INTRODUCTION

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Clinafloxacin is an extremely potent member of the fluoroquinolone class of synthetic antimicrobial agents. Compared with available quinolone antibiotics, clinafloxacin usually requires lower drug concentrations for bacterial inhibition and is active against a broader spectrum of organisms. It is effective against many multiple-drug-resistant organisms, including quinolone-resistant strains (5, 6, 7, 10, 12, 16). Clinafloxacin has been studied primarily in hospitalized adults for the treatment of serious and potentially life-threatening infections, including nosocomial pneumonia, community-acquired pneumonia, febrile neutropenia, complicated intra-abdominal infections, complicated skin and soft tissue infections, endocarditis, and acute gynecologic infections (16). It became apparent from initial clinical studies that twice-daily 100- to 400-mg doses were required to maintain concentrations in plasma within the effective range for most infections.

Single and multiple-dose pharmacokinetics of clinafloxacin have been reported previously (2, 17). Following administration of 200- and 400-mg twice-daily intravenous doses, the mean total body clearance and volume of distribution values are approximately 320 ml/min and 156 liters, respectively, and the mean terminal elimination half-life (t_1/2) is approximately 5.8 h. Clinafloxacin is approximately 50% bound to plasma proteins, independent of concentration.

Approximately 50 to 70% of a clinafloxacin dose is excreted unchanged in urine, indicating that renal clearance (CL_R) is a primary route of drug elimination. Therefore, it is expected that clinafloxacin concentrations in patients having decreased renal function will be higher than those in patients having normal renal function when both sets of patients receive clinafloxacin at the same dose. Accordingly, single-dose clinafloxacin pharmacokinetic profiles were evaluated in subjects with various degrees of renal function to establish dosing recommendations for patients with decreased renal function. A major age-related physiological change that could potentially affect pharmacokinetic profiles is a change in excretion due to reduced glomerular filtration and diminished renal tubular function. Additional age-related changes that could affect pharmacokinetic profiles include changes in absorption due to reduced gastric acid production, lower gastric emptying rate, decreased motility, reduced blood flow, and reduced absorptive surface area; changes in distribution due to decreased total body mass, reduced proportion of body water, less plasma albumin and ₁-acid glycoprotein, increased proportion of body fat, and altered tissue perfusion; and changes in metabolism due to reduced liver mass, decreased liver blood flow, and reduced hepatic metabolic capacity. (11) Therefore, a study was also conducted to compare clinafloxacin pharmacokinetic profiles in young and elderly subjects to establish dosing recommendations in elderly subjects. In addition, a study was conducted in patients with severe renal impairment requiring hemodialysis to determine if additional clinafloxacin doses are required to maintain concentrations in plasma within the safe and effective range in these patients.

(Preliminary results of these studies have been presented elsewhere [E. J. Randinitis, J. R. Koup, G. Rausch, N. J. Bron, N. J. Hounslow, A. B. Vassos, and A. J. Sedman, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-018, 1998], and brief reports of portions of this work have been published [18, 19].)

	MATERIALS AND METHODS

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Subjects and study conduct. Study protocols were approved by institutional review boards associated with the study sites, and all studies were conducted according to the ethical principles stated in the Declaration of Helsinki. All subjects provided written informed consent before entering the study and were free to withdraw at any time at their own discretion. Eligible subjects were men and women in good to excellent health according to degree of renal function and who had no unstable medical problems. Health was evaluated by medical history, physical examination, and clinical laboratory measurements. Subjects were confined to the clinic for 24 h following the administration of the clinafloxacin dose for safety evaluation by physicians and returned to the clinic for additional scheduled blood sampling.

Study 1: young and elderly subjects. Sixteen healthy subjects between 18 and 35 years old and 16 healthy elderly subjects (>65 years old) were enrolled in this study. Subject enrollment groups were equally divided by sex in order to evaluate any possible differences in clinafloxacin pharmacokinetic profiles between the sexes.

Study 2: subjects having mild, moderate, and severe renal impairment. To ensure enrollment of subjects having a wide range of renal function, 20 subjects were enrolled in one of three groups based on creatinine clearance (CL_CR) values estimated using the method of Cockcroft and Gault (4). Groups had CL_CR values of >60 ml/min, between 30 and 60 ml/min, and <30 ml/min but not on dialysis. At least three subjects in the third group were to have a CL_CR of <15 ml/min.

