Effect of total and partial nephrectomyon the elimination of ciprofloxacin in humans

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Effect of total and partial nephrectomy

on the elimination of ciprofloxacin in humans

Edyta Sza³ek¹, Wojciech Po³om², Agnieszka Karbownik¹, Tomasz Grabowski³, Agnieszka Konko³owicz¹, Anna Wolc⁴, Marcin Matuszewski², Kazimierz Krajka², Edmund Grzeœkowiak¹

1Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences, Œw. Marii Magdaleny 14, PL 61-861 Poznañ, Poland

2Department of Urology, University Clinical Centre, Kliniczna 1a, PL 80-402 Gdañsk, Poland

3Polpharma Biologics, Trzy lipy 3, PL 80-172 Gdañsk, Poland

4Department of Genetics and Animal Breeding, Poznañ University of Life Sciences, Wo³yñska 33, PL 60-637 Poznañ, Poland

Correspondence: Edyta Sza³ek, e-mail: szalekedyta@wp.pl

Abstract:

Background: Renal cell carcinoma (RCC) is the most common form of kidney cancer. Surgery is a standard procedure to resect the tumor during total (TN) or partial (nephron-sparing) nephrectomy (PN). Ciprofloxacin is most often administered at the usual intravenous dose of 100–400 mg/12 h. The application of such low doses of ciprofloxacin as 200 mg/24 h carries the risk of achieving subtherapeutic concentrations even in patients with limited renal function. The aim of the study was a comparison of concentrations and pharmacokinetics for ciprofloxacin at steady-state in patients after total and partial nephrectomy and evaluation of the effective- ness of the iv dose 200 mg/24 h against the theoretical value of MIC, 0.5 µg/ml.

Methods: The research was carried out on two groups of patients after nephrectomy: total (group 1, n = 21; mean [SD], age, 62.9 [14.4] years; weight, 76.0 [14.6] kg; creatinine clearance, CL_CR, 90.7 [22.2] ml/min) and partial (group 2, n = 15; 61.7 [9.3] years;

87.8 [16.4] kg; CL_CR, 107.8 [36.4] ml/min). The patients were treated with ciprofloxacin in the dose of 200 mg/24 h (iv). Plasma concentrations of ciprofloxacin at steady state were measured with validated HPLC method with UV detection.

Results: The mean values of plasma concentrations of ciprofloxacin at steady state in group 1 and 2 were: C_ssmax, 2.012 and 1.345;

C_ssmin, 0.437 and 0.244 µg/ml, respectively. The main pharmacokinetic parameters for ciprofloxacin in group 1 and 2 were as fol- lows: AUC_(0last), 30.9 [17.9] and 19.5 [8.7] µg h/ml; AUMC_(0last), 177.91 [11.1] and 91.9 [66.5] µg h²/ml; t_1/2b, 13.9 [7.7] and 9.8 [3.3] h; MRT, 16.5 [12.1] and 9.77 [5.4] h; V_d, 115.0 [67.2] and 142.2 [78.7] l; CL, 6.2 [3.3] and 10.8 [5.7] l/h, respectively. With the assumed MIC = 0.5 µg/ml, the values of C_ssmax/MIC < 10 and AUC/MIC < 125 were obtained in all the patients.

Conclusion: In our patients we observed significant differences in some pharmacokinetic parameters of ciprofloxacin after two types of nephrectomy.

Key words:

total nephrectomy, nephron sparing surgery, ciprofloxacin, pharmacokinetics

Pharmacological Reports 2012, 64, 673679 ISSN 1734-1140

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Renal cell carcinoma (RCC) is the most common form of kidney cancer [1]. Rates of RCC are generally high in Europe and North America [15]. The main risk factors for renal cell carcinoma include age, obesity, cigarette smoking, hypertension, gender, race, long-term dialysis and particular hereditary diseases [1, 15]. Surgery is a standard procedure to resect the tumor during total (TN) or partial (nephron-sparing) nephrectomy (PN) [1]. Both types of nephrectomy cause decrease in renal function. We observe short- and long-term structural and functional adaptations of the remaining renal tissue [1].

However, there is the question whether drugs eliminated through the urinary tract can be handled effectively by the remaining kidney, especially in the early stage after surgery. Ciprofloxacin is an antibacterial drug frequently used in infections of the urinary tract in the peri-operative period.

