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The following message was posted to: PharmPK
I would be grateful if I could get better understanding from all on this topic.
What is the pharmacokinetic principle behind having the strength of a molecule available at low strength for oral and the IV as high strength ?
E.g Cefuroxime axetil tablet is availabe as 250mg or 500mg while the IV Cefuroxime Sodium is 750mg
Thanks
Muyiwa
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This is a topic that has been bothering my mind too. Going by the literature information, however, the following point might contribute to our understanding of the topic:
1. Cefuroxim axetil is a prodrug that is hydrolyzed to cefuroxime in the blood stream. The oral bioavailability from cefuroxim axetil is only 37 % (fasting) and 52 % (fed state). 2. The axetil moiety is metabolized to acetaldehyde and acetic acid. These might make the oral dose of cefuroxim axetil more toxic than the cefuroxime sodium which is used in injection. 3. A gentler rise and fall in plasma level of cefuroxime from oral dose would imply longer mean residence time (MRT) than from sodium salt injection and, of course, a slower concentration-driven renal clearance. dC/dt = kC and Cl=kVd
Cl=0.693/t1/2*(D/Cp). The higher the dose of free cefuroxime, the faster the clearance.
4. A faster clearance is expected from the IV sodium salt than from oral axetil analogue (which has to be metabolized to cefuroxime) by concentration-driven renal elimination (reported as 66 - 100%) with half-life of 1.2 hours.
**Anderson et al Handbook of clinical drug data 10th ed.**
I also welcome a more definitive reason from molecular engineers.
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The following message was posted to: PharmPK
Hi Muyiwa,
I don't know about cefuroxime but one reason could be that the administered molecule is a prodrug, biotransformed in the liver to the active drug. An oral dose undergoing a first pass effect produces the active compound faster and in greater extent compared to the iv dose. It seems then logical that the iv dose is larger than the oral.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.-a-.tgordi.com
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The following message was posted to: PharmPK
Muyiwa:
The oral and IV formulations of cefuroxime are approved for different indictions. The oral formulation has peak concentrations 2 - 13 mcg/mL as is approved to treat relatively mild infections such as otitis media and tonsillitis. The IV formulation peaks at concentrations 50 - 100 mcg/mL and is used to treat serious infections such as meningitis. They are not meant to be interchangeable.
Sincerely,
Carol Collins
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The following message was posted to: PharmPK
Hi Muyiwa,
One of the simpler reasons could be that the oral dose is indicated for
uncomplicated infections like UTI & respiratory infections, while the
intravenous injection is indicated for severe infections like meningitis,
which require higher concentration of the drug at its site of action.
Best Regards,
Dr Srinivas
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Hi Muyiwa,
As you noted, there are differences between the IV formulation of cefuroxime and the oral. The IV form is the sodium salt which is not readily absorbed systemically hence the need to formulate the axetil salt for oral use, the latter allowing GI absorption. The peak plasma concentration is achieved after about 2 hours for the axetil salt so exposure to bioactive concentration is expected to be longer than that of the IV form (hence bid vs tid). The latter argument is more mechanistically plausible considering that beta lactams exhibit time (above MIC) dependent killing. In addition, as you know the indications for the IV form is more geared toward surgical prohylaxis and relatively more severe infections requiring higher drug exposure relative to the oral formulation which is indicated for community acquired infections amenable to oral therapy. Best regards!
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