Pharmacokinetics of Ketoconazole Administered Intravenously to Dogs and Orally as Tablet and Solution to Humans and Dogs

Pharmacokinetics of Ketoconazole Administered Intravenously to Dogs and Orally as Tablet and Solution to Humans and Dogs JAMES G. BAXTER*§,CORSTIAAN BRASS*, JEROME J. SCHENTAG*~, AND RICHARDL. SLAUGHTER*§' Received May 6,1985,from the Schools of 'Pharmacy and *Medicine, State University of New York at Buffalo, Amherst, NY 14260, and 5Clinical Accepted Pharmacokinetics Laboratories of the Buffalo General Hospital, Buffalo, NY 14203 and A Millard Fillmore Hospital, Buffalo, NY 14209. for publication February 10,1986. ~~~~

Abstract

~

~

0 The single-dose pharmacokinetics and bioavailability of

three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg PO of ketoconazole as tablet (Ktab) and solution (K-,) formulations. The dogs received 400 mg PO of Ktaband L,, and 376 mg iv of an intravenous dose (KJ. In humans the AUC value for ,,K (62.21 2 21.2 pg . h/mL; mean * SD) was significantly greater than for Ktab (50.0 ? 15.2 pg .h/mL; p <0.05).Peak serum concentrations (Cmax),time to peak serum concentrations (tmax), ti,2, and the terminal elimination rate constant (k,)did not differ between Klab and K-,. This suggests that the administration of Kso, may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected.The mean systemic clearance (CL) of K,, in dogs was 2.74 f 1.10 mL/min/kg, the volume of distribution at steady state (Vd,,) was 0.72 2 0.28 Ukg, and the half-life was 2.7 2 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of K,, was 0.50 ? 0.38,which did not differ statistically from that of K,, 0.56 2 0.23.The K,, showed less variability in AUC, ,, C and F values than did Ktab,and two dogs with low bioavailability with ,K,, (0.04 and 0.07)had substantially greater bioavailability with Kwl (F = 0.96and 0.57,respectively). Evaluation of K,, in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.

Fungal infections are a major source of morbidity and mortality in the neutropenic Autopsy studies have shown that 30-50% of patients with hematological malignancies have demonstrable invasive fungal infections. It is hypothesized that colonization and local infection of the oral cavity and GI tract are important precursors to disseminated infe~tion.~ Therefore, much interest has developed in chemoprophylaxis of fungal infections as a means of reducing morbidity and mortality in patients with neutropenia.4 Ketoconazole, an oral imidazole antifungal agent, is effective in the treatment of mucocutaneous fungal infections. Its mode of action is similar to those of other imidazole antifungal agents currently available ke., miconazole and clotrimazole), except that ketoconazole can be used in oral dosage form. Compared with other antifungal agents, it also has a broad spectrum of activity and has few unwanted side effects. For these reasons, ketoconazole is being investigated for prophylaxis against fungal infections in neutropenic patient~."~ Studies using oral tritiated ketoconazole administered to dogs (formulations not included) have shown that the drug is extensively metabolized to a number of inactive metabolites.8 Bioavailability was, however, limited. Over 80%of the administered radioactivity was recovered in the stool and 55% of the total administered radioactivity was recovered as unchanged parent drug. Less than 10% of administered radioactivity was recovered in the urine. Collected urine and bile samples had no apparent antifungal activity, which suggests that the unchanged drug in stool was present as a 0022-3549/86/05OO-0443$0 1 .0010 0 1986, American Pharmaceutical Association

result of incomplete absorption and not enterohepatic recycling. Furthermore, these data suggest that virtually all of the systemically available drug was metabolized to inactive compounds. Several reports demonstrate that ketoconazole exhibits low apparent oral bioavailability which results in low serum concentrations when it is administered with cimetidine or antacids.9J0 Furthermore, there is strong evidence that ketoconazole is poorly absorbed by neutropenic patients,11J2 and this may account for prophylactic failure.9." This study was undertaken to: (a) assess the absolute bioavailability of ketoconazole tablets and solution in the dog; (b) determine the systematic clearance of ketoconazole following intravenous administration in the dog; and (c) determine if the bioavailability of ketoconazole can be improved when administered as a solution in humans.

