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`ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1986, p. 206-210
`0066-4804/86/080206-05$02.00/0
`Copyright © 1986, American Society for Microbiology
`
`Vol. 30, No. 2
`
`Pharmacokinetics and Dose Proportionality of Ketoconazole in
`Normal Volunteers
`YIH-CHAIN HUANG,'* JOHN L. COLAIZZI,' ROBERT H. BIERMAN,2 R. WOESTENBORGHS,3
`AND J. HEYKANTS3
`College of Pharmacyl and Hurtado Health Center,2 Rutgers-The State University of New Jersey, Piscataway, New Jersey
`08854, and Department ofDrug Metabolism and Pharmacokinetics, Janssen Pharmaceutica, B-2340 Beerse, Belgium3
`Received 16 December 1985/Accepted 13 May 1986
`
`Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and
`bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied
`in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for
`up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of
`ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 ,g/ml
`attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution,
`respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h,
`respectively. The mean oral clearance of the solution dose was 209 (+82.9 [standard deviation]) ml/min, and
`the mean apparent volume of distribution was 88.31 (±68.72) liters. The relative bioavailabilities for the tablet
`and suspension were 81.2 (±33.5) and 89.0 (±23.1)%, respectively, of that of the solution. The data indicated
`the bioequivalence of the tablet to the suspension and of the suspension to the solution. Dose proportionality of
`ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg.
`Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the
`maximum concentration, and the area under the concentration-time curve were observed. However, the
`increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed
`to decay at a lower rate after 400- and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6
`and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent
`kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which
`become saturated at higher doses.
`
`Ketoconazole is a synthetic imidazole-dioxolane deriva-
`tive with a broad spectrum of antifungal activity. Although
`its spectrum of activity is similar to those of other imidazole
`derivatives, e.g., miconazole, econazole, and clotrimazole,
`ketoconazole has the advantage of being effective when
`administered orally. Its therapeutic efficacy was reviewed
`recently (7). After a 200-mg tablet dose to healthy subjects,
`peak ketoconazole concentrations in plasma (Cmax) of 3 to
`4.5 ,ug/ml were reached within 1 to 2 h and the therapeutic
`activity was maintained for several hours after administra-
`tion of the drug (8). The recommended dosage for ketocon-
`azole is 200 mg daily. In serious infections, higher doses may
`be required. Ketoconazole is available as a 200-mg tablet
`(10).
`The objectives of this study were (i) to determine the
`bioavailabilities of the ketoconazole tablet and an experi-
`mental suspension formulation relative to a reference aque-
`ous solution and (ii) to evaluate in healthy, male volunteers
`the dose proportionality of ketoconazole in doses ranging
`from 200 to 800 mg.
`
`MATERIALS AMD METHODS
`Subjects. Our subjects were 24 healthy, nonsmoking, male
`college students ranging in age from 18 to 25 years (mean, 20
`years), in body weight from 61.2 to 95.3 kg (mean, 76.4 kg),
`and in height from 167.6 to 188 cm (mean, 180 cm). The
`subjects were judged to be in good health based on thorough
`
`* Corresponding author.
`
`prestudy physical examinations and the results from com-
`plete hematology, urinalysis, and biochemical tests. The
`purposes and protocol of the study were explained to them,
`and they all gave informed consent. On the evening before
`the study day, the subjects reported to the hospital. Vital
`signs were monitored at the time of check-in, and the
`subjects were provided with a standard dinner. The subjects
`fasted overnight. The drug was administered around 8:00
`a.m. on the next day, and a standard lunch was provided
`about 3 to 4 h later. The subjects were allowed to drink water
`freely except for a period from 2 h preadministration to 1 h
`postadministration.
`The study protocol was approved by the Review Board for
`the Protection of Human Subjects in Research at Rutgers-
`The State University of New Jersey. The investigation was
`performed at the Hurtado Rutgers Student Health Center,
`New Brunswick, N.J.
`Study design and protocol. The investigation was done in
`two phases. Phase 1 was a comparative bioavailability study
`(200-mg single dose) involving 24 subjects, and phase 2 was
`a dose proportionality study (200-, 400-, and 800-mg solution
`doses) involving the 12 subjects who had completed phase 1.
