ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1990, p. 974-979 0066-4804/90/060974-06$02.00/0 Copyright 0 1990, American Society for Microbiology
Vol. 34, No. 6
Multiple-Dose Pharmacokinetics and Safety of Oral Amifloxacin in Healthy Volunteers JACK A. COOK,'* MICHAEL H. SILVERMAN,lt DONALD J. SCHELLING,' DAVID E. NIX,2 JEROME J. SCHENTAG,2 RICHARD R. BROWN,' AND RONALD M. STROSHANE'*
Sterling Research Group, Rensselaer, New York 12144,1 and Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospitals, and State University of New York, Buffalo, New York 140292 Received 6 September 1989/Accepted 12 March 1990
The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (ql2h) and .400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was admistered on day 11. Concentrations of amifoxacin i plasma and urine were measur on days 1, 5, and 11 by highperformance liquid chromatography. Steady-state amiloxac concentrations were reached by day S. Mean' standard deviation mamum observed amifoxacin concentrations in plasma were 2.52 1.12, 4.98 1.44, 5.40 ±'2.02, 4.59 2.17, 6.53 . 2.44, and 8.01 3.00 ,ug/nl after the initial dose and 2.30 0.98, 5.41 0.74, 8.05 1.68, 6.87 2.81, 9.53 0.50, and 11.9 1.92 ,.L/ml on day 11 of'the study for the 200-, 400-, and 600-mg ql2h and 400-, 600-, and m800-g q8h regimens, respectively. Am was rapidly absorbed, as evidenced by. the mean time to the mimum observed amidloxacin concentration of 0.98 h. Mean values for the terminal amilloxac half-life in plasma ranged from 3.58 to 5.78 h. Mean amllloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 jig/ml for the 200-, 400-, and 600-mg ql2h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the'urine as amifloxaci was 53.9%. Amlfioxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically sig nt adverse reactions, including pruritus and t n ase elevations, occurred only at doses of 1,200 mg/day or above. Clincal and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections. were
Amifloxacin (Win 49375) is a fluorinated quinolone-carboxylic acid antibacterial agent with activity against a broad range of gram-negative organisms. The MICs for 90% of isolates of representative urinary tract pathogens are 0.125 ,ig/ml for Escherichia coli, 0.5 ,ug/ml for Klebsiella pneumoniae, 1.0 ,ug/ml for Proteus vulgaris, 0.5 ,ug/ml for Citrobacterfreundii, 2.0 jig/mi for Pseudomonas aeruginosa, and 0.5 ,ug/ml for Serratia marcescens (8). Previous studies in laboratory animals have shown that renal excretion is a major component of amifloxacin elimination, with high concentrations in urine being achieved after both oral and intravenous dosing (6). Taken together, these properties suggest that amifloxacin has potential in the treatment of infections of the human urinary tract. A number of fluoroquinolones have been characterized with respect to pharmacokinetics in humans, and they generally demonstrate consistent and predictable behavior (9). This report documents the human pharmacokinetics of amifloxacin following multiple oral administrations to 36 healthy male volunteers in a double-blind, placebo-controlled trial. Tolerability is also reported for these 36 subjects, as well as for 24 subjects who received amifloxacin in a separate tnral.
MATERIALS AND METHODS Subjects. Both study protocols received the approval of the Institutional Review Board (Millard Fillmore Hospitals, Buffalo, N.Y., or Harris Laboratories Inc., Lincoln, Nebr.), and all subjects gave written informed consent. A total of 48 healthy male subjects (age, 18 to.46 years; weight, 62.3 to 102.3 kg) were enrolled in the pharmacokinetic study. Volunteers were evaluated for general good health by history, physical examination, and laboratory screening. Subjects were excluded from the study if they had a history or presence of 'any significant disease state, hypersensitivity to a quinolone agent, or history of substance abuse; were not within 15% of ideal body weight (height and weight tables, Metropolitan Life Insurance Co., New York, N.Y., 1983); or smoked more than one pack of cigarettes per day. Subjects did not receive prescription or proprietary medication during a period of at least 3 days prior to test drug administration through the course of the study. Volunteers were housed in the study unit from approximately 36 h prior to the first administration of drug until approximately 36 h following the last administration of drug. Study design. The pharmacokinetic study was a doubleblind, placebo-controlled trial in which amifloxacin was orally administered in one of six dose regimens: 200, 400, or 600 mg every 12 h (ql2h) and 400, 600, or 800 mg every 8 h (q8h). Six subjects in each group received active drug and two subjects received a placebo formulation. Amifloxacin was administered orally as 200-mg capsules. Placebo formulations were identical in appearance to active drug formulations. Each regimen lasted for 10 days, with one additional dose being administered the morning of day 11. No subject
Corresponding author. t Present address: Sandoz Research Institute, East Hanover, NJ
*
07936. *
Present address: Harris Laboratories Inc., Lincoln, NE 68501.
974
VOL. 34, 1990
PHARMACOKINETICS AND SAFETY OF ORAL AMIFLOXACIN
was allowed to participate in more than one dosage group. No food was allowed after midnight on the night prior to the initial drug administration. Subjects fasted for a period of 4 h following first-dose administration on days 1, 5, and 11, after which a meal was provided. Subjects were placed on a standardized balanced diet, and except as specified above, meals were served no closer than 2 h prior to or 1 h after medication administration. Each dose was administered with 250 ml of water. Additionally, 250 ml of water was taken by each volunteer 1 h prior to the first dose on days 1, 5, and 11. Water was allowed ad libitum 1 h after drug administration. Tolerability. Tolerability data are presented for the 48 subjects dosed in the pharmacokinetic study. Also included in the tolerability analysis are 30 normal male volunteers (age, 19 to 51 years; weight, 60.9 to 88.6 kg) dosed in a study of virtually identical design. A total of 12 subjects received amifloxacin at 600 mg ql2h, 12 subjects received amifloxacin at 400 mg q8h, and 6 subjects received placebo. All subjects were under close, continuous observation in the study unit throughout the dosing periods. Evidence of drug-related intolerance was sought and assessed through spontaneous subject reporting, questioning by medical personnel, and physical examinations. Subjects were also monitored during and after dosing with hemograms, clinical chemistries, complete urinalyses, and electrocardiograms. Pre- and postdose 24-h creatinine clearances were performed. All adverse events were recorded and evaluated by an investigator in a blinded fashion. Sample collection. Blood samples (10 ml) for determination of amifloxacin concentrations in plasma were collected in tubes containing potassium oxalate anticoagulant at time zero (predose); at 15, 30, and 45 min; and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10 (ql2h regimen only), and 12 (ql2h regimen only) h postdose on days 1, 5, and 11. Additionally, blood samples were drawn just prior to the first and second doses on days 3 and 7 and at 10, 12, 16, 18, and 24 h postdose on day 11. The plasma was separated by centrifugation and stored frozen at approximately 20°C until subsequent analysis. Urine samples were collected from all subjects on days 1, 5, and 11 at time zero (predose) and over 0 to 2, 2 to 4, 4 to 6, 6 to 8 (q8h regimen only), 6 to 12 (ql2h regimen only), 8 to 24 (q8h regimen only, day 11), and 12 to 24 (ql2h regimen only, day 11) h postdose. Urine samples for analysis were kept refrigerated during these periods. At the end of each collection period, the volume and pH were measured and recorded. Duplicate 10-ml portions were frozen at approximately 20°C until subsequent analysis. Analytical methods. Plasma and urine samples were analyzed for amifloxacin by a validated column-switching highperformance liquid chromatography method with UV detection (B. P. Crawmer, J. A. Cook, and R. R. Brown, submitted for publication). Briefly, plasma or urine samples were spiked with internal standard, diluted 1:1 with 0.5 M sodium citrate buffer (pH 2.5), and directly injected onto a cation-exchange precolumn. Following a 2.0-min wash of the precolumn with water at a flow rate of 1.1 ml/min, the effluent from the precolumn was directed to the analytical column by a column-switching device. Quality-control pools (100 ml) were prepared in control human plasma or urine at nominal concentrations of 0.80 and 20.0 ,ug/ml, respectively, and stored frozen with study samples until analysis. Four quality-control samples were included in each analytical run. Study samples, quality-control samples, and calibration curve standards were injected according to a computergenerated randomized sequence. In general, all of the sam-
975
ples for a given subject were included in the same analytical run.