Experimental Section Human Studies-Five normal, healthy adult male volunteers participated in the study. The average age was 27.2 years (range: 2333 years) and the mean weight was 70.3 kg (range: 66-76 kg). All subjects were determined to be healthy by both physical examination and routine laboratory blood tests. All subjects gave their written informed consent. None were known to be allergic to any medication. In a randomized cross-over fashion, each subject received ketoconmole on two occasions. Subjects were in the fasting state on both days, with no oral intake for at least 8 h prior to and 4 h following administration of ketoconazole. Study days were separated by at least 7 d for each subject. Before drug administration, an indwelling catheter was placed in a forearm vein of each subject for blood sampling. Patency of the catheter was maintained by periodic flushing with small injections of heparin in normal saline (10unitdml). On each study day, subjects received 400 mg PO of ketoconazole base as two commercially available tablets (Janssen Pharmaceutica, lot 81307/198)or as a solution prepared from two tablets. The tablets were administered with 240 mL of orange juice. The test solution was prepared by dissolving two ketoconazole tablets in 10 mL of 0.1 M HC1 and mixing the subsequent solution in 240 mL of orange juice before ingestion. Blood samples for determination of ketoconazole serum concentrations were drawn at the following times: immediately prior to drug administration (time O), and 0.5, 1.0, 1.5, 2.0,4.0, 6.0,8.0, and 12.0 h following drug administration. Blood samples were drawn into plain collecting tubes and immediately centrifuged. The serum was removed and stored a t -70°C until analyzed. Animal S t u d i e s S i x normal, healthy adult male mongrel dogs were used. In a randomized, balanced, cross-over design, each dog received: 400 mg iv of ketoconazole hydrochloride (equivalent to 376 mg of ketoconazole (Kiv);400 mg PO of ketoconazole as two tablets of 200 mg each (Kta,,);and 400 mg PO of ketoconazole as an acidified solution (K-,).Ketoconazole was administered to each dog in the fasting state, with no food intake for at least 8 h prior to drug administration. The dogs were placed in a restraining sling for the initial 30 min of each study day to allow catheter placement and drug administration. No sedative or anesthetizing drugs were given. Study days for each dog for the three dosage forms were separated by at least 6 d. Journal of Pharmaceutical Sciences / 443 Vol. 75, No. 5, May 1986

The intravenous dose, Kiv, was prepared by dissolving 400 mg of ketoconazole hydrochloride (Janasen Pharmaceutica, Belgium) in 30 mL of 0.1 M HCl and 20 mL of distilled de-ionized water. This solution was sterilized by passing it through a 0.22-pn filter into 60 mL of normal saline. The final volume was 100 mL with a pH of -2.8. Intravenous ketoconazole infusions were administered over -20 min in a foreleg vein opposite the site of blood sampling. The tablet dosage, Khb, was administered aa two tablets (Janseen Pharmaceutical of 200 mg each with 30 mL of distilled de-ionized water. The solution formulation, KmI, was prepared by crushing and dissolving two of the ketoconazole tablets (Janseen Pharmaceutica, lot 813071198 for KI.b and Ll) in 10 mL of 0.1 M HCI. This was diluted to a total volume of 30 mL with distilled de-ionized water and administered with a syringe (final pH -4.8). This was followed by administration of an additional 30 mL of distilled de-ionized water. While none of the preparations were analyzed for ketoconazole content, care was taken to ensure proper and complete administration of the three dosage forms. Blood samples were obtained through an indwelling catheter placed in a peripheral foreleg vein, which was maintained patent with a constant slow infusion of normal saline or a small injection of heparin flush (10 units per mL). Blood samples for all dosage forms were drawn into plain collecting tubes at the following times: immediately prior to drug administration (time 0), immediately &r completing the intravenous infusion, and 0.25,0.50,0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, and 12.00 h following drug administration. Collected blood samples were immediately centrifuged and the serum was separated and stored at -70°C until analyzed. Analytical ProcedureeKetoconazole serum concentrations were analyzed using a specific high-performance liquid chromatographic procedure developed and performed by the Department of Drug Metabolism and Pharmacokinetics at the Janssen Pharmaceutica Co. Laboratories, Beerse, Belgium, under the supervision of Robert Woestenborgh.13 Samples spiked with terconazole (internal standard) were adjusted to pH 9.0 with 0.01 M NaOH and extracted with heptan+isoamyl alcohol. The samples were evaporated and reconstituted with mobile phase (acetonitri1e:water:diethylaminein a 70:30:0.05 ratio) and injected onto a reversed-phase column. Absorbance of ketoconazole and terconazole was monitored at 205 nm. The CV of the procedure was 4.61%. The lower limit of aensitivity of the assay procedure was 0.010 pg/mL. Data AnalysigPharmacokinetic parameters were assessed by noncompartmental analysis.14J6 The area under the serum concentration (C)versus time (t) curve was determined by LaGrange interpolation in combination with linear and log trapezoidal methods, from time 0 to infinity (AUC). The area under the first moment curve (AUMC) was determined by the same methods applied to the (C)(t)versus t curve. Systemic clearance (CLJof Ki, was calculated as DoselAUC, and the mean residence time of Ki, (MRT), corrected for infusion time, was determined by AUMCIAUC. The steady-state volume of distribution of Ki, was calculated as CL. x MRT. The observed terminal elimination rate constant (kJ was determined by linear regression, and the elimination half-life (tin) was determined at O.693/kel.The absolute bioavailability (F)of oral ketoconazole formulations was determined by the relationship:

Table C-Comparlaon of Pharmacoklnetlc Parametera of

Subject BJ DC LT

SR BC Mean SD

Weight, kg

76 66 68 75 66 70 4.4

24 25 23 31 33 27 4

Kub 0.29 0.43 0.22

0.30 0.22 0.29.

0.077

Vol. 75, No. 5, May 1986

Human StudieP-All five subjects completed the protocol. Table I shows the calculated pharmacokineticparameters for each subject. Figure 1 shows the mean (f SEMI serum concentration versus time profile of Ktaband K,1 for the five human volunteers. All five subjecta had greater AUC values with Kmlthan with Ktab. The mean AUC for Ktabwas 50.0 & 15.2 pg h/mL and the mean AUC for was 62.2 & 21.2 pg * h/mL (p < 0.05; Fig. 2). The average percentage increase in the AUC value was 23.6 5 10.7. Four of the five subjects showed a >20% increase in the AUC value following K,l. The mean,,C for Ktab was 9.31 5 2.5 pg/mL compared with 10.5 f 2.0 pglmL for K8,,l. There were no significant differ-

-

10.0

10.0

8.0 6.0

6 J

4.0

ri

5

2.0

E

5

I: €I

5

Y

OA 0.4

az

0.1

1

1

1

2

1

3

1

4

5

1

6

1

1

7

8

V

1

1

l

O

1

1

1

1

1

1

1

Time, h

Flgure 1-Mean serum concentration versus time curves for Kub (--0--) and L,+ () administered to ht38lthy human volunteers (n = 5). Error bars indicete SEM for each measured concentration versus time point.

G-,

-

truI*h

MmL

&

L

Kml

L

0.30 0.33 0.22 0.33 0.16 0.27. 0.067

9.3 7.3 9.0 7.1 14.0 9.3. 2.5

8.6 8.5 12 9.6 13.3 10.5. 2.0

2.0 1.5 4.0 4.0 1.5 2.6. 1.2

'Comparison between Kub and L,was not significant. bp < 0.05.

444 /Journal of Pharmaceutical Sciences

Results

kb and I(.,,, In Healthy Volunteer8

kiph-'

Age,

years

Peak serum concentrationa C (), and the associated time to ob) determined from served peak serum concentrations ( k were inspection of the C veraua t profiles. Statistical analysis was done by two-way analysis of variance (ANOVA) or the paired t test. Results are e x p r e d aa the mean k SD unleee otherwise specified. Differences were considered to be significant when p < 0.05.