`Phase 1: relative bioavailability study. The 24 subjects were
`randomly assigned to two groups. Subject numbers were
`sequentially assigned at the time of initial drug administra-
`tion. Ketoconazole (200 mg) in the form of a tablet, suspen-
`sion (20 mg/ml), or aqueous solution (20 mg/ml) was admin-
`istered with 200 ml of water to each subject according to a
`randomized crossover schedule. A washout period of 1
`week separated each treatment. Blood samples (10 ml)
`were collected from an antecubital vein into heparinized
`
`206
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`VOL. 30, 1986
`
`PHARMACOKINETICS OF KETOCONAZOLE
`
`207
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`
`at 24 h after a 200-mg dose, the precision of the assay was
`greatly improved (with a 9.8% coefficient of variation).
`Pharmacokinetic and statistical analyses. The individual Cp
`versus time (t) data were first plotted on semilogarithmic
`papers. The individual elimination rate constant (kel) was
`calculated by linear regression analysis by using the datum
`points on the terminal log linear portion of the Cp-t plot.
`Half-life (t4/2) values. were calculated by the following equa-
`tion: t1/2 = 0.693/kel. The area under the Cp-t curve from time
`zero to infinity (AUC) was calculated by the linear trapezoi-
`dal method up to t (AUC,) and by extrapolation to infinity,
`i.e., AUC = AUC, + CIkel, in which Cpis the Cp observed
`at t, the last sampling time with a measurable Cp.
`The relative bioavailability for the tablet or suspension at
`the 200-mg level in each subject was calculated from the
`ratio of the AUC value after administration of the tablet or
`suspension to the AUC value of the solution dose.
`The apparent oral clearance (CL/F) and the apparent
`volume of distribution (V/F) were calculated from the data
`obtained after administration of the 200-mg solution dose by
`using the following equations: CL/F = dose /AUC and V/F
`(CL/F)/ke1, in which F is the fraction of the dose absorbed
`and entered into systemic circulation.
`Statistical analyses of variance were performed on the
`following parameters obtained after each treatment: (i) Cp at
`each sampling time, (ii) Cmax, (iii) the time of peak concen-
`tration in plasma (Tmax), and (iv) the AUC.
`To evaluate the dose proportionality of ketoconazole in
`doses ranging from 200 to 800 mg, linear regression analyses
`of the pharmacokinetic parameters (Cmax, Tmax, AUC, and
`CL/F) and the dose were performed.
`All of the data are expressed as the mean ± the standard
`deviation.
`
`RESULTS
`Phase 1: relative bioavailability study. Twenty-three sub-
`jects completed all three treatments required for phase 1.
`One subject withdrew from the study after one treatment for
`a reason not related to the drug tested; his data were
`therefore not included in the analysis. The absorption of
`ketoconazole after oral administration was rapid. Ketocon-
`azole was detectable in the plasma at 0.5 h after the
`administration of the tested formulations. The mean Cmaxs
`were reached as follows: 4.22 pLg/ml (200-mg tablet at 1.74 h),
`5.04 ,ug/ml (200-mg suspension at 1.17 h), and 6.17 pLg/ml
`(200-mg solution at 1.02 h). The mean ketoconazole Cp-t
`profiles are shown in Fig. 1 and Table 1. Of the 69 Cp-t plots,
`33 showed multiexponential characteristics after a 200-mg
`dose. After the Cm.x was reached, the plasma decline was
`biphasic, with a mean tl2 of 1.7 (±0.6), 1.5 (±0.4), and 1.6
`(±0.5) h during the first 8 to 12 h and a mean t1/2 of 7.9
`
`la
`
`0.1.
`
`cm
`aL.
`
`z0
`
`P:
`
`z z0
`
`: C
`
`O)
`
`0L
`
`12
`TIME (hours)
`FIG. 1. Mean ketoconazole Cp-t profiles for 23 volunteers after
`the administration of 200-mg doses. 0, Tablet; Z, suspension; A,
`solution.