Study 3: subjects having severe renal impairment requiring hemodialysis. Twelve subjects having renal impairment severe enough to require hemodialysis and maintained on hemodialysis at least once weekly were enrolled in this study. Subjects could be anuric (< 50 ml of urine per 24 h).

Design of studies. All studies were open-label, single-dose, parallel-group designs. Subjects having various degrees of renal impairment, including those having severe renal impairment requiring hemodialysis, received single 200-mg clinafloxacin oral doses with 240 ml of water. Young and elderly subjects received single 400-mg clinafloxacin oral doses. Subjects maintained on hemodialysis received the dose approximately 24 h before their next scheduled hemodialysis treatment. Subjects not maintained on hemodialysis fasted overnight before and for 4 h following administration of the dose. Subjects requiring hemodialysis fasted for 4 h before and after the dose. Identical lunches and identical dinners were served to each subject after collection of the 4- and 10-h blood samples, respectively. Essential medication was allowed before and after the 8-h fasting period in these subjects in order to eliminate any potential drug interaction. It has been shown that oral clinafloxacin should be administered at least 2 h before or 4 h after administration of a magnesium- or aluminum-containing antacid and that clinafloxacin may be administered without regard to meals or meal timing (1).

Safety. Subjects were required to remain in the clinic for 24 h following the administration of the dose for safety observation by physicians. Physical examinations including vital signs were conducted prior to the dose, at 4 and 24 h following the dose, and at closeout. Clinical laboratory tests were conducted prior to and at 24 h following the dose.

Sampling. For subjects not maintained on hemodialysis, venous blood samples (3 ml) were collected into heparinized tubes before the clinafloxacin dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 h postdose. For subjects maintained on hemodialysis, 2-ml samples were collected before the clinafloxacin dose and at 1, 2, 4, 8, and 12 h postdose. Blood samples were also collected from subjects entering and exiting the dialyzer before as well as 1, 2, 3, and 4 h after the beginning of hemodialysis (equivalent to 24, 25, 26, 27, and 28 h postdose). Additional blood samples were collected 1 and 2 h after the end of hemodialysis (equivalent to 29 and 30 h postdose) and at 32, 36, and 48 h postdose. Blood samples were immediately centrifuged, and plasma was separated and stored frozen in plastic containers at 20°C until assayed. For all subjects, a 100-ml urine specimen was collected before the dose. All urine voided during the 0- to 6-, 6- to 12-, 12- to 24-, 24- to 48-, 48- to 72-, and 72- to 96-h time intervals was collected. Total urine volumes were measured for each urine collection period, and 20-ml portions were stored frozen at 20°C until assayed. Dialysate samples (20 ml) were collected at the start of hemodialysis; at 1, 2, and 3 h after beginning hemodialysis; and upon completion of hemodialysis (equivalent to 24, 25, 26, 27, and 28 h postdose). Hemodialysate flow rate, blood inflow rate, dialyzer membrane surface area, and temperature were recorded. Dialysate samples were stored frozen at 20°C until assayed.

Assay of clinafloxacin. Plasma and urine samples were assayed for clinafloxacin concentration using validated liquid chromatographic methods with UV detection as described previously (17). Dialysate samples were assayed by the urine method. Detector responses were linear over the calibration range of 0.025 to 10 µg/ml and 2.5 to 200 µg/ml for plasma and urine, respectively. Intra- and interday assay precision, as measured by the coefficient of variation, was <15% for both plasma and urine. No interfering peaks were evident in samples collected prior to clinafloxacin dosing, indicating that essential medications required by some subjects did not interfere with the clinafloxacin assay.