AUC, p.g hlmL L l

1.5 1.5 2.0 1 .o 1.5 1.5' 0.32

Kub 44.4 32.8 62.6 37.6 72.8 50.0b

15.2

L

l

47.6 39.7 77.2 50.4 96.3 62.2 21.2

ences between Ktab and Kml in tmm, t1/2,and k,l values. Animal Studies-All six dogs received the three ketoconazole formulations. Pharmacokinetic parameters of Ki, for the six individual dogs are shown in Table 11. The mean CL,was 2.74 f 1.10mL/min/kg, and Vd,,averaged 0.72 2 0.28Lkg. The elimination rate constant, k,l, was determined to be 0.33 ? 0.15 h-'. The mean residence time averaged 4.8 f 2.1 h with a range from 3.0to 7.3h. There was considerable interdog variability in the AUC of Kiv, with a mean of 147 68.4 pg * h/mL and a range of 67.8to 265 pg * h/mL. A comparison of Ktab and Ksol parameters is shown in Table 111. There was no statistical difference in AUC values (when corrected for dose) of KiV,Ktab, and K-1 (ANOVA).The F value of Ktab (0.50 f 0.38 was not significantly different from that of Keel (0.56 2 0.23).Where differences do exist in the data, the large degree of variability decreased the usefulness of the ANOVA in detecting a difference. Peak serum concentrations showed considerable inter-dog variability, especially for Ktab (mean: 17.4 f 16.7 pg/mL; range: 1.10-45.6pg/mL). Peak serum concentrations of Ktab did not differ significantly from the, ,C of Gl(mean: 15.4 f 9.4 pg/mL; range: 8.8-34.0 pg/mL). The tmm values were also similar for the two oral preparations (K,b 2.7 2 1.1;K,I 2.4 f 0.9h). Dogs #4 and 6 (Fig. 3 for dog #6)had extremely small AUC values and low, ,C values for Ktab, resulting in low F values. These parameters were all substantially increased when ketoconazole was administered in solution form (Fig. 3).

*

Discussion

k

b

Intravenous Administration of Ketoconazole-In this investigation, considerable variability was observed in most pharmacokinetic parameters following intravenous administration of ketoconazole (Table 11). The CL, of ketoconazole averaged 2.74 f 1.10 mL/min/kg and ranged from 1.49 to 4.51 d m i n / k g . Assuming complete hepatic elimination and an average liver plasma flow in dogs of 20-40 mllminkg, these data suggest that hepatic extraction (Elof ketoconazole from plasma in dogs is -0.05-0.10.16J7

KaOI

Figure 2-Comparison of AUC for a 400 mg po dose of ketmnazole administered to healthy human volunteers. Ketooonezole was administered as two tablets of 200 mg each (L) or as a solution prepared from two tablets (LJ. Key: (a) the mean AUC of GIwas significanrly ., (p < 0.05 by paired t test). different from meah AUC of ,,K

Table ICPharmacokinetic Parameters of KI, In Normal Mongrel Dog8

Weight, 1 2 3 4 5 6

20.1 17.3 15.9 16.8 20.5 19.1 18.3 1.9

Mean SD

AUC,

MRT, h

kg 2.02 2.23 1.49 2.67 4.51 3.49 2.74 1.10

0.60 0.40 0.64 1.17 0.93 0.58 0.72 0.28

0.29 0.48 0.25 0.12 0.30 0.51 0.33 0.15

2.4 1.4 2.7 5.7 2.3 1.4 2.7 1.6

pg * hlmL

4.9 3.0 7.2 7.3 3.4 2.7 4.8 2.1

155 162 265 140 67.8 93.8 147 68.4

Table IlCComparlson of the Pharmacoklnetlc Paramaerr of Gband LlIn Normal Mongrel Dogs' kit h-'