`
`VACUTAINER tubes (Becton Dickinson Vacutainer Sys-
`tems, Rutherford, N.J.) through a butterfly catheter or by
`venipuncture before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36,
`and 48 h after the administration of ketoconazole. The
`plasma was separated immediately by centrifugation and
`stored frozen until analyzed.
`Phase 2: dose proportionality study. Twelve subjects who
`had completed phase 1 were given two additional ketocon-
`azole solution doses (400 mg/20 ml and 800 mg/40 ml) in a
`randomized crossover sequence. The blood sampling sched-
`ule was identical to that of phase 1. The subjects were
`monitored for any possible adverse effects related to keto-
`conazole administration.
`Drug assay. The plasma samples were analyzed for keto-
`conazole by a sensitive high-performance liquid chromato-
`graphic method. The method involved an extraction proce-
`dure with a heptane-isoamyl alcohol (95/5) mixture. The
`separations were achieved by using a reverse-phase column
`and a mobile phase of water-acetonitrile-diethylamine
`(40/60/0.05). Both ketoconazole and terconazole (internal
`standard) were detected at a wavelength of 254 nm (13).
`When 2 ml of the plasma sample was extracted and recon-
`stituted in 75 ,u of the elution solution and a 40-,ul aliquot
`was injected, the lower limit of detection was 2 ng/ml (with
`a 30% coefficient of variation). At a plasma concentration
`(Cp) of 10 ng/ml, which corresponds to the mean Cp observed
`
`TABLE 1. Mean Cp for 23 volunteers after administration of 200-mg doses of ketoconazole
`Cp (,ug/ml) (±SD) after h:
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`3.0
`
`4.0
`
`6.0
`
`8.0
`
`12.0
`
`24.0
`
`Keto-
`conazole
`formula-
`tion
`Tablet
`
`Suspen-
`sion
`Solution
`
`1.71
`2.61
`3.10
`3.26
`2.70
`1.72
`0.67
`0.34
`0.11
`(±2.55)a
`(±1.70)
`(±2.12)b
`(±2.06)b
`(±1.96)
`(+1.10)
`(+0.51)
`(+0.34)
`(+0.20)
`2.69
`4.66
`4.19
`3.91
`2.46
`1.53
`0.53
`0.25
`0.05
`(+2.19)
`(+1.61)
`(±1.34)
`(+1.60)
`(+1.10)
`(±0.89)
`(+0.41)
`(+0.26)
`(+0.08)
`4.27
`5.16
`4.73
`3.88
`2.67
`1.70
`0.66
`0.34
`0.07
`(±1.36)
`(±0.89)
`(±2.96)
`(+1.88)
`(+1.46)
`(±0.98)
`(+0.47)
`(+0.29)
`(+0.09)
`a Statistically significantly different (P < 0.05) from the solution only, based on analysis of variance and Tukey's multiple range test.
`b Statistically significantly different (P < 0.05) from the suspension and the solution, based on analysis of variance and Tukey's multiple range test.
`
`0.01
`(±0.01)
`0.01
`(±0.01)
`0.01
`(+0.005)
`
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`

`

`208
`
`HUANG ET AL.
`
`ANTIMICROB. AGENTS CHEMOTHER.
`
`TABLE 2. Summary of pharmacokinetic and bioavailability data after administration of 200-mg doses of ketoconazole to 23 volunteersa
`C.G.. (pLg/ml)
`T.. (h)
`formulation
`Tablet
`1.7 (±0.9)d
`4.22 (±2.47)C
`Suspension
`1.2 (±0.5)
`5.04 (±1.58)
`Solution
`1.0 (±0.4)
`6.17 (±2.29)
`a All values are given as the mean ± the standard deviation.
`b Bioavailability relative to the solution, based on the AUC ratio.
`c Statistically significantly different (P < 0.05) from the solution only, based on analysis of variance and Tukey's multiple range test.
`d Statistically significantly different (P < 0.05) from the suspension and the solution, based on analysis of variance and Tukey's multiple range test.