During the validation procedure, the precisions (the overall standard deviations of the percent differences from nominal values for the validation samples) of the plasma and urine methods were estimated to be 2.1 and 2.1%, respectively. The accuracies (the overall range of mean percent differences from nominal values for the validation samples) of the methods were within a range of 0.17 to 1.5% and -2.9 to 0.99%o for plasma and urine, respectively. Recovery of both amifloxacin and the internal standard from plasma and urine was quantitative. Linear detector responses were observed for the calibration curve standards in the range of 0.10 to 5.0 ,ug/ml for plasma and 0.50 to 100 ,ug/ml for urine. The minimum quantifiable levels were 0.10 and 0.50 p,g/ml for plasma and urine, respectively. Freezing of samples for approximately 1 week did not have any appreciable influence on assay values. Pharmacokinetic calculations. Noncompartmental parameters were calculated by standard methods (4). The apparent first-order terminal elimination rate constant (kei) was calculated by linear regression of the natural logarithm of the amifloxacin concentrations in plasma as a function of time, beginning 2 h postdose (semilogarithmic plots of individual amifloxacin concentration in plasma profiles indicated that this was after the apparent absorption and distribution phases in each case). The half-life (t112) was calculated from the equation tl2 = ln (2)/kei. Concentrations of amifloxacin which were less than the minimum quantifiable level of the assay were not included in the linear regression analysis. The areas under the amifloxacin-concentration-in-plasmaversus-time curves (AUCs) were calculated by the trapezoidal rule method over the dosing interval for days 1, 5, and 11. The AUC from day 1 was extrapolated to infinity with the addition of the term Ck,,Ik, where C,, is the concentration of the last sample with a quantifiable concentration and where kei was calculated by using data from day 1. The following pharmacokinetic parameters were also calculated: Varea/F = dose/(AUC x ke, x wt); CL/F = dose/(AUC x wt); and CLR AJ(AUC x wt), where V.,,./F is that volume which, when multiplied by the amifloxacin concentration in plasma during the terminal log-linear phase, was equal to the amount of drug in the body unadjusted for the extent of bioavailability (F); CL/F is the total plasma clearance unadjusted for F; CLR is the renal clearance; and Ae is the amount of amifloxacin excreted renally over the dosing interval. The parameters described above were normalized for the subject's
weight (wt). The maximum observed amifloxacin concentration in plasma (Cm.), its corresponding time of occurrence (Tma), as well as the minimum observed concentration in plasma (Cmin) were obtained by inspection of the observed concentration in plasma data. The amount of drug excreted in urine was obtained by multiplying the urine volume by the amifloxacin concentration in urine. The percentage of the dose excreted in the urine as amifloxacin was obtained by dividing the amount of amifloxacin excreted by the administered dose (X 100%). Statistical treatment. The model-independent parameters Cma, Tmax t1/2, Cminj, AUC, and the amount of unchanged amifloxacin excreted in the urine were examined. The analyses of these variables were generally the same, although the approach varied according to the distributional characteris-
tics of each variable. All variables were analyzed with a repeated-measures analysis of variance. The proportionality of relevant response variables to dose was examined, first,
976
ANTIMICROB. AGENTS CHEMOTHER.
COOK ET AL. 100
z 0
z LUL u z
10
0
U2.
0
*.M U..
z
U.IL
.M.-
ui
amifloxacin concentrations. Concentrations of drug in plasma for one subject on day 1 were inexplicably low (200 mg q12h; C.ax = 0.29 jig/ml; AUC = 2.1 pug- h/ml). Therefore, day 1 data for that individual were omitted from the analysis. All other pharmacokinetic data were analyzed for the 36 amifloxacin recipients. Plots of mean amifloxacin concentration in plasma versus time on day 11 are presented in Fig. 1. The noncompartmental pharmacokinetic parameters are presented in Tables 1 (after a single dose) and 2 (after multiple doses). The results of the estimation of k,, yielded coefficients of determination greater than 0.9 in all cases, and visual examination of the residual values revealed no apparent heteroscedasticity. The overall mean + standard deviation Cmin values for data from days 3 through 11 were 0.41 + 0.15, 0.90 + 0.40, 2.03 0.70, 2.67 0.89, 4.26 + 1.27, and 5.19 + 1.84 ,ug/ml for the 200-, 400-, and 600-mg ql2h groups and the 400-, 600-, and 800-mg q8h groups, respectively. In general, mean AUCs (Fig. 2, day 11 data), Cmax, Cmin, and amount of amifloxacin excreted in the urine were adequately described by a dose-proportional model. Exceptions included greater than dose-proportional increases in AUC on day 11 for the ql2h groups and the morning and evening Cmin values on days 3, 5, and 11 for the ql2h groups. While these increases were only slightly greater than dose proportional, they were statistically significant. Additionally, there were no statistically significant differences in these parameters between days 5 and 11, indicating that steady state was reached by day 5. Small but statistically significant differences were generally found between day 1 values and steady-state values of AUC and t1/2. Because the magnitudes of these differences were small and considerable overlap occurred in the range of the values between day 1 and steady state, these findings are of minimal clinical importance. Amifloxacin was rapidly absorbed, as evidenced by the overall mean Tma. of 0.98 0.56 h. As would be expected with concentration-related changes in t1/2 and greater than dose-proportional increases in AUC (day 11, q8h group), mean values for CL/F, CLR and Varea/F were also concentration related. CL values tended to decrease with increasing dose, and mean values ranged from 150 to 294 and 66 to 128 ml/h per kg for CL/F and CLR, respectively. Mean values for Varea/F ranged from 1.89 to 1.16 liters/kg. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 ,ug/ml in the 200-, 400-, and 600-mg ql2h and 400-, 600-, and 800-mg q8h groups, respectively. In general, steady-state amifloxacin concentrations in urine were consistently above 100 ,ug/ml for doses greater than 200 mg ql2h and were consistently above 40 ,ug/ml for the ±
Us
0.1
h 0
2
4
6
8 10 12 14 16 18 20 22 24
TIME IN HOURS
FIG. 1. Steady-state amifloxacin concentrations in plasma (from day 11 of the study). Symbols: *, 200 mg ql2h; *, 400 mg ql2h; 0, 600 mg ql2h; A, 400 mg q8h; +, 600 mg q8h; *, 800 mg q8h.