Dog Ktab

1 2 3 4

5 6

Mean SD

0.24 0.31 0.12 0.17 0.25 1.15 0.37 0.39

C,,, l

Ktab

0.24 0.30 0.25 0.12 0.19 0.67 0.30 0.19

21.7 22.9 45.6 1.1 11.6 1.5 17.4 16.7

L

ham h

NlmL Kl, 10.5 13.6 34.0 14.7 8.8 10.6 15.4 9.4

AUC,

&ab

&I

2.0 1.8 4.0 2.5 4.15 1.5 2.7 1.1

2.5 4.0 1.3 2.5 2.0 2.0 2.4 0.9

*

h/mL

Fb

Kw,

L l

Klab

L l

176 118 452 4.4 68.5

65.7 101 192 143 56.8 43.4 100.0 57.5

0.89 0.44 0.78 0.04 0.77 0.07 0.50 0.38

0.34 0.37 0.66 0.96 0.49 0.57 0.57 0.23

3.0 137.0 168.0

Klab, k,,,and K,, are not statistically differentusing two-way ANOVA. G a b and Llare not statistically different using a paired t test. 'Adjusted for (400 mg) PO versus (376 mg) iv dose of ketoconazole. Journal of Pharmaceutical Sciences / 445 Vol. 75, No. 5, May 1986

mo 1

i

JI

\

.\

\

\,

0.1

bioavailability of ketoconazole administered in tablet form with considerable intersubject variability. The mean AUC of ketoconazole tablets in humans was increased 24% by administration of the drug as a solution (range: 7.242%). Ginsberg and co-workers have reported an approximate doubling of the ketoconazole C,, and AUC with a commercially manufactured ketoconazole suspension (no longer available) when compared with the use of crushed tablets administered to children.21These findings suggest that the administration of ketoconazole as a solution may be a reasonable alternative to dosage increases in patients with suspected or documented limited bioavailability with ketoconazole tablets. Such administration may be useful in preventing therapeutic or prophylactic failures that may occur as a result of poor absorption with the use of tablets. There is a limited amount of published data on orally administered ketoconazole in dogs.* In that study, an oral dose of 10 mglkg administered to dogs gave a peak concentration of 8.9 MImL and a tmaxoccurring at 1-2 h (range and number of animals not given). In the current investigation, doses ranging from 19.5 to 25.2 mglkg yielded peak concentrations of 17.4 * 16.7pg/mL for Ktab and 15.4 2 9.4 pg/mL for Kao1. Thus, the results of these two studies appear to be quite consistent. The pharmacokinetic parameters obtained for Ktab and K,, from the dogs in the present study are shown in Table 111. Unlike the results in humans, there was no significant difference in the mean F or AUC values for the two oral formulations. Likewise, no difference was observed in AUC values between the three dosage formulations (KiV, Ktab, and K,I). However, analysis of individual results indicate that there was limited bioavailability in every dog with a t least one of the oral formulations and in some dogs with both formulations. In four dogs (dogs #1,2,3,and 51,F values were higher following administration of Ktab than after Kaol dosage (0.72 * 0.19 versus 0.47 5 0.15). In contrast, dogs #4 and 6 showed low F values after administration of Ktabbut exhibited substantially increased F values after Ksol administration. The reason for the varied response among the dogs studied is not clear. It is known that dissolution and absorption of ketoconazole is dependent on gastric pH.9.10 This parameter was not evaluated in the present study. The dogs, however, were healthy and were studied under constant conditions (including time and method of administration, degree of fasting, and degree of physical activity). It is, therefore, unlikely that changes in gastric acid pH could be responsible for the observed variability in measured F after administraton of Kao1and Ktab. This investigation has shown that the bioavailability of ketoconazole tablets is incomplete in healthy humans and dogs. It also suggests that in patients with documented or suspected poor bioavailability of ketoconazole tablets, an oral solution of ketoconazole may enhance absorption and increase the serum concentrations obtained.

.A. 1

1

3

4

I

6

7

8

9

1011

I21314

Time, h

Flgure 3-Concentration versus time profile for Dog #6 after receiving K, (-0-), K, (- -x- -;F = 0.57),and Ktllb (- - -0-- -; F = 0.07). The

12-h sample for GIwas lost during procesSing. The 4-h sample for K(not shown) was 0.083 FgmL and the 6-, 8-. and 12-h samples were below the detection limits of the assay.