`
`AUC (jig
`h/ml)
`14.74 (±8.48)c
`15.84 (±7.05)
`18.16 (±6.66)
`
`Relativeiyb
`0.81 (±0.34)C
`0.89 (±0.23)
`
`/2 (h)
`7.9 (±3.8)
`7.9 (±4.3)
`7.5 (±2.3)
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`(±3.8), 7.9 (±4.3), and 7.5 (±2.3) h thereafter after the
`administration of the tablet, suspension, and solution, re-
`spectively (Fig. 1).
`Statistical analysis showed that, although there were dif-
`ferences in the early hours (0.5 to 1.5 h) after treatment,
`there were no statistically significant differences (P > 0.05)
`in the ketoconazole Cps observed from 2 to 24 h. The
`suspension and solution formulations exhibited higher rates
`of absorption than that of the tablet, and the mean ketocon-
`azole Cmax attained after administration of the solution was
`significantly higher than that attained after administration of
`the tablet (P < 0.05) (Table 2). However, there was no
`statistically significant difference in the Cmax between the
`suspension and solution formulations. The mean AUCs after
`each treatment are also shown in Table 2. The mean relative
`bioavailabilities for the tablet and suspension were 81.0
`(±34.0)% and 89.0 (±23.0)% of that of the solution dose,
`respectively; the difference between the tablet and solution
`formulations was statistically significant (P < 0.05), whereas
`the difference between the suspension and solution formu-
`lations was not.
`The mean CL/F, calculated by using the AUC from the
`200-mg solution dose, was 209.9 (±82.9) ml/min, and the
`mean V/F was 88.31 (±68.72) liters, suggesting an extensive
`distribution of the drug in the body. Since no intravenous
`injection was made, the absolute bioavailability (F) cannot
`be evaluated.
`Phase 2: dose proportionality study. All 12 subjects com-
`pleted phase 2. As in the case of the 200-mg dose, ketocon-
`azole was rapidly absorbed after 400- and 800-mg doses.
`However, the Tmaxs were slightly longer after the 400- and
`800-mg doses. The mean Cmaxs of 5.38 (±1.67), 11.77
`(±2.35), and 21.83 (±2.84) ,ug/ml were reached at 0.92
`(±0.29), 1.08 (±0.15), and 2.04 (±0.66) h after oral admin-
`istration of single solution doses of 200, 400, and 800 mg,
`respectively (Table 3). Except for the Cp at 0.5 h after the
`400- and 800-mg doses, the Cps of ketoconazole observed at
`all sampling times were significantly different from each
`other after the 200-, 400-, and 800-mg doses. The ketocona-
`
`zole Cp seemed to decay at lower rates after the 400- and
`800-mg doses than after the 200-mg dose (Fig. 2). For
`example, the mean ketoconazole Cp at 12 h after the 200-mg
`dose was 0.044 ,ug/ml as compared with 0.51 and 4.78 ,ug/ml
`at the same time after the 400- and 800-mg doses, respec-
`tively. Although only 8 (of 12) subjects had detectable
`ketoconazole Cps at 24 h after the 200-mg dose (mean, 0.01
`,ug/ml), all 12 subjects had detectable ketoconazole Cp at 24
`h after the 400- and 800-mg doses (means, 0.03 and 0.21
`,ug/ml, respectively).
`The correlations of Cmax, Tmax, and AUC with the doses
`are shown in Fig. 3. There was a linear increase in the values
`of these three pharmacokinetic parameters over the dose
`range studied. Although the AUC increased linearly with the
`dose, it should be noted that the increase in the AUC was
`more than proportional. For example, there was a 3.9-fold
`(2.7- to 4.9-fold) increase in the AUC for a 2-fold increase in
`dose (from 200 to 400 mg), and a 4-fold increase in dose
`(from 200 to 800 mg) resulted in a 11.8-fold (6.8- to 15.5-fold)
`increase in the AUC.
`The mean CL/F decreased as the dose increased. It
`decreased from 244.9 (+96.0) to 123.6 (+31.4) to 80.8
`(+17.8) ml/min as the dose increased from 200 to 400 to 800
`mg, respectively; the differences in the CL/F between the
`200- and 800-mg doses and between the 200- and 400-mg
`doses were statistically significant (Tukey's test).