by testing for curvature in a quadratic model by using dose or logarithmic dose and then by testing for slopes or intercepts equal to zero in the straight-line model. Assuming proportionality, the proportionality constants were estimated for each day and compared across days. Satterthwaite approximate F statistics (12) were computed for tests to account for the imbalance of the data and the two error terms in these models, one within subjects and one between subjects. For variables for which proportionality was not of interest (Tmax and t4/2), interactions and main effects of day and dose were examined.
RESULTS The performance characteristics of the analytical method were considered to be acceptable. The mean + standard deviations for the quality-control samples were 0.80 0.02 and 19.9 + 0.3 ,ug/ml for plasma (nominal concentration, 0.80 p,g/ml) and urine (nominal concentration, 20.0 p,g/ml), respectively. The coefficient of determination from each calibration curve was 0.998 or greater. The coefficients of variation for the mean values of the calibration curve slopes were 5% for the plasma analyses and 6% for the urine analyses. Selected plasma samples from each subject who received placebo were analyzed, and none contained quantifiable
±
TABLE 1. Single-dose pharmacokinetic parameters for amifloxacina Dose group
Cmax (p.g/ml)
± ± ± ± ± ±
Tm. (h)
t1m2 (h)
(Lg.AUC h/ml)
Varea/F
(liter/kg)
CL/F
(ml/h per kg)
CLR (ml/h per kg)
101 ± 29 261 ± 42 1.35 ± 0.27 0.29 99 ± 14 233 ± 35 1.32 ± 0.11 0.49 80 ± 14 258 ± 96 1.78 ± 0.67 0.72 ± 0.53 66 ± 15 254 ± 160 1.74 ± 1.46 0.79 69 ± 16 ± 0.56 209 ± 51 1.34 ± 0.23 1.37 79 ± 33 276 ± 110 ± 0.45 1.59 ± 0.64 0.65 a Values are means ± standard deviation and were calculated from six observations, except for the 200-mg ql2h group, for which there were five observations.
200 mg ql2h 400 mg ql2h 600 mg ql2h 400 mg q8h 600 mg q8h 800 mg q8h
2.52 4.98 5.40 4.59 6.53 8.01
1.12 1.44 2.02 2.17 2.44 3.00
0.85 0.88 1.13 0.% 1.08 1.20
± 0.13 ± 0.34 ± 0.95
11.0 22.3 33.5 23.8 38.8
±
± ± ± ± 41.0 ±
4.3 4.2 13.0 8.3 11.2 16.1
3.58 3.96 4.83 4.51 4.67 4.07
± ± ± ± ± ±
VOL. 34, 1990
PHARMACOKINETICS AND SAFETY OF ORAL AMIFLOXACIN
977
TABLE 2. Steady-state pharmacokinetic parameters for amifloxacin following 11 days of oral administrationa Dose group (no. of observations)
Cmax (~Lg/ml)
200 mg ql2h (6) 400 mg ql2h (6) 600 mg ql2h (6) 400 mg q8h (5) 600 mg q8h (4) 800 mg q8h (4)
2.30 5.41 8.05 6.87 9.53 11.87
± ± ± + ± ±
AUC (ug h/mi)
TM (h)
0.98 0.74 1.68 2.81 0.50 1.92
0.88 0.96 1.46 1.05 1.25 0.50
± 0.56 ± 0.56 ± 1.28
10.6 28.2 48.2 31.5 49.8 56.7
± 0.67 ± 0.50 ± 0.20
± ± ± ± ± ±
3.0 6.8 12.2 8.1 6.5 14.4
4/2 (h)
4.25 4.48 5.28 5.32 5.50 5.78
± 0.62 ± 0.81
± ± ± ±
Vae/F
CL/F
(liter/kg)
(ml/h per kg)
1.89 1.18 1.24 1.21 1.16 1.43
0.82 1.31 1.21 0.67
± 1.19
± ± ± ± ±
0.11 0.29 0.27 0.09 0.30
294 187 165 163 150 176
± ± ± ± ± ±
CLR (ml/h per kg)
126 36 35 47 25 59
128 122 87 88 81 73
± ± ± ± ± ±
13 18 22 11 12 12
Amifloxacin excreted (%)
48.0 65.8 54.6 56.0 55.0 43.4
± ± ± ± ± ±
13.1 7.1 15.8 8.0 10.2 9.5
a Values are means ± standard deviations.
