Pharmacokinetic/pharmacodynamic modelling of ciprofloxacin 250 mg/12 h versus 500 mg/24 h for urinary infections

M. Dolores Sánchez Navarro, M. Luisa Sayalero Marinero and Amparo Sánchez Navarro*

Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Salamanca, Avenida del Campo Charro SN, 37007 Salamanca, Spain

Received 10 July 2001; returned 12 November 2001; revised 21 February 2002; accepted 27 March 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A simulation study was performed to evaluate and compare the standard dosage regimen of 250 mg/12 h versus 500 mg/24 h of ciprofloxacin for the treatment of urinary tract infections (UTIs). Pharmacokinetic parameters reported for healthy young and old individuals were used for the simulation of drug levels in urine, at different mean urine flow rates (1–2.5 L/day). Pharmacokinetic/pharmacodynamic analysis of the results revealed that 500 mg ciprofloxacin once a day produced a more favourable profile in urine than 250 mg/12 h, particularly in the elderly, due to the slower elimination of the drug in this group of patients. Circadian rhythms were also considered for the simulation of drug levels in urine. According to the results, 500 mg once a day administered in the morning would be a better choice than 250 mg/12 h at least for uncomplicated UTI; nevertheless, clinical assays are needed to prove this hypothesis.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The number of pharmacokinetic/pharmacodynamic studies aimed at defining optimal dosing regimens for fluoroquinolone antimicrobial agents has increased progressively over the last decade. Fluoroquinolones share some pharmacodynamic properties with aminoglycosides, since both have to access the internal structures of the pathogen in order to exert their bactericidal effect, which is concentration dependent.1,2 Both groups of drugs demonstrate a post-antibiotic effect.3,4 Recently, Lister & Sanders5 have suggested the development of adaptive resistance to the fluoroquinolones in an attempt to explain the decreased bactericidal effect observed for ciprofloxacin against Streptococcus pneumoniae after the first exposure, similar to the ability of aminoglycosides to induce adaptive resistance mediated by a reversible phenotype alteration.6 Accordingly, some of the pharmacodynamic principles established for aminoglycosides might be extrapolated to fluoroquinolones, such as the relevance of the maximal concentration (Cmax)/MIC as a predictor of efficacy. In fact, numerous experimental studies710 have confirmed this hypothesis, which has been corroborated by a more restricted number of clinical assays,5,11,12 as shown in the recent review of the application of fluoroquinolone pharmacodynamics by Wright et al.13

Ciprofloxacin at 250 mg/12 h is a standard treatment for patients with complicated urinary tract infection (UTI). A recent study14 of prescriptions dispensed at community pharmacies in Spain has shown that the above dosage regimen is widely used as a standard for UTI, due to increasing resistance to older agents, such as co-trimoxazole or penicillin antibiotics, as well as its efficacy, safety and convenient oral administration. However, reports of common uropathogens such as Escherichia coli, Staphylococcus saprophyticus and Klebsiella pneumoniae resistant to ciprofloxacin1517 are leading to concerns about the use of these drugs. The development of bacterial resistance is related to the abuse but also to the misuse of antibiotics, particularly as regards dosage regimens that lead to low Cmax at the site of infection. Information about the pharmacokinetics and pharmacodynamics of fluoroquinolones is now much greater than that available 20 years ago, when the first-generation fluoroquinolones such as ciprofloxacin, norfloxacin and ofloxacin emerged. It is now well known that the bactericidal activity of the fluoroquinolones might be decreased by several in vivo conditions, including the presence of cations18 or acidic urine pH,19 and that certain susceptible uropathogens have become less sensitive, leading to higher MICs. In accordance with this, the initial low dosages (100 mg of ciprofloxacin or 200 mg of ofloxacin) approved for the treatment of acute cystitis in women should no longer be recommended. The results from recent studies reveal that the bactericidal action for Gram-negative pathogens differs from that seen for Gram-positive bacteria. It has been found that the AUIC breakpoint value (minimal value related to clinical efficacy) of ciprofloxacin is not the same for all types of bacteria; 12520,21 and 4022,23 for Gram-negative and Gram-positive bacteria, respectively, have been reported as AUIC breakpoint values. These findings show the importance of PK/PD studies in optimizing dosage regimens of antimicrobial agents in clinical practice.