`
`DISCUSSION
`Single-dose pharmacokinetics and bioavailability of keto-
`conazole in healthy males after overnight fasting were stud-
`ied by using a sensitive reverse-phase high-performance
`liquid chromatography method. Our study compared the
`bioavailability of a ketoconazole tablet and an experimental
`suspension formulation to a reference aqueous solution in a
`relatively large sample population (24 healthy volunteers) for
`a longer duration (up to 48 h) after each treatment. The
`results obtained indicated that ketoconazole from both the
`tablet and suspension formulations was rapidly absorbed on
`
`TABLE 3. Mean Cps for 12 volunteers after administration of 200-, 400-, and 800-mg solution doses of ketoconazole
`C, (,ug/ml) (±SD) after h:
`
`0-5
`
`1.0
`
`1.5
`
`2.0
`
`3.0
`
`4.0
`
`6.0
`
`8.0
`
`12.0
`
`24.0
`
`1.48
`(±1.04)
`6.75
`(±1.57)
`16.38
`(±2.71)
`
`0.55
`(±0.51)
`3.33
`(±1.22)
`11.95
`(±2.09)
`
`0.27
`(±0.26)
`2.00
`(±1.16)
`8.71
`(±1.69)
`
`0.04
`(±0.04)
`0.51
`(±0.55)
`4.78
`(±2.03)
`
`0.01
`(+0.04)a
`0.03
`(±0.02)
`0.21
`(±0.22)
`
`36.0
`
`NDb
`
`48.0
`
`ND
`
`0.01
`(±0.01)
`0.06
`(±0.08)
`
`0.008
`(±0.004)
`0.03
`(±0.03)
`
`Keto-
`conazole
`dose
`(mg)
`200
`
`400
`
`800
`
`2.3;
`3.52
`4.15
`5.04
`4.02
`(±1.15)
`(±1.16)
`(±1.37)
`(±1.72)
`(+2.13)
`7.97
`9.60
`7.53
`10.46
`11.46
`(±1.30)
`(±1.41)
`(±1.87)
`(±2.88)
`(±2.65)
`20.88
`18.45
`16.84
`7.53
`20.03
`(±3.93)
`(±2.94)
`(±3.84)
`(±2.69)
`(±5.78)
`a Mean value for eight volunteers with detectable ketoconazole Cp.
`b ND, Not detectable.
`
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`

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`VOL. 30, 1986
`
`PHARMACOKINETICS OF KETOCONAZOLE
`
`209
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`
`differences in the absorption and disposition kinetics of
`ketoconazole among the subjects. The greater intersubject
`variation observed after administration of the tablet formu-
`lation (Table 2) may have been due to the fact that the
`dissolution, and therefore the absorption, of ketoconazole
`requires a low gastric pH (pH <3) (2) and the fasting gastric
`pH values vary among subjects (1).
`The doses used in our dose proportionality study covered
`a wider range than in an earlier study (5). The data obtained
`from 12 subjects who received three ascending solution
`doses (200, 400, and 800 mg) suggest that dose-dependent
`kinetics were operative under our study conditions. This
`conclusion was reached based on the following results. (i)
`Dose-normalized Cp-t plots were not superimposable. (ii)
`The increase in the AUC was more than proportional to the
`increase in the dose. (iii) The semilogarithmic plots of Cps
`curved inward at higher dose levels (Fig. 2) (12). These
`dose-dependent phenomena may be attributed to the first-
`pass metabolism in the liver or in the gastrointestinal tract or
`both, which became saturated at higher doses (see the AUC
`versus dose plot in Fig. 3). A similar observation was made
`earlier in 12 subjects after the administration of 100-, 200-,
`and 400-mg tablets (5). After absorption, ketoconazole un-
`dergoes extensive hepatic metabolism (5). Ketoconazole is
`widely distributed and has very high plasma protein binding
`(99% bound at a drug concentration of 1 ,ug/ml in an in vitro
`study with human plasma [7]). Whether there is a capacity-
`limited hepatic metabolism or a change in distribution pat-
`tern of ketoconazole due to a change in tissue or plasma
`protein binding or both at higher doses remains to be
`investigated. Better absorption, nonlinear elimination, satu-
`rable first-pass metabolism, or a change in the V of ketocon-
`azole have also been suggested as explanations for the
`
`Y = 0.437 + 0.002 X
`R = 0.756
`
`Y = 266.3 - 0.25 X
`R = 0.896
`
`3
`
`2
`
`1
`
`3601
`
`3001
`
`c 24C
`.E
`E 18(
`U-
`0E
`-j 120
`
`0-
`
`6C
`
`Y = 0.359 + 0.027 X
`R = 0.948
`
`30
`
`25
`
`201
`
`15
`
`10
`
`5
`
`E 0 x
`
`160
`
`. 120
`-S
`
`80
`
`0=
`
`)
`
`0
`
`200
`
`800
`
`400
`400
`DOSE (mg)
`DOSE (mg)
`FIG. 3. Correlation of ketoconazole dose with Cmax, Tmax, AUC,
`and CL/F. Bars, + Standard deviation.