200-mg ql2h group. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Sixty subjects who received amifloxacin and 18 subjects who received placebo were included in the tolerability analysis (Table 3). In general, the incidence of adverse events was equally distributed between the two studies. Adverse events were generally mild and self-limited. Dosing was discontinued in one subject who experienced pruritus while taking amifloxacin at 800 mg q8h and in three subjects (one each receiving 400, 600, and 800 mg of amifloxacin q8h) who experienced asymptomatic and transitory elevations of serum glutamic pyruvic transaminase to five to eight times the upper limit of normal. Asymptomatic crystalluria, which was thought to be drug related, was seen in three subjects who received amifloxacin; one subject received the drug at 600 mg ql2h and two subjects received it at 800 mg q8h. The crystalluria was not associated with other changes in the urinary sediment or with alterations in serum creatinine or 24-h creatinine clearance. DISCUSSION The reductions in mean CL/F and CLR values with increasing dose as well as the reductions in mean CL/F values and the increase in mean AUC and tl,2 values between day 1 and steady state suggest concentration-dependent pharma-
cokinetics for amifloxacin. Conversely, statistical analysis did not find consistent deviations from the dose-proportional model for Cma, Cmi., or AUC. However, this was most likely due to the fact that the deviations from the doseproportional model were relatively small in comparison with the intersubject variabilities. Therefore, a study design in which each subject received doses of amifloxacin at a number of different dosage levels would be more likely to detect deviations from the dose-proportional model. Concentration-dependent pharmacokinetics have been previously reported for other quinolones. Mean values for t1/2 of norfloxacin increased with increasing dose (1). Mean values for t112 of ciprofloxacin have been shown to be dose dependent (5) and to increase from day 1 values with repeated administration (2). There is also an increase in the t1/2 of fleroxacin during repeated administration (10). In general, the values for amifloxacin pharmacokinetic parameters were comparable to those reported for other quinolone antibacterial agents (9). While dose-related increases in mean t1/2 values and dose-related decreases in mean CL/F and CLR values indicate that at least some component of amifloxacin's elimination is concentration dependent, the resultant deviations appear to be of minor clinical importance over the dosage TABLE 3. Subjects experiencing adverse events
90 _
Adverse event
80 _
70 U
60
z E
5o
**
*2**
9
Gastrointestinal Nausea Flatulence Abdominal pain Dyspepsia
4 (22.2) 1 (5.6) 3 (16.7)
Other
(40.0) (15.0) (11.7) (8.3) (6.7) 4 (6.7)
Nervous
33 (55.0)
6 (33.3) 5 (27.8) 1 (5.6)
24 9 7 5 4
*
FJ-o
/
No. (%) of subjects Amifloxacin Placebo (n = 18)' (n = 60)'
*
40 a
*
30
20 10
0 0
1
2
3
4
5
6
7
8
9
10 11 12
DOSE/WEIGHT (mg/kg) FIG. 2. Steady-state amifloxacin AUCs versus dosage (from day 11 of the study). Symbols: *, ql2h; *, q8h.
Headache Lightheadedness Insomnia Tinnitus Other
17 5 2 2 11
(28.3) (8.3) (3.3) (3.3) (18.3)
Skin Pruritus
5 (8.3)
Other
3 (5.0)
1 (5.6)
3 (5.0)
Elevated serum glutamic pyruvic transaminase
3 (5.0)
Other
7 (11.7)
an indicates the total number of subjects studied.
1 (5.6)
978
COOK ET AL.
range studied. For example, if increases in AUCs were proportional to dose, the mean AUC of the 800-mg q8h dose group would be four times that of the 200-mg ql2h dose group. In the present study the respective day 1 and day 11 mean values of the 800-mg q8h group were 3.7 times those of the 200-mg ql2h dose group after a single dose and 5.3 times those of the 200-mg ql2h dose group on day 11. These values represents concentrations in plasma that are 7.5% lower and 32.5% higher, respectively, than what would be estimated by a dose-proportional model. Similarly, chronic dosing may produce a greater than expected measure of accumulation as clearance mechanisms become saturated. The extent of amifloxacin accumulation predicted by day 1 mean t112 values [accumulation = (1 - 1/2tlf')-l where T is the dosing interval] ranges from 16% (by using the day 1 value of the 200-mg ql2h group) to 62% (by using the steady-state value of the 800-mg q8h group). These values are in relatively close agreement with the observed extent of accumulation, as measured by increases in mean Cm. values, which ranged from 7 to 50%o (steady-state/day 1 values). The dose-proportional or nearly dose-proportional (day 11, q8h group) increases in AUC values and the close agreement between the observed and predicted amounts of accumulation indicate either that the saturable processes involved in the disposition of amifloxacin are a minor component of the overall clearance of amifloxacin or that they are only slightly saturated after oral administration over the dosage range of 200 mg q12h or 800 mg q8h. In either case, the dose-proportional model appears to allow adequate prediction of amifloxacin concentrations in plasma in the clinic for well-tolerated dose regimens. The renal excretion of amifloxacin accounts for at least part of its concentration-dependent pharmacokinetics, as mean values calculated for CLR decreased by 30%o when the dose was increased from 200 to 600 mg ql2h. Furthermore, amifloxacin appears to undergo active secretion in the kidney. Since amifloxacin is approximately 50%o bound to human plasma proteins (D. P. Benziger and A. Pratt, unpublished data), one would expect a CLR of 50 to 60 mlIh per kg if the renal excretion of amifloxacin were solely the result of glomerular filtration. However, mean values for CLR ranged from 66 to 128 ml/h per kg, indicating the net active secretion of amifloxacin. Evidence supporting the hypothesis of active renal secretion has also been demonstrated for ciprofloxacin and norfloxacin (9). Amifloxacin concentrations in urine were consistently higher than those in plasma over the range of doses studied. At these doses, amifloxacin concentrations in urine ranged from 43 to 204 pLg/ml up to 12 h postdose. These concentrations are several hundred-fold above those required to inhibit most urinary tract pathogens (8). Therefore, amifloxacin may have some utility in treating urinary tract infections. The overall tolerability of amifloxacin was good; adverse events were generally mild and did not interrupt dosing. Subjective complaints were notably referable to three body systems, namely, gastrointestinal (40.0%), nervous (55.0%), and skin (8.3%). Relative to the gastrointestinal system, nausea (15.0%), abdominal pain (8.3%), and dyspepsia (6.7%) occurred more frequently in amifloxacin-dosed than in placebo-dosed subjects. Although the incidence of headache was equivalent in the two groups, light-headedness (8.3%), insomnia (3.3%), and tinnitus (3.3%) were experienced by more subjects in the amifloxacin group. Finally, regarding cutaneous symptoms, 5.0% of amifloxacin-dosed subjects reported pruritus.
ANTIMICROB. AGENTS CHEMOTHER.