Ciprofloxacin is a broad spectrum fluoroquinolone, which was introduced to the antibacterial therapy in the 1980s [4]. Ciprofloxacin is currently one of the most commonly prescribed fluoroquinolones in medical practice due to its good efficacy in the treatment of infections caused by most Gram-negative pathogens [8]. Fluoroquinolones have limited Gram-positive ac- tivity. Therefore, they should not be considered as first-line agents for skin and soft tissue infections [17]. Ciprofloxacin still maintains the best in vitro ac- tivity against Pseudomonas aeruginosa [27]. This drug is considered one of the best choice in the treatment of urinary tract infections, sexually transmitted diseases, skin and bone infections, gastrointestinal infections caused by multiresistant organisms, lower respiratory tract infections, febrile neutropenia, intra- abdominal infections (combined with other antibiotics against anaerobic bacteria) and malignant external otitis [4, 17]. This antibacterial has good penetration into most tissues and body fluids [4, 22]. Therefore, it has such wide application. Quinolone resistance often results from the application of too low doses and in consequence, from too low concentrations of the drug at the place of infection. Many authors suggest that the efficacy of fluoroquinolones in bacterial infections is determined by the possibility to obtain appropriate values of pharmacokinetic and pharmacodynamic indexes (PK/PD): area under the inhibitory time curve AUIC = AUC₍₀₂₄₎/MIC (the area under the

(µg/ml) [15]. The recommended values of the above- mentioned indexes for total drug are: AUIC ³ 125, or C_max/MIC > 10 [19–21, 23]. The aim of the study was a comparison of concentrations and pharmacokinetics for ciprofloxacin at steady-state in patients after TN and PN and evaluation of the effectiveness of the iv dose 200 mg/24 h against the theoretical value of MIC, 0.5 µg/ml.

Materials and Methods

This study was performed in the Department of Urol- ogy, University Clinical Centre, Gdañsk (Poland), and at the Department and Unit of Clinical Pharmacy and Biopharmacy, University of Medical Sciences, Poznañ (Poland). All the described procedures were reviewed and approved by the Institutional Review Board at Poznañ University of Medical Sciences. The study was carried out on 36 patients (16 men and 20 women), who were hospitalized for nephrectomy due to renal carcinoma. Group 1 included 21 patients after TN (12 males, 9 females). Group 2 included 15 patients after PN. Table 1 presents the characteristics of the analyzed groups. The patients were treated with ciprofloxacin (Cipronex^®, Polpharma SA; solution for infusion) in the intravenous dose of 200 mg (100 ml of solution; 2 mg/ml), which was infused for a 30-min period, once a day. All the patients were treated with the intravenous low-dose ciprofloxacin

Tab. 1. Patients’ characteristics

Parameter Total nephrectomy (S ± SD)

Partial nephrectomy (S ± SD)

n 21 15

Males/females 12/9 8/7

Age (years) 62.9 ± 14.4 61.7 ± 9.3 Body mass (kg) 76.0 ± 14.6 87.8 ± 16.4

BMI (kg/m²) 26.4 ± 3.5 30.3 ± 4.2 CL_CR(ml/min) 90.7 ± 22.2 107.8 ± 36.4

S – arithmetic mean; SD – standard deviation; CL_CR– creatinine clearance estimated by the Cockroft-Gault formula [2]

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regimen irrespective of their body weight, sex and age. Creatinine clearance for each patient was calculated using the Cockroft-Gault formula from creatinine concentration value obtained on the day of meas- urement of ciprofloxacin concentration [2].

To determine the drug concentrations at steady state, blood samples (2 ml) were collected from the cubital vein 0.5 (C^ss_max); 23 and 24 h (C^ss_min) after fin- ishing the intravenous infusion of the fifth dose of ciprofloxacin (3–4 days after nephrectomy). The steady state is achieved after about 5t_0.5. The biologi- cal half-life of ciprofloxacin equals about 3.4 h in patients with normal renal function [12] and about 3.7 in critically ill patients [3], therefore, the concentrations measured after the fifth dose correspond to the steady state.

Assays

Ciprofloxacin was detected by means of HPLC adapted by the May et al. method [13]. The chromatog- raphy separation parameters were: XTerra^® column RP-18, 3.5 µm 4.6 × 150 mm (Waters), mobile phase:

acetic acid (5%) – methanol – acetonitrile (90:5:5, v/v/v), flow rate of the mobile phase 1 ml/min, detec- tor UV wavelength 280 nm. Samples were eluted iso- cratically during the 8 min run. The limit of quantifi- cation was estimated at 0.05 mg/l and the limit of detection was estimated at 0.007 mg/l. Inter- and intra-day coefficients of variation were less than 10%.

The calibration for ciprofloxacin was linear in the range 0.05–8.0 mg/l (r = 0.999).

Pharmacokinetic analysis

The pharmacokinetic parameters were estimated by means of non-compartmental methods with validated software (WinNonlin^® Professional Version 5.3;

Pharsight^®Corp., USA). The following pharmacokinetic parameters were calculated for ciprofloxacin:

elimination rate constant (b), area under the plasma concentration-time curve from time zero to infinity (AUC_0–inf), area under the plasma concentration-time curve from zero to the time of last measurable concentration (AUC_0–last), half-life in elimination phase (t_1/2b), clearance (CL), volume of distribution (Vd), area under the first moment curve (AUMC_0–t), mean residence time (MRT).