The aim of this study was to compare and evaluate the usual dosage regimen of 250 mg/12 h versus 500 mg/24 h of ciprofloxacin for the treatment of urinay infections, using simulation techniques based on population pharmacokinetics of the drug. Pharmacokinetic/pharmacodynamic principles applied previously by numerous authors to serum levels are here applied to urinary levels.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
From the parameters reported in the literature the plasma concentration curves (Cp) corresponding to 250 mg/12 h or 500 mg/24 h of ciprofloxacin were simulated, using a methodology described previously24 applied to retrospective pharmacokinetic/pharmacodynamic studies performed with ciprofloxacin25 and ceftizoxime.26 A further simulation step was performed to obtain the urine levels (Cu) estimated from the simulated plasma curves, renal drug clearance and urinary flow rate. The equations and parameter values used for the simulations are as follows:

where F is the bioavailable fraction, D the dose, Ka the absorption rate constant, Vd the distribution volume, Ke the elimination rate constant, n the number of doses, {tau} the dosage interval, CLr the renal clearance and Qu the urinary flow rate.

The pharmacokinetic parameters of ciprofloxacin for healthy young adult and geriatric populations27 were used as shown in Table 1, irrespective of gender because the drug shows gender-independent pharmacokinetic behaviour.28


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Table 1.  The pharmacokinetic parameters of ciprofloxacin reported for healthy young adult and geriatric populations
 
Simulations were performed with a range of Qu of 1–2.5 L/day, since for both groups this parameter shows a high inter- and intra-individual variability, independent of age and dependent mostly on the type of diet or the liquid intake of individuals. Additional simulations with lower values of Qu (half the daytime value) for the night period were performed in accordance with the reported circadian decrease in diuresis at night.29

Simulation was performed using the PKS Pharmacokinetic Computer System (Abbot Laboratories Diagnostic Division, Abbot Park, IL, USA).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Figure 1 shows the simulated concentrations in urine coresponding to dosage regimens of 250 mg/12 h and 500 mg/24 h of ciprofloxacin for young patients with a standard weight of 70 kg, with urinary flow rates of 1 or 2.5 L/day throughout the simulation period. With Qu at 1 L/day, the maximal and minimal concentrations were 243 and 40 mg/L, respectively, for the standard regimen of 250 mg/12 h, compared with 427 and 10 mg/L for 500 mg/24 h. The increase in Qu produced a proportional decrease in simulated drug urine levels, which had maximal and minimal values of 97 and 16 and 171 and 4 mg/L for 250 mg/12 h and 500 mg/24 h, respectively, when a flow rate of 2.5 L/day was used.



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Figure 1. Simulated ciprofloxacin concentrations in urine for the dosage regimen of 250 mg/12 h versus 500 mg/24 h in young patients considering urinary flow rates of 1 L/day and 2.5 L/day.

 
Figure 2 shows the results of the simulations performed for elderly patients under the same conditions as described above. At a urinary flow rate of 1 L/day the simulated curves showed maximal and minimal concentrations of 236 and 83 mg/L for 250 mg/12 h and 359 and 38 mg/L for 500 mg/24 h. At 2.5 L/day, the simulated urine levels took values of 94 and 33 and 143 and 15 mg/L for the former and latter dosage regimens.



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Figure 2. Simulated ciprofloxacin concentrations in urine for the dosage regimen of 250 mg/12 h versus 500 mg/24 h in the elderly considering urinary flow rates of 1 L/day and 2.5 L/day.

 
Assuming the diuresis for the sleeping period (last 8 h of the dosage interval) to be half the diurnal value, the simulated values of Cmin for both the young and old patients after 500 mg/24 h were 20–8 and 76–30 mg/L (for diurnal Qu = 1–2.5 L/day), respectively.

Figure 3 illustrates how the reported circadian changes of ciprofloxacin pharmacokinetics30 would affect the urinary drug levels. Curves corresponding to 500 mg administered in the morning (F = 0.7) or 250 mg administered at 8.00 a.m. (F = 0.7) and 250 mg at 20.00 p.m. (F = 0.35) for young and old patients were simulated. If such reduction in absorption happens at night optimal Cmax/MIC ratio values as well as higher AUIC24 values would be obtained for a once daily dose.