Qualitatively, the adverse event profile seen in these trials parallels those reported for other quinolones. The clinical experience with norfloxacin (3), ciprofloxacin (11), and ofloxacin (7) demonstrates that gastrointestinal, neuropsychiatric, and dermatologic reactions are common to all three drugs and appear to be phenomena related to the class of drug. Elevations of serum glutamic pyruvic transaminase, sometimes accompanied by serum glutamic oxalacetic transaminase elevations, were somewhat unexpected findings in amifloxacin-dosed subjects, since these findings are reported infrequently with other fluoroquinolones (3, 11). It should be noted that each of the three incidences of serum glutamic pyruvic transaminase elevations occurred in the pharmacokinetic study. In the subsequent safety and tolerability study, in which amifloxacin was given at 1,200 mg/day, there were no incidences of elevated enzymes. Enzyme elevations in our subjects were asymptomatic and self-limited, resolving completely after the discontinuation of amifloxacin. Of note is the fact that enzyme elevations were seen only in subjects who were dosed three times times daily with doses of .1,200 mg/day; no abnormalities of hepatic function were noted in individuals who received ql2h dosing or
Vol. 34, No. 6
Multiple-Dose Pharmacokinetics and Safety of Oral Amifloxacin in Healthy Volunteers JACK A. COOK,'* MICHAEL H. SILVERMAN,lt DONALD J. SCHELLING,' DAVID E. NIX,2 JEROME J. SCHENTAG,2 RICHARD R. BROWN,' AND RONALD M. STROSHANE'*
Sterling Research Group, Rensselaer, New York 12144,1 and Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospitals, and State University of New York, Buffalo, New York 140292 Received 6 September 1989/Accepted 12 March 1990
The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (ql2h) and .400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was admistered on day 11. Concentrations of amifoxacin i plasma and urine were measur on days 1, 5, and 11 by highperformance liquid chromatography. Steady-state amiloxac concentrations were reached by day S. Mean' standard deviation mamum observed amifoxacin concentrations in plasma were 2.52 1.12, 4.98 1.44, 5.40 ±'2.02, 4.59 2.17, 6.53 . 2.44, and 8.01 3.00 ,ug/nl after the initial dose and 2.30 0.98, 5.41 0.74, 8.05 1.68, 6.87 2.81, 9.53 0.50, and 11.9 1.92 ,.L/ml on day 11 of'the study for the 200-, 400-, and 600-mg ql2h and 400-, 600-, and m800-g q8h regimens, respectively. Am was rapidly absorbed, as evidenced by. the mean time to the mimum observed amidloxacin concentration of 0.98 h. Mean values for the terminal amilloxac half-life in plasma ranged from 3.58 to 5.78 h. Mean amllloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 jig/ml for the 200-, 400-, and 600-mg ql2h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the'urine as amifloxaci was 53.9%. Amlfioxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically sig nt adverse reactions, including pruritus and t n ase elevations, occurred only at doses of 1,200 mg/day or above. Clincal and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections. were
Amifloxacin (Win 49375) is a fluorinated quinolone-carboxylic acid antibacterial agent with activity against a broad range of gram-negative organisms. The MICs for 90% of isolates of representative urinary tract pathogens are 0.125 ,ig/ml for Escherichia coli, 0.5 ,ug/ml for Klebsiella pneumoniae, 1.0 ,ug/ml for Proteus vulgaris, 0.5 ,ug/ml for Citrobacterfreundii, 2.0 jig/mi for Pseudomonas aeruginosa, and 0.5 ,ug/ml for Serratia marcescens (8). Previous studies in laboratory animals have shown that renal excretion is a major component of amifloxacin elimination, with high concentrations in urine being achieved after both oral and intravenous dosing (6). Taken together, these properties suggest that amifloxacin has potential in the treatment of infections of the human urinary tract. A number of fluoroquinolones have been characterized with respect to pharmacokinetics in humans, and they generally demonstrate consistent and predictable behavior (9). This report documents the human pharmacokinetics of amifloxacin following multiple oral administrations to 36 healthy male volunteers in a double-blind, placebo-controlled trial. Tolerability is also reported for these 36 subjects, as well as for 24 subjects who received amifloxacin in a separate tnral.
MATERIALS AND METHODS Subjects. Both study protocols received the approval of the Institutional Review Board (Millard Fillmore Hospitals, Buffalo, N.Y., or Harris Laboratories Inc., Lincoln, Nebr.), and all subjects gave written informed consent. A total of 48 healthy male subjects (age, 18 to.46 years; weight, 62.3 to 102.3 kg) were enrolled in the pharmacokinetic study. Volunteers were evaluated for general good health by history, physical examination, and laboratory screening. Subjects were excluded from the study if they had a history or presence of 'any significant disease state, hypersensitivity to a quinolone agent, or history of substance abuse; were not within 15% of ideal body weight (height and weight tables, Metropolitan Life Insurance Co., New York, N.Y., 1983); or smoked more than one pack of cigarettes per day. Subjects did not receive prescription or proprietary medication during a period of at least 3 days prior to test drug administration through the course of the study. Volunteers were housed in the study unit from approximately 36 h prior to the first administration of drug until approximately 36 h following the last administration of drug. Study design. The pharmacokinetic study was a doubleblind, placebo-controlled trial in which amifloxacin was orally administered in one of six dose regimens: 200, 400, or 600 mg every 12 h (ql2h) and 400, 600, or 800 mg every 8 h (q8h). Six subjects in each group received active drug and two subjects received a placebo formulation. Amifloxacin was administered orally as 200-mg capsules. Placebo formulations were identical in appearance to active drug formulations. Each regimen lasted for 10 days, with one additional dose being administered the morning of day 11. No subject
Corresponding author. t Present address: Sandoz Research Institute, East Hanover, NJ
*
07936. *
Present address: Harris Laboratories Inc., Lincoln, NE 68501.
974
VOL. 34, 1990
PHARMACOKINETICS AND SAFETY OF ORAL AMIFLOXACIN
was allowed to participate in more than one dosage group. No food was allowed after midnight on the night prior to the initial drug administration. Subjects fasted for a period of 4 h following first-dose administration on days 1, 5, and 11, after which a meal was provided. Subjects were placed on a standardized balanced diet, and except as specified above, meals were served no closer than 2 h prior to or 1 h after medication administration. Each dose was administered with 250 ml of water. Additionally, 250 ml of water was taken by each volunteer 1 h prior to the first dose on days 1, 5, and 11. Water was allowed ad libitum 1 h after drug administration. Tolerability. Tolerability data are presented for the 48 subjects dosed in the pharmacokinetic study. Also included in the tolerability analysis are 30 normal male volunteers (age, 19 to 51 years; weight, 60.9 to 88.6 kg) dosed in a study of virtually identical design. A total of 12 subjects received amifloxacin at 600 mg ql2h, 12 subjects received amifloxacin at 400 mg q8h, and 6 subjects received placebo. All subjects were under close, continuous observation in the study unit throughout the dosing periods. Evidence of drug-related intolerance was sought and assessed through spontaneous subject reporting, questioning by medical personnel, and physical examinations. Subjects were also monitored during and after dosing with hemograms, clinical chemistries, complete urinalyses, and electrocardiograms. Pre- and postdose 24-h creatinine clearances were performed. All adverse events were recorded and evaluated by an investigator in a blinded fashion. Sample collection. Blood samples (10 ml) for determination of amifloxacin concentrations in plasma were collected in tubes containing potassium oxalate anticoagulant at time zero (predose); at 15, 30, and 45 min; and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10 (ql2h regimen only), and 12 (ql2h regimen only) h postdose on days 1, 5, and 11. Additionally, blood samples were drawn just prior to the first and second doses on days 3 and 7 and at 10, 12, 16, 18, and 24 h postdose on day 11. The plasma was separated by centrifugation and stored frozen at approximately 20°C until subsequent analysis. Urine samples were collected from all subjects on days 1, 5, and 11 at time zero (predose) and over 0 to 2, 2 to 4, 4 to 6, 6 to 8 (q8h regimen only), 6 to 12 (ql2h regimen only), 8 to 24 (q8h regimen only, day 11), and 12 to 24 (ql2h regimen only, day 11) h postdose. Urine samples for analysis were kept refrigerated during these periods. At the end of each collection period, the volume and pH were measured and recorded. Duplicate 10-ml portions were frozen at approximately 20°C until subsequent analysis. Analytical methods. Plasma and urine samples were analyzed for amifloxacin by a validated column-switching highperformance liquid chromatography method with UV detection (B. P. Crawmer, J. A. Cook, and R. R. Brown, submitted for publication). Briefly, plasma or urine samples were spiked with internal standard, diluted 1:1 with 0.5 M sodium citrate buffer (pH 2.5), and directly injected onto a cation-exchange precolumn. Following a 2.0-min wash of the precolumn with water at a flow rate of 1.1 ml/min, the effluent from the precolumn was directed to the analytical column by a column-switching device. Quality-control pools (100 ml) were prepared in control human plasma or urine at nominal concentrations of 0.80 and 20.0 ,ug/ml, respectively, and stored frozen with study samples until analysis. Four quality-control samples were included in each analytical run. Study samples, quality-control samples, and calibration curve standards were injected according to a computergenerated randomized sequence. In general, all of the sam-
975
ples for a given subject were included in the same analytical run.