Statistical analysis

The statistical calculations were made with SAS software package (SAS Institute Inc. 2002–2003. The SAS System for Windows version 9.1. Cary, NC 27513-2414 USA). The distribution of all of the measured parameters was checked for agreement with the normal distribution by the Shapiro-Wilk test (p = 0.05). Student’s t-test was used to estimate statistical significance of differences between the results obtained in the groups of men and women. Pearson’s correlation coefficient was applied to specify the de- gree of dependence between pairs of normally distrib- uted parameters; Student’s t-test was used to estimate its statistical significance.

Results

All the data were expressed as the mean ± standard deviation (SD). The two analyzed groups under study did not differ significantly in age. Part of the patients (52.4%) after TN was characterized by overweight (BMI 25–30 kg/m²), whereas 60% of the patients after PN suffered from class I obesity (BMI > 30 kg/

m²). Plasma creatinine clearance was significantly higher in the patients after PN as compared with the patients after TN.

The mean concentrations of ciprofloxacin in the blood plasma are shown in Figure 1. In the patients after PN elevated levels of ciprofloxacin were noted.

Statistically significant differences were observed at 0.5 (p < 0.05), 23 (p < 0.05) and 24 (p < 0.05) h following drug administration to nephrectomized patients.

The pharmacokinetic parameters of ciprofloxacin in the patients after TN were significantly different from those in the patients after PN (Tab. 2). In comparison with group 2, an increase in AUC_0last by 58.7% (p < 0.01) was observed. The elimination of ciprofloxacin was impaired in the patients after TN.

Value of t_1/2b was prolonged by 42.7% (p < 0.05) as compared with group 2. Similarly, CL decreased significantly by 72.8% (p < 0.05). The volume of distribution was comparable in the evaluated patient groups and no statistically significant differences were revealed.

Pharmacokinetics of ciprofloxacin in patients after nephrectomy

Edyta Sza³ek et al.

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Significant correlation between creatinine clearance (CL_CR) and ciprofloxacin clearance (CLciprofloxacin) was found for group TN (p = 0.0028) and not quite significant for group PN (p = 0.0621). Figure 2 shows the relationship between ciprofloxacin clearance and creatinine clearance in the patients subjected to group with TN (A) and group with PN (B). No significant correlation between C_CRand CLciprofloxacinwas found in either group under study.

Discussion

Because ciprofloxacin has high renal clearance and great renal concentration, it is an optimal drug for the treatment of urinary tract infections [17]. There is no available data on the pharmacokinetics of ciprofloxacin in nephrectomized patients and only little data re-

Tab 2. Pharmacokinetic parameters for ciprofloxacin

Parameter Group 1

total nephrectomy (S ± SD)

Group 2 partial nephrectomy

(S ± SD)

Gr 1 vs. gr 2 p value

AUC_0–last(µg h/ml) 30.90 ± 17.95 19.47 ± 8.73 0.0168

AUC_0–inf(µg h/ml) 41.70 ± 21.55 23.61 ± 12.53 0.0033

AUMC_0–last(µg h²/ml) 177.91 ± 122.08 91.86 ± 66.51 0.0119

b (h^–1) 0.066 ± 0.036 0.081 ± 0.034 0.2093

t_b(h) 13.94 ± 7.72 9.77 ± 3.29 0.0354

MRT (h) 16.51 ± 12.13 9.77 ± 5.41 0.0318

CL (l/h) 6.24 ± 3.33 10.78 ± 5.69 0.0118

V_d(l) 115.03 ± 67.25 142.24 ± 78.69 0.2726

C^ss_max(µg/ml) 2.012 ± 1.209 1.345 ± 0.553 0.0339

C^ss_min(µg/ml) 0.437 ± 0.298 0.244 ± 0.205 0.0373

0 0.5 1 1.5 2 2.5

0 5 10 15 20 25

Time [h]

Concentration[µg/ml] subjects with mean observed concen-

tration values during the 24-h period after administration of the fifth dose of the drug

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lated to other drugs in humans [5, 26] and animals [6, 24, 25]. In view of the frequent application of ciprofloxacin to that group of patients the study was justi- fied. Too high doses increase the risk of occurrence of adverse drug reactions. On the other hand, too low doses contribute to the development of resistance of microorganisms.

Ciprofloxacin is usually administered by means of intravenous drip infusion, which lasts 30–60 min, in the dose of 100–400 mg/12 h. In the case of severe and life-threatening infections 400 mg/8 h is administered. The maximum dose within 24 h is 1200 mg.