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Figure 3. Simulated ciprofloxacin concentrations in urine for a single daily dose of 500 mg versus two doses of 250 mg administered in the morning and at night taking into consideration the reported circadian decrease in the oral absorption of this drug.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This simulation suggests favourable pharmacodynamics of ciprofloxacin for UTI at a dosage regimen of 500 mg/24 h, particularly in older patients. In younger patients, a higher renal clearance is responsible for a higher concentration of the drug in urine (higher Cmax values) and more rapid elimination leading to lower values of Cmin. Since the AUC24 is the same for the same daily dose (250 mg/12 h or 500 mg/24 h), the proposed regimen of 500 mg/24 h, which produces higher Cmax/MIC values, would be hypothetically more advantageous than 250 mg/12 h as regards clinical efficacy and the avoidance of resistance. The information reported in the literature supports this hypothesis: pharmacokinetic/pharmacodynamic analysis of in vitro assays, animal models and clinical studies performed with ciprofloxacin and other fluoroquinolones reveal that higher values of Cmax/MIC are related to increased efficacy and a decreased likelihood of the development of resistance.1116,22,23

Naber et al.31 found that after administration of 500 mg of ciprofloxacin to healthy volunteers, bactericidal titres of urine samples collected between 16 and 24 h were low, despite concentrations being above the corresponding MICs. These results, which seem to be contradictory might be explained by a decreased activity of fluoroquinolones in acidic urine as compared with broth. Kromery et al.32 compared once versus twice daily doses of ciprofloxacin in the treatment of complicated urinary infections. Although the authors recommended the 500 mg divided into two daily doses on the basis of elimination of bacteriuria and superinfection, the difference in clinical results is not so clear and some results even point to advantages of 500 mg/24 h over 250 mg/12 h, such as the higher clinical cure rate reported for the once daily dose (97.3% versus 95.5%, although this difference is surely not significant).

Once-a-day dosage regimens, which increase compliance, become particularly important in the case of fluoroquinolones, whose oral absorption is markedly reduced by the presence of Ca, Al, Mg or Fe in the gastrointestinal tract.3338 Accordingly, it is important to avoid drugs or foods containing these cations for a minimum of 2–3 h before and after quinolone administration. The only argument against the administration of ciprofloxacin once a day versus twice a day would be related to the Cmin values achieved in urine, but these values are sufficiently high in old patients due to the slower elimination constant. However, in young patients, 500 mg/24 h leads to simulated Cmin values of only 10–4 mg/L versus 40–16 mg/L for 250 mg/12 h. Nevertheless, according to pharmacokinetic/pharmacodynamic criteria, Cmin values are not essential for the efficacy of fluoroquinolones. Another factor to consider is the existence of circadian rhythms, which reduce diuresis in humans during the dark period and decrease the rate and extent of gastrointestinal absorption of many drugs. The simulated levels of ciprofloxacin administered once a day in the morning, assuming a reduction in the urinary flow rate to half the diurnal value for a standard sleeping period of 8 h at the end of the dosage interval, show that the Cmin would reach 20–8 mg/L and 76–30 mg/L in young and old patients, respectively, these values being adequate even for young patients. Additionally, the proposed regimen of 500 mg/24 h would produce similar Cmin values to those reached after 250 mg/12 h taking into consideration a 50% decrease in the absorption fraction for the evening dose, according to the results reported from a study about the circadian variation in the urinary excretion of ciprofloxacin after its oral administration at 10 h or 22 h in humans.30

In conclusion, this simulation study of the kinetic profile of ciprofloxacin in urine, together with current views on the pharmacokinetic/pharmacodynamic criteria related to efficacy and the development of resistance for the fluoroquinolones, support the advantage of 500 mg/24 h versus 250 mg/12 h for uncomplicated UTI, particularly for the elderly. The same considerations should apply for complicated infections, although it is more difficult to reach a conclusion for these cases since additional factors related to the causes responsible for the pathology seem to be more relevant as regards the eventual clinical outcome. Clinical assays aimed at comparing urinary drug concentrations together with clinical efficacy for both regimens of ciprofloxacin in different population groups and different types of urinary infection would be very helpful in proving or disproving the hypothesis that ciprofloxacin 500 mg once a day is a better choice than 250 mg/12 h for UTI.


    Footnotes
 
* Corresponding author. Fax: +34-923-294515; E-mail: asn{at}gugu.usal.es Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Schentag, J. J., Nix, D. E. & Forrest, A. (1993). Pharmacodynamics of the fluoroquinolones. In Quinolone Antimicrobial Agents, 2nd edn (Hooper, D. C. & Wolfson, J. S., Eds), pp. 259–70. American Society for Microbiology, Washington, DC.

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