During the validation procedure, the precisions (the overall standard deviations of the percent differences from nominal values for the validation samples) of the plasma and urine methods were estimated to be 2.1 and 2.1%, respectively. The accuracies (the overall range of mean percent differences from nominal values for the validation samples) of the methods were within a range of 0.17 to 1.5% and -2.9 to 0.99%o for plasma and urine, respectively. Recovery of both amifloxacin and the internal standard from plasma and urine was quantitative. Linear detector responses were observed for the calibration curve standards in the range of 0.10 to 5.0 ,ug/ml for plasma and 0.50 to 100 ,ug/ml for urine. The minimum quantifiable levels were 0.10 and 0.50 p,g/ml for plasma and urine, respectively. Freezing of samples for approximately 1 week did not have any appreciable influence on assay values. Pharmacokinetic calculations. Noncompartmental parameters were calculated by standard methods (4). The apparent first-order terminal elimination rate constant (kei) was calculated by linear regression of the natural logarithm of the amifloxacin concentrations in plasma as a function of time, beginning 2 h postdose (semilogarithmic plots of individual amifloxacin concentration in plasma profiles indicated that this was after the apparent absorption and distribution phases in each case). The half-life (t112) was calculated from the equation tl2 = ln (2)/kei. Concentrations of amifloxacin which were less than the minimum quantifiable level of the assay were not included in the linear regression analysis. The areas under the amifloxacin-concentration-in-plasmaversus-time curves (AUCs) were calculated by the trapezoidal rule method over the dosing interval for days 1, 5, and 11. The AUC from day 1 was extrapolated to infinity with the addition of the term Ck,,Ik, where C,, is the concentration of the last sample with a quantifiable concentration and where kei was calculated by using data from day 1. The following pharmacokinetic parameters were also calculated: Varea/F = dose/(AUC x ke, x wt); CL/F = dose/(AUC x wt); and CLR AJ(AUC x wt), where V.,,./F is that volume which, when multiplied by the amifloxacin concentration in plasma during the terminal log-linear phase, was equal to the amount of drug in the body unadjusted for the extent of bioavailability (F); CL/F is the total plasma clearance unadjusted for F; CLR is the renal clearance; and Ae is the amount of amifloxacin excreted renally over the dosing interval. The parameters described above were normalized for the subject's
weight (wt). The maximum observed amifloxacin concentration in plasma (Cm.), its corresponding time of occurrence (Tma), as well as the minimum observed concentration in plasma (Cmin) were obtained by inspection of the observed concentration in plasma data. The amount of drug excreted in urine was obtained by multiplying the urine volume by the amifloxacin concentration in urine. The percentage of the dose excreted in the urine as amifloxacin was obtained by dividing the amount of amifloxacin excreted by the administered dose (X 100%). Statistical treatment. The model-independent parameters Cma, Tmax t1/2, Cminj, AUC, and the amount of unchanged amifloxacin excreted in the urine were examined. The analyses of these variables were generally the same, although the approach varied according to the distributional characteris-
tics of each variable. All variables were analyzed with a repeated-measures analysis of variance. The proportionality of relevant response variables to dose was examined, first,
976
ANTIMICROB. AGENTS CHEMOTHER.
COOK ET AL. 100
z 0
z LUL u z
10
0
U2.
0
*.M U..
z
U.IL
.M.-
ui
amifloxacin concentrations. Concentrations of drug in plasma for one subject on day 1 were inexplicably low (200 mg q12h; C.ax = 0.29 jig/ml; AUC = 2.1 pug- h/ml). Therefore, day 1 data for that individual were omitted from the analysis. All other pharmacokinetic data were analyzed for the 36 amifloxacin recipients. Plots of mean amifloxacin concentration in plasma versus time on day 11 are presented in Fig. 1. The noncompartmental pharmacokinetic parameters are presented in Tables 1 (after a single dose) and 2 (after multiple doses). The results of the estimation of k,, yielded coefficients of determination greater than 0.9 in all cases, and visual examination of the residual values revealed no apparent heteroscedasticity. The overall mean + standard deviation Cmin values for data from days 3 through 11 were 0.41 + 0.15, 0.90 + 0.40, 2.03 0.70, 2.67 0.89, 4.26 + 1.27, and 5.19 + 1.84 ,ug/ml for the 200-, 400-, and 600-mg ql2h groups and the 400-, 600-, and 800-mg q8h groups, respectively. In general, mean AUCs (Fig. 2, day 11 data), Cmax, Cmin, and amount of amifloxacin excreted in the urine were adequately described by a dose-proportional model. Exceptions included greater than dose-proportional increases in AUC on day 11 for the ql2h groups and the morning and evening Cmin values on days 3, 5, and 11 for the ql2h groups. While these increases were only slightly greater than dose proportional, they were statistically significant. Additionally, there were no statistically significant differences in these parameters between days 5 and 11, indicating that steady state was reached by day 5. Small but statistically significant differences were generally found between day 1 values and steady-state values of AUC and t1/2. Because the magnitudes of these differences were small and considerable overlap occurred in the range of the values between day 1 and steady state, these findings are of minimal clinical importance. Amifloxacin was rapidly absorbed, as evidenced by the overall mean Tma. of 0.98 0.56 h. As would be expected with concentration-related changes in t1/2 and greater than dose-proportional increases in AUC (day 11, q8h group), mean values for CL/F, CLR and Varea/F were also concentration related. CL values tended to decrease with increasing dose, and mean values ranged from 150 to 294 and 66 to 128 ml/h per kg for CL/F and CLR, respectively. Mean values for Varea/F ranged from 1.89 to 1.16 liters/kg. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 ,ug/ml in the 200-, 400-, and 600-mg ql2h and 400-, 600-, and 800-mg q8h groups, respectively. In general, steady-state amifloxacin concentrations in urine were consistently above 100 ,ug/ml for doses greater than 200 mg ql2h and were consistently above 40 ,ug/ml for the ±
Us
0.1
h 0
2
4
6
8 10 12 14 16 18 20 22 24
TIME IN HOURS
FIG. 1. Steady-state amifloxacin concentrations in plasma (from day 11 of the study). Symbols: *, 200 mg ql2h; *, 400 mg ql2h; 0, 600 mg ql2h; A, 400 mg q8h; +, 600 mg q8h; *, 800 mg q8h.