However, prescribing low doses of ciprofloxacin, such as 200 mg/24 h may cause subtherapeutic concentrations even in patients with limited renal function. Nephrectomy reduces the number of active nephrons. Altered permeability of capillaries causes migration of fluids to extravascular areas. A consequence of nephrectomy may also be local inflamma- tion, which causes hypoalbuminemia, which results in

migration of fluids beyond the lumen of the vessel.

Furthermore, patients with renal failure have been proved to produce uremic compounds, which displace xenobiotics from bonding with proteins. This may re- sult their increased volume of distribution [9]. The patients under analysis did not exhibit either significant differences in the volume of distribution between the groups (p = 0.2726) or differences from the data in the literature [7, 11].

The results of numerous studies say that the pharmacokinetics of ciprofloxacin is well described by the two-compartment model [10, 14, 16]. However, due to the limited possibilities of collection of many blood samples from patients subjected to the trial (at least for ethical reasons) the authors adopted the noncom- partmental analysis, limiting the sampling to this part of the curve whose phase of distribution was practi- cally finished. The estimation of C_max0.5 h after fin- ishing the intravenous infusion is also a great simplifi- cation. Nevertheless, in order to develop a routine

C l

ciprofloxacin

0 2 4 6 8 10 12 14 16 18

0 20 40 60 80 100 120 140

Cl CR

R = 0.3821²

C l

ciprofloxacin

0 5 10 15 20 25 30

0 50 100 150 200 250

R = 0.2426²

Cl CR

A

B

Fig. 2. The relationship between cipro- floxacin clearance (CLciprofloxacin) and creatinine clearance (Cl_CR) in the analyzed groups: A – total nephrec- tomy, B – partial nephrectomy

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study analyzes the concentrations and pharmacokinetic parameters of ciprofloxacin in patients after total and partial kidney resection. In the study concentrations of the chemotherapeutic agent in the blood plasma were calculated in 21 patients after TN and in 15 patients subjected to renal parenchyma conserving resection, who were hospitalized due to renal cancer.

The comparison of both groups revealed statistically significant differences for the values of concentrations calculated in individual time points, i.e., 0.5 h (p

= 0.0339), 23 h (p = 0.008), 24 h (p = 0.0373). Much higher concentrations of ciprofloxacin were observed in patients after TN. In that group 19% of the patients had C^ss_max< 1 µg/ml, whereas in the group after PN as many as 33.3% had C^ss_max < 1 µg/ml. The obtained values of maximum concentrations in all the patients did not guarantee C_max/MIC >10 for the theoretical value of MIC = 0.5 µg/ml.

The parameter which may also change after nephrectomy is the drug elimination rate constant. In the patients after TN b is 0.066 (± 0.036) h¹, whereas in the patients after PN it is 0.081 (± 0.034) h¹. The values prove reduced elimination rate in the patients as compared with healthy subjects (in young and geri- atric patients it is 0.17 h¹and 0.10 h¹, respectively) [18]. Another significantly altered parameter is the elimination half-life. In both groups it was longer than in the data from the literature, i.e., t_1/2b: 13.94 (± 7.72) h in the patients after TN vs. 9.77 (± 3.29) h in the pa- tients after renal parenchyma conservation surgery (p = 0.0354) vs. 3.4 h in healthy volunteers [12]. The clearance of ciprofloxacin also revealed significant differences between the groups: 6.24 (± 3.33) ml/h in the patients after TN vs. 10.78 (± 5.69) ml/h in the pa- tients after PN (p = 0.0118). The patients after TN proved a strong correlation between creatinine clearance and ciprofloxacin clearance (r = 0.6181), which facilitates dosage of the drug on the basis of creatinine clearance. In the patients after total kidney resection a significant increase in the values of such parameters as AUC_last, AUC_infand AUMC_lastwas proved, as compared with the patients after renal parenchyma conservation surgery (Tab. 2). In practice, this means higher exposure to the drug. However, the obtained AUC values for ciprofloxacin in both groups under analysis do not guarantee recommended values for the pa- rameter AUC/MIC ³ 125 if MIC = 0.5 µg/ml.

significant differences between the analyzed groups were obtained (Tab. 2). This fact speaks in favor of an individual approach in the process of pharmacother- apy in those groups of patients and the need to con- tinue research of other therapeutic substances.

Conclusion

The comparison of the values of ciprofloxacin concentration at steady state and the pharmacokinetic parameters in both groups proved the purposefulness of the research. For most of the analyzed parameters statistically significant differences were proved, which suggest the need of an individual approach to dosage of the drug. Even if the significant difference has been found between the two groups, there was no risk of toxic levels. The obtained values of pharmacodynamic parameters suggest considering an increase of the dose of ciprofloxacin to 400 mg/24 h or 200 mg/

12 h both in patients after partial and total kidney resection. However, it is necessary to remember that too low doses contribute to the development of resistance of microorganisms.

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Received: September 20, 2011; in the revised form: January 11, 2012; accepted: February 2, 2012.