and T1/2ab between (p value > 0.05)
omeprazole mainly affects on the extent of absorption of cefixime and it has little effect on the rate of absorption
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39. Comparison of Kel of taking cefixime alone and cefixime with omeprazole
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40. Comparison of T1/2el of taking cefixime alone and cefixime with omeprazole
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41. Comparison of of AUC0-10 of taking cefixime alone and cefixime with omeprazole
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42. Comparison of AUC0-α of taking cefixime alone and cefixime with omeprazole
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43. RESULTS AND DISCUSSION (Cont.)
When cefixime was taken with omeprazole,
mean ± SD of Kel, T1/2el and AUC0-10 were not statistically significant different (p value > 0.05)
This showed that same fraction of cefixime was removed per hour, change in gastric pH may affect mainly the absorption phase of the drug and may not affect the elimination phase
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44. Limitations
Single oral dose
Within 24 hours
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45. CONCLUSION
The MIC levels of cefixime was µg/mL for Escherichia coli, µg/mL for Haemophilus influenza, µg/mL for Neisseria gonorrhoeae (CLSI, 2018).
Although the decreased in Cmax of cefixime which was coadministered with omeprazole, the Cmax was above the MIC level against these infectious organisms.
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46. CONCLUSION (Cont.)
cefixime and omeprazole could be administered simultaneously without changing the dose or dosage regimen to achieve therapeutic effect of cefixime for some infectious conditions.
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47. ACKNOWLEDGEMENT
Professor Dr. San San Nwè, Rector (Retired)/ Expert, University of Pharmacy, Yangon
Professor Dr. Yee Yee Tin, Rector, University of Pharmacy, Yangon
Dr. Su Su Yee, Associate Professor and Head (Retired), Department of Pharmacognosy, University of Pharmacy, Yangon
Professor Dr. Latt Latt Win, Professor and Head, Department of Pharmacology, University of Medicine
Dr. Shwe Su Mon, Lecturer, Department of Pharmacology, University of Medicine (1), Yangon
Dr. Khin Hnin Pwint, Research Scientist, Pharmaceutical Toxicology Research Division, Department of Medical Research, Yangon
DMR External Grant Committee for giving the External Grant (2018)
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48. REFERENCES
Arunkumar, R., Olaganthan, A., Rao, N., Sankar, V. and Gunasakaran, S. (2013) A Liquid Chromatography-Mass Spectrometry/Mass Spectrometry Method for the Quantification of Cefixime in Human Plasma. Research and Reviews: Journal of Medical and Health Sciences: 2(1); p
Bioanalytical Method Validation (2001). In “Guidance for Industry”, US Food and Drug Administration., U.S.A. [Online] avalilable from: < guidance/index.htm > (Accessed on 18 May, 2018).
Choi, D.H. and Burm, J.P. (2007) Bioequivalence Evaluation of Two Brands of Cefixime 100 mg Capsule (Suprax and Alpha-Cefixime) in Korea Healthy Volunteers. The Journal of Applied Pharmacology: 15; p
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49. REFERENCES
Guay, D. (2010) Cefixime. In “Kucers’ The Use of Antibiotics”, ed. Grayson, M.L., Vol I, 6th ed, p CRC Press. ISBN: 13:
Khan, A. (2012) Impact of Omeprazole, Rosuvastatin And Clopidogrel on the Pharmacokinetics of Cefixime in healthy adult human subjects, Doctoral thesis, University of Peshawar, Peshawar.
McQuaid. K.R. (2015) Drugs used in the treatment of Gastrointestinal Diseases. In “Basic and clinical pharmacology”, ed. Katzung, B.G., Masters, S.B. and Trevor,J.A., 13th ed, p McGraw Hill: United States of America. ISBN:
Sweetman, S. C. (2009) Antibacterials. In “Martindale: the Complete Drug Reference”, 36th ed. p , Pharmaceutical press, U.K:London.
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50. Thank you.
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