by testing for curvature in a quadratic model by using dose or logarithmic dose and then by testing for slopes or intercepts equal to zero in the straight-line model. Assuming proportionality, the proportionality constants were estimated for each day and compared across days. Satterthwaite approximate F statistics (12) were computed for tests to account for the imbalance of the data and the two error terms in these models, one within subjects and one between subjects. For variables for which proportionality was not of interest (Tmax and t4/2), interactions and main effects of day and dose were examined.
RESULTS The performance characteristics of the analytical method were considered to be acceptable. The mean + standard deviations for the quality-control samples were 0.80 0.02 and 19.9 + 0.3 ,ug/ml for plasma (nominal concentration, 0.80 p,g/ml) and urine (nominal concentration, 20.0 p,g/ml), respectively. The coefficient of determination from each calibration curve was 0.998 or greater. The coefficients of variation for the mean values of the calibration curve slopes were 5% for the plasma analyses and 6% for the urine analyses. Selected plasma samples from each subject who received placebo were analyzed, and none contained quantifiable
±
TABLE 1. Single-dose pharmacokinetic parameters for amifloxacina Dose group
Cmax (p.g/ml)
± ± ± ± ± ±
Tm. (h)
t1m2 (h)
(Lg.AUC h/ml)
Varea/F
(liter/kg)
CL/F
(ml/h per kg)
CLR (ml/h per kg)
101 ± 29 261 ± 42 1.35 ± 0.27 0.29 99 ± 14 233 ± 35 1.32 ± 0.11 0.49 80 ± 14 258 ± 96 1.78 ± 0.67 0.72 ± 0.53 66 ± 15 254 ± 160 1.74 ± 1.46 0.79 69 ± 16 ± 0.56 209 ± 51 1.34 ± 0.23 1.37 79 ± 33 276 ± 110 ± 0.45 1.59 ± 0.64 0.65 a Values are means ± standard deviation and were calculated from six observations, except for the 200-mg ql2h group, for which there were five observations.
200 mg ql2h 400 mg ql2h 600 mg ql2h 400 mg q8h 600 mg q8h 800 mg q8h
2.52 4.98 5.40 4.59 6.53 8.01
1.12 1.44 2.02 2.17 2.44 3.00
0.85 0.88 1.13 0.% 1.08 1.20
± 0.13 ± 0.34 ± 0.95
11.0 22.3 33.5 23.8 38.8
±
± ± ± ± 41.0 ±
4.3 4.2 13.0 8.3 11.2 16.1
3.58 3.96 4.83 4.51 4.67 4.07
± ± ± ± ± ±
VOL. 34, 1990
PHARMACOKINETICS AND SAFETY OF ORAL AMIFLOXACIN
977
TABLE 2. Steady-state pharmacokinetic parameters for amifloxacin following 11 days of oral administrationa Dose group (no. of observations)
Cmax (~Lg/ml)
200 mg ql2h (6) 400 mg ql2h (6) 600 mg ql2h (6) 400 mg q8h (5) 600 mg q8h (4) 800 mg q8h (4)
2.30 5.41 8.05 6.87 9.53 11.87
± ± ± + ± ±
AUC (ug h/mi)
TM (h)
0.98 0.74 1.68 2.81 0.50 1.92
0.88 0.96 1.46 1.05 1.25 0.50
± 0.56 ± 0.56 ± 1.28
10.6 28.2 48.2 31.5 49.8 56.7
± 0.67 ± 0.50 ± 0.20
± ± ± ± ± ±
3.0 6.8 12.2 8.1 6.5 14.4
4/2 (h)
4.25 4.48 5.28 5.32 5.50 5.78
± 0.62 ± 0.81
± ± ± ±
Vae/F
CL/F
(liter/kg)
(ml/h per kg)
1.89 1.18 1.24 1.21 1.16 1.43
0.82 1.31 1.21 0.67
± 1.19
± ± ± ± ±
0.11 0.29 0.27 0.09 0.30
294 187 165 163 150 176
± ± ± ± ± ±
CLR (ml/h per kg)
126 36 35 47 25 59
128 122 87 88 81 73
± ± ± ± ± ±
13 18 22 11 12 12
Amifloxacin excreted (%)
48.0 65.8 54.6 56.0 55.0 43.4
± ± ± ± ± ±
13.1 7.1 15.8 8.0 10.2 9.5
a Values are means ± standard deviations.
