Dear Mostafa

Such rules are taken from regulations related to bioequivalence and cross-over studies. Aim of such studies is different from yours but idea is the same, limit interactions and be sure that from PK (and in your case PD) point of view wash-out is complete, so ....

EMA recomendation for synthetic drugs sounds:

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"Normally at least 5 elimination half-lives are necessary (...)"

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf

But pleaser remember such calculations usually cover only "chemical" wash-out not pharmacodynamic wash-out. So if some effects can persist longer than plasma concentration (for example postantibiotic effect) be careful about simple predictions based on plasma half-life.

Article Post-Exposure Effects of Cefepime and Cefpirome on Isogenic ...

FDA recomendations for synthetic drugs:

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This is one from many reasons why other Health Authorities use "adequate" or more than 5 x t1/2kel:

" adequate washout period (e.g., more than five half-lives (...) "

https://www.fda.gov/media/87219/download

and in older version

" For drugs which follow a one or two compartment open body model, the duration of the washout time should be approximately 10x the plasma apparent terminal elimination half-life, to provide for 99.9% of the administered dose to be eliminated from the body."

" If more highly complex kinetic models are anticipated (e.g., drugs for which long withdrawal times have been assigned due to prolonged tissue binding), or for drugs with the potential for physiologic carryover effects, the washout time should be adjusted accordingly. "

https://www.fda.gov/media/70115/download

WHO recomendations for synthetic drugs:

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WHO recomendation take into account also active metabolites kinetics:

" (...) not be less than five terminal elimination half-lives of the active compound or metabolite, if the latter is measured (...) "

https://www.who.int/medicines/areas/quality_safety/quality_assurance/trs1003_annex6.pdf?ua=1

and variability

" If the product has high variability in elimination rate between subjects (...) The minimum wash-out period should be at least 7 days."

.... so for product with t1/2kel = 12h its 14 x half-life

https://www.who.int/medicines/services/expertcommittees/pharmprep/QAS04_093Rev4_final.pdf

What about biologics:

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More about wash-out and half-life in biologics: Article Pharmacokinetics Definitions in Regulatory Documents: Transf...

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Concluding all, from my point of view in your case therapy could be continued even one day gap. Its not optimal because such gap have impact on steady state and PD but continuation of therapy sounds reasonable.

Hope it will be helpful,

Best regards

Tomasz

PK profile of cefepime (https://www.medicines.org.uk/emc/product/9671/smpc)

Elimination

The elimination average half-life of cefepime is about 2 hours, and is independent of the dose for the range of 250 mg to 2 g. There is no evidence of accumulation in the healthy individuals receiving doses up to 2 g IV every 8 hours for 9 days. The total body clearance is 120 ml/min. The average renal clearance of cefepime is 110 ml/min, suggesting an elimination almost exclusively via the kidneys, mainly by glomerular filtration.

According to the PK theory and guidelines, the five times of a drug half-life (i.e. 5 x 2 hours = 10 hours) is a general rule of complete drug elimination. However, in this case your med is cefepime, which is an antibiotic indicated for UTI. You thus need to consider the high drug distribution in the urine, patient's age and renal clearance, spectrum and sensitivity. Usually a 10-day treatment of UTI can eradicate gram- bacilli up to 70 - 90% depending on the patient's condition. For your case, probably complicated UTI, it is suggested in practice to continue the drug with 1 g i.m. ASAP to complete the 14-day treatment course even though the missed dose of one day. Do not worry too much about the drug resistance, which is minimal.

basically their is no any clinical evidence of accumulation of the drug when injected tid mean while the total elimination of cefepime in the body is 2hrs independent of the dose administered to the patient or the volunteers during the clinical trials of the drug