Pharmacokinetic analysis. For all subjects, maximum concentrations in plasma (C_max) and time to C_max (T_max) were recorded as observed. The area under the concentration-time curves (AUC) values were estimated using the linear trapezoidal rule. AUC values were calculated from zero time to the time of the last quantifiable concentration (LQC). Values of terminal-phase elimination rate constants (_z) were estimated as the absolute values of the slope of a least-squares regression line of natural logarithm (ln) concentration-time profiles during the terminal phase. The t_1/2 values were calculated as ln(2)/_z. In subjects not maintained on hemodialysis, values of AUC at infinity (AUC) were calculated as the sum of corresponding values of AUC at the LQC and LQC/_z values. Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL_oral) was calculated as dose/AUC. The apparent volume of distribution after oral administration (V_oral) was calculated as (CL_oral)/_z. The total amount of drug excreted in urine during the 96-h postdose interval as unchanged clinafloxacin (Ae) was calculated as the product of urine volume and concentration. The percentage of the dose excreted (Ae%) as unchanged clinafloxacin was calculated as (Ae/dose) · 100. CL_R was calculated as Ae/AUC. Because the absolute bioavailability of clinafloxacin from capsules in normal subjects is approximately 90% (17), nonrenal clearance (CL_NR) values were approximated as the difference between CL_oral and CL_R. In subjects maintained on hemodialysis, AUC values were calculated as the sum of corresponding AUC₂₄ and C₂₄/_z values, where AUC₂₄ is the AUC at 24 h postdose and C₂₄ is the concentration in the sample collected 24 h postdose, immediately before the start of hemodialysis. These values represent pharmacokinetic parameters for subjects requiring hemodialysis who were not on hemodialysis at the time. Values for t_1/2 were estimated during as well as after hemodialysis. Hemodialysis clearance (CL_d) values were calculated as follows: CL_d = [(C_in  C_out)/C_in] · [Qb · (1  HCT)], where C_in and C_out are plasma clinafloxacin concentrations measured in blood samples entering and exiting the dialyzer, respectively, and, Qb and HCT are blood flow rate entering the dialyzer and hematocrit measured at each collection time, respectively (11). Individual time point CL_d values obtained by this method were used to calculate an average subject CL_d. The fraction of dose removed from the body by hemodialysis was calculated as follows: F_d = 100% · A_d/dose, where A_d is the amount of clinafloxacin removed by the hemodialysis; A_d is calculated as follows: A_d = CL_d · AUC, where AUC is measured during the 4-h hemodialysis period. Values for Ae% and CL_R for anuric subjects were set at zero for evaluation of descriptive statistics. Clinafloxacin concentrations in dialysate were below the limit of quantitation (2.5 µg/ml) in all samples for all subjects. Therefore, dialysate concentrations were not used in data analyses.

Statistical methods. Mean clinafloxacin pharmacokinetic parameter values following administration of single 400-mg oral doses were compared between age groups and between sexes within age groups for possible clinically important differences. To assess which physiologic variable might best predict changes in key pharmacokinetic parameters, an analysis of covariance model consisting of CL_CR, body weight, age (as a continuous variable), and sex as main effects was fitted using forward stepwise regression (SAS Institute, Cary, N.C.). Parameter estimates and coefficients of multiple determination were evaluated. The ability of each successive model to predict a given pharmacokinetic parameter was assessed by comparing variability with those of simpler models.

	RESULTS

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Subject demographics and safety. Subject demographics are summarized in Table 1 and dialysis specifications are given in Table 2. In general, single, 200- and 400-mg clinafloxacin oral doses were well tolerated by subjects with various degrees of renal impairment as well as healthy young and elderly subjects. In the young-elderly study, a 25-year-old male subject with a history of migraine headaches and a family history of childhood seizures in a sibling experienced a tonic-clonic seizure considered to be probably related to clinafloxacin, about 45 min following administration of the single 400-mg dose. The subject fully recovered within 30 min. The clinafloxacin pharmacokinetic profile in this subject was similar to that observed in other younger subjects in this study, and data from this subject were utilized in pharmacokinetic and statistical evaluations. No other serious adverse events were recorded in these studies. Clinical laboratory abnormalities were in general sporadic and transient and appeared to be unrelated to drug administration. Many quinolone anti-infective agents are reported to have central nervous system-related adverse events, including seizures (3, 9, 13).

Pharmacokinetics. (i) Elderly versus young subjects. Mean clinafloxacin concentration-time profiles following administration of single 400-mg oral doses to young and elderly subjects are illustrated in Fig. 1. Clinafloxacin pharmacokinetic parameter values are given in Table 3. Parameter values determined for young healthy subjects were similar to those reported previously (17). Clinafloxacin was rapidly absorbed in young and elderly subjects. Values for T_max ranged from 0.5 to 3 h and were independent of subject age. The mean C_max for elderly subjects was approximately 18% higher than that observed in younger subjects. This difference probably reflects differences in clearance. The mean AUC following administration of clinafloxacin capsules in elderly subjects was 57% higher than that observed in younger subjects. The mean t_1/2 in elderly subjects was 41% higher than that in younger subjects. Mean CL_oral and CL_R values in the elderly were 35 and 45% lower than those in younger subjects. As a result of these differences in CL_oral and CL_R values, plasma clinafloxacin concentrations were higher in elderly subjects than in young subjects. V_oral and Ae% values in elderly subjects were similar to those in younger subjects, with differences in mean values being approximately 9% and 14%, respectively.