`
`0
`
`200
`
`800
`
`100'
`
`10'
`
`I-
`
`0.1
`
`E z0
`
`zU
`
`l0 O
`
`0 0 -
`
`I
`
`LI.
`
`0.01
`
`20
`30
`TIME (hours)
`FIG. 2. Mean ketoconazole Cp-t profiles for 12 volunteers after
`the administration of 200-, 400-, and 800-mg doses. A, 200 mg; *,
`400 mg; *, 800 mg.
`
`an empty stomach. CmaxS were reached within 2 h after
`administration. The Cmax (4.22 p.g/ml) found after the admin-
`istration of the tablet was comparable to those of other
`studies performed either under fasting conditions (4.1 ,ug/ml;
`9), with meals (3.6 ,ug/ml; 4), or before meals (3.2 jig/ml; 5).
`The relative bioavailability of the tablet formulation found in
`the present study (81%) was slightly higher than that re-
`ported earlier (75%) in a similar study of 12 male volunteers
`(5). In the earlier study, ketoconazole was given to the
`subjects immediately before meals.
`In the present study, the disposition of ketoconazole
`appeared to follow a multiexponential pattern, and distribu-
`tion equilibrium was not reached until about 8 to 12 h
`postadministration. In most of the earlier studies, a single-
`compartment model was adapted to describe the disposition
`of ketoconazole in humans (3). This may have been so
`mainly because less sensitive analytical methods or shorter
`blood sampling schedules or both were used in the earlier
`studies. In this study, we monitored the Cp of ketoconazole
`for up to 48 h with a more sensitive high-performance liquid
`chromatography assay (detection limit, 2 ng/ml) and found a
`biphasic decline in the Cp-t profiles, with the values of the
`initial and terminal t1/2 very similar to that reported in an
`earlier study (5), which used a sensitive gas chromatography
`method to determine the ketoconazole Cp.
`The mean area under the curve from 0 to 12 h was found
`to contribute more than 95% (tablet, 95.6 [±6.2]%; suspen-
`sion, 98.0 [±2.51%) of the total AUC; this suggests that the
`accumulation of ketoconazole in the body after multiple
`administration (a regimen of once or twice a day) might be
`minimal if the superposition principle applies (6). In this
`regard, it is interesting that 1.5 to 3 h after the daily dose, the
`ketoconazole Cps were found to remain relatively stable, in
`the range of 3 to 5 ,g/ml, in 30 patients on a 200-mg/day
`regimen for 28 weeks (11). Antipyrine clearance also re-
`mained relatively constant in healthy subjects after a multi-
`ple-dose regimen of ketoconazole (3).
`There was wide intersubject variation in the Cp-t profiles
`observed after the administration of ketoconazole. A similar
`observation was reported earlier (4). This may reflect the
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`HUANG ET AL.
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`ANTIMICROB. AGENTS CHEMOTHER.
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`dose-dependent phenomena observed when doses increase
`from 100 to 400 mg (3).
`
`ACKNOWLEDGMENTS
`We thank W. Lorreyne for his help in the determination of the
`ketoconazole levels in plasma and Carolyn Rock for the preparation
`of the manuscript.
`
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`Corcept Ex. 2062, Page 5
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