200-mg ql2h group. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Sixty subjects who received amifloxacin and 18 subjects who received placebo were included in the tolerability analysis (Table 3). In general, the incidence of adverse events was equally distributed between the two studies. Adverse events were generally mild and self-limited. Dosing was discontinued in one subject who experienced pruritus while taking amifloxacin at 800 mg q8h and in three subjects (one each receiving 400, 600, and 800 mg of amifloxacin q8h) who experienced asymptomatic and transitory elevations of serum glutamic pyruvic transaminase to five to eight times the upper limit of normal. Asymptomatic crystalluria, which was thought to be drug related, was seen in three subjects who received amifloxacin; one subject received the drug at 600 mg ql2h and two subjects received it at 800 mg q8h. The crystalluria was not associated with other changes in the urinary sediment or with alterations in serum creatinine or 24-h creatinine clearance. DISCUSSION The reductions in mean CL/F and CLR values with increasing dose as well as the reductions in mean CL/F values and the increase in mean AUC and tl,2 values between day 1 and steady state suggest concentration-dependent pharma-
cokinetics for amifloxacin. Conversely, statistical analysis did not find consistent deviations from the dose-proportional model for Cma, Cmi., or AUC. However, this was most likely due to the fact that the deviations from the doseproportional model were relatively small in comparison with the intersubject variabilities. Therefore, a study design in which each subject received doses of amifloxacin at a number of different dosage levels would be more likely to detect deviations from the dose-proportional model. Concentration-dependent pharmacokinetics have been previously reported for other quinolones. Mean values for t1/2 of norfloxacin increased with increasing dose (1). Mean values for t112 of ciprofloxacin have been shown to be dose dependent (5) and to increase from day 1 values with repeated administration (2). There is also an increase in the t1/2 of fleroxacin during repeated administration (10). In general, the values for amifloxacin pharmacokinetic parameters were comparable to those reported for other quinolone antibacterial agents (9). While dose-related increases in mean t1/2 values and dose-related decreases in mean CL/F and CLR values indicate that at least some component of amifloxacin's elimination is concentration dependent, the resultant deviations appear to be of minor clinical importance over the dosage TABLE 3. Subjects experiencing adverse events
90 _
Adverse event
80 _
70 U
60
z E
5o
**
*2**
9
Gastrointestinal Nausea Flatulence Abdominal pain Dyspepsia
4 (22.2) 1 (5.6) 3 (16.7)
Other
(40.0) (15.0) (11.7) (8.3) (6.7) 4 (6.7)
Nervous
33 (55.0)
6 (33.3) 5 (27.8) 1 (5.6)
24 9 7 5 4
*
FJ-o
/
No. (%) of subjects Amifloxacin Placebo (n = 18)' (n = 60)'
*
40 a
*
30
20 10
0 0
1
2
3
4
5
6
7
8
9
10 11 12
DOSE/WEIGHT (mg/kg) FIG. 2. Steady-state amifloxacin AUCs versus dosage (from day 11 of the study). Symbols: *, ql2h; *, q8h.
Headache Lightheadedness Insomnia Tinnitus Other
17 5 2 2 11
(28.3) (8.3) (3.3) (3.3) (18.3)
Skin Pruritus
5 (8.3)
Other
3 (5.0)
1 (5.6)
3 (5.0)
Elevated serum glutamic pyruvic transaminase
3 (5.0)
Other
7 (11.7)
an indicates the total number of subjects studied.
1 (5.6)
978
COOK ET AL.
range studied. For example, if increases in AUCs were proportional to dose, the mean AUC of the 800-mg q8h dose group would be four times that of the 200-mg ql2h dose group. In the present study the respective day 1 and day 11 mean values of the 800-mg q8h group were 3.7 times those of the 200-mg ql2h dose group after a single dose and 5.3 times those of the 200-mg ql2h dose group on day 11. These values represents concentrations in plasma that are 7.5% lower and 32.5% higher, respectively, than what would be estimated by a dose-proportional model. Similarly, chronic dosing may produce a greater than expected measure of accumulation as clearance mechanisms become saturated. The extent of amifloxacin accumulation predicted by day 1 mean t112 values [accumulation = (1 - 1/2tlf')-l where T is the dosing interval] ranges from 16% (by using the day 1 value of the 200-mg ql2h group) to 62% (by using the steady-state value of the 800-mg q8h group). These values are in relatively close agreement with the observed extent of accumulation, as measured by increases in mean Cm. values, which ranged from 7 to 50%o (steady-state/day 1 values). The dose-proportional or nearly dose-proportional (day 11, q8h group) increases in AUC values and the close agreement between the observed and predicted amounts of accumulation indicate either that the saturable processes involved in the disposition of amifloxacin are a minor component of the overall clearance of amifloxacin or that they are only slightly saturated after oral administration over the dosage range of 200 mg q12h or 800 mg q8h. In either case, the dose-proportional model appears to allow adequate prediction of amifloxacin concentrations in plasma in the clinic for well-tolerated dose regimens. The renal excretion of amifloxacin accounts for at least part of its concentration-dependent pharmacokinetics, as mean values calculated for CLR decreased by 30%o when the dose was increased from 200 to 600 mg ql2h. Furthermore, amifloxacin appears to undergo active secretion in the kidney. Since amifloxacin is approximately 50%o bound to human plasma proteins (D. P. Benziger and A. Pratt, unpublished data), one would expect a CLR of 50 to 60 mlIh per kg if the renal excretion of amifloxacin were solely the result of glomerular filtration. However, mean values for CLR ranged from 66 to 128 ml/h per kg, indicating the net active secretion of amifloxacin. Evidence supporting the hypothesis of active renal secretion has also been demonstrated for ciprofloxacin and norfloxacin (9). Amifloxacin concentrations in urine were consistently higher than those in plasma over the range of doses studied. At these doses, amifloxacin concentrations in urine ranged from 43 to 204 pLg/ml up to 12 h postdose. These concentrations are several hundred-fold above those required to inhibit most urinary tract pathogens (8). Therefore, amifloxacin may have some utility in treating urinary tract infections. The overall tolerability of amifloxacin was good; adverse events were generally mild and did not interrupt dosing. Subjective complaints were notably referable to three body systems, namely, gastrointestinal (40.0%), nervous (55.0%), and skin (8.3%). Relative to the gastrointestinal system, nausea (15.0%), abdominal pain (8.3%), and dyspepsia (6.7%) occurred more frequently in amifloxacin-dosed than in placebo-dosed subjects. Although the incidence of headache was equivalent in the two groups, light-headedness (8.3%), insomnia (3.3%), and tinnitus (3.3%) were experienced by more subjects in the amifloxacin group. Finally, regarding cutaneous symptoms, 5.0% of amifloxacin-dosed subjects reported pruritus.
ANTIMICROB. AGENTS CHEMOTHER.
Qualitatively, the adverse event profile seen in these trials parallels those reported for other quinolones. The clinical experience with norfloxacin (3), ciprofloxacin (11), and ofloxacin (7) demonstrates that gastrointestinal, neuropsychiatric, and dermatologic reactions are common to all three drugs and appear to be phenomena related to the class of drug. Elevations of serum glutamic pyruvic transaminase, sometimes accompanied by serum glutamic oxalacetic transaminase elevations, were somewhat unexpected findings in amifloxacin-dosed subjects, since these findings are reported infrequently with other fluoroquinolones (3, 11). It should be noted that each of the three incidences of serum glutamic pyruvic transaminase elevations occurred in the pharmacokinetic study. In the subsequent safety and tolerability study, in which amifloxacin was given at 1,200 mg/day, there were no incidences of elevated enzymes. Enzyme elevations in our subjects were asymptomatic and self-limited, resolving completely after the discontinuation of amifloxacin. Of note is the fact that enzyme elevations were seen only in subjects who were dosed three times times daily with doses of .1,200 mg/day; no abnormalities of hepatic function were noted in individuals who received ql2h dosing or