View larger version (12K): [in this window] [in a new window]   FIG. 1.   Mean clinafloxacin concentrations in plasma following administration of single 400-mg oral doses to young and elderly subjects.

(ii) Subjects with various degrees of renal function not maintained on hemodialysis. Relationships between CL_oral and CL_R values with subject CL_CR values are illustrated in Fig. 2 and 3, respectively. Young and elderly subjects were included with those having various degrees of renal function. Both CL_oral and CL_R correlated with decreasing renal function with the following relationship: CL_oral = 2.3 · CL_CR + 77 and CL_R = 1.74 · CL_CR. As expected for a drug eliminated primarily by renal excretion, CL_oral correlated well with CL_CR. Correlation coefficients were 0.88 and 0.93 relating CL_oral and CL_R to CL_CR, respectively. A positive intercept in the relationship between CL_oral and CL_CR indicated the presence of a significant nonrenal clearance component, representing approximately 25 to 30% of CL_oral. This was supported by the approximate CL_NR values in young subjects having normal renal function given in Table 3.

View larger version (17K): [in this window] [in a new window]   FIG. 2.   Relationship between CLCR and clinafloxacin oral clearance CLoral in subjects with various degrees of renal function as well as young and elderly subjects. The outlier was not used in regression analysis.

View larger version (17K): [in this window] [in a new window]   FIG. 3.   Relationship between CLCR and clinafloxacin CLR in subjects with various degrees of renal function. The intercept was not significantly different from zero. Therefore regression was forced through the origin. The outlier was not used in regression analysis.

(iii) Subjects maintained on hemodialysis. Mean clinafloxacin concentration-time profiles following administration of single 200-mg oral doses to subjects maintained on hemodialysis are shown in Fig. 4. The figure also illustrates concentrations in plasma exiting the dialyzer. Pharmacokinetic parameter values for this group of subjects are summarized in Table 5. Parameter values were similar to those in subjects with CL_CR values of <40 ml/min who were not maintained on hemodialysis. Approximately 4% of a single 200-mg clinafloxacin dose was removed by the 4-h hemodialysis procedure.

View larger version (10K): [in this window] [in a new window]   FIG. 4.   Mean plasma clinafloxacin concentrations following administration of single 200-mg oral doses to subjects with renal failure requiring hemodialysis. Subjects received a 4-h hemodialysis procedure beginning at 24 h postdose.

	DISCUSSION

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Based on similar T_max and C_max values, rates of clinafloxacin absorption are similar in young and elderly male and female subjects. Small differences in C_max values among these groups is of no clinical importance. Based on similar V_oral values between age groups, distributions of clinafloxacin were similar in young and elderly male and female subjects. V_oral values were greater than total body water, suggesting extensive distribution of clinafloxacin into tissues in all subjects. Based on similar CL_NR values in young and elderly male and female subjects, clinafloxacin metabolism and/or other elimination mechanisms (that is, biliary excretion) are not influenced by age or sex differences. The major factor responsible for higher clinafloxacin concentrations in plasma in the elderly is an age-related decrease in renal function. Therefore, reduction in daily clinafloxacin dose based on degree of renal function as measured by CL_CR values may be appropriate for the elderly. Differences in pharmacokinetic parameter values between male and female subjects, regardless of age, are not clinically important and do not warrant clinafloxacin dose adjustment based on sex.

The recommended clinafloxacin dose in patients with normal renal function is 200 mg twice daily. Based on the relationship between clinafloxacin CL_oral and subject CL_CR values, it is recommended that patients with CL_CR values of <40 ml/min, regardless of age, have their daily clinafloxacin dose halved. Therefore, these patients should receive either 100 mg of clinafloxacin twice daily or 200 mg once daily to maintain plasma clinafloxacin concentrations within the range effective for most organisms. This dosing regimen is also recommended for patients on hemodialysis. As only 4% of the clinafloxacin dose is removed by the 4-h hemodialysis procedure, supplemental clinafloxacin doses are not required during or after hemodialysis.