Several factors need to be considered when evaluating this estimate of E. First, the dogs received a high dose of ketoconazole as compared with the humans (20.7-+ 1.9mg/kg versus 5.7 2 0.16 mglkg). Therefore, systemic clearance estimates may be underestimated because of nonlinear disposition of ketoconazole, as reported in mice and humans.SJSJ9 Second, whole blood concentration profiles were not determined. In vitro studies in human blood have shown that 15% of labeled ketoconazole blood concentrations are associated with red blood cells.20 Extrapolating these data to the dog increases the estimated value of E to -0.11-0.15. Finally, gut wall metabolism and protein binding studies are needed to confirm this estimate. Despite these limitations in the estimate of extraction, the estimated systemic clearance values suggest that significant first-pass metabolism probably does not occur after oral ketoconazole administration to dogs. Similar assumptions cannot be made in humans until data from intravenous administration are available. The t112 of Ki, ranged from 1.37 to 5.69 h, and was not significantly different from the t1/2 observed with the oral formulations. However, as mentioned previously, dose-dependent elimination of ketoconazole has been r e p ~ r t e d . ~ J ~ J @ Since we did not investigate the disposition of different dose sizes, we cannot comment on this aspect of ketoconazole 1. elimination in dogs. Previous reports have suggested that in humans, an initial til2 of. -2-4 h is seen, followed by a 2. terminal tlI2 of 6-9 h. This longer t112 is usually noted a t 3. concentrations that are near or below the lower limits of sensitivity of most available assay procedures for ketocona4. zole. The tlI2observed in dogs, however, is similar to what we 5. found in humans and is consistent with previous reports 6. evaluating the pharmacokinetics of ketoconazole in humans. Tablet Versus Solution Administration of Ketocona7. zole--There is strong evidence for incomplete and highly variable bioavailability of oral ketoconazole in human pa8. tients and normal volunteers."' Our data also show low 446 /Journal of Pharmaceutical Sciences Vol. 75, No. 5, May 1986

References and Notes DeGregorio, M. W.;Lee, W. M. F.; Linker, C. A.; Jacobs, R. A.; and Ries, C. A. Am. J . Med. 1976 73, 543-548. Meunier-Carpentier, F.; Kiehn, 'r.E.; Armstrong, D. Am. J . Med. 1981, 71, 363-370. DeGregorio, M.W.;Lee, M. W. F.; Ries, C. A. Cancer 1982, 50, 2180-2784. Meunier-Ca entier, F. Am. J . Med. 1984, 76, 652-656. Hann, I. M.;L'gorringham,R.; Keaney, M.; Noone, P.; Fox, J.; et al. Lancet 1982, I , 826-839. Meunier-Carpentier, F.; Cruciani, M.; Klastersky, J. Eur. J . Cancer Clin. Oncol. 1983, 19, 43-48. Jones, P. G.; KauEman, C. A.; McAuliffe, L. S.; Liepman, M. K.; B e r p a n , A. G. Arch. Znt. Med. 1984,144, 549-551. Levine, H.B. "Ketoconazole in the Management of Fungal Disease"; ADIS: Sydney. 1982, PP 67-73.

9. van der Meer, J. W. M.; Keuning, J. J.; Schiej ong H. W.;

Heykants, J.; van Cutsem, J.; Brugmans, J. fAnhmicrob. Chemother. 1980, 6, 552-554. 10. Brass, C.; Galgiani, J. N.; Blaschke, T. F.; Defelice, R.; O’Reilly, R. A.; Stevens, D. A. Antimicrob. Agents Chemother. 1982,21, 151-158. 11. Hann, I. M.; Prentice, H. G.; Keane

M.; Corrin ham, R.; Blacklock, H. A.; et al. J. Antimicrob. CXhmother. 19tf2,10,489-496. 12. Maksymiuk, A. W.; Levine, H. W.; Bodey, G. P. Antimicrob. A ents Chemother. 1982,21, 43-46. 13. Afbn, K. B. J. Chromatogr. Bwmed. Ap 1. 1980,221,337344. 14. “Ap lied Pharmacokinetics”; Evans, E.; Schentag, J. J.; Jusfo, W. J., Eds.; Applied Therapeutics Inc.: San Fkancisco, CA, 1980; i p 639-680.. . 15. “Pharmaco inetics”; Gibaldi, M.; Perrier, D., Eds.; Decker: New York, 1982; p 409-17. 16. Greenway, C! V.;Stark, R. D. Ph swl.Rev. 1971,51,23-65. 17. Wilkinson, G. R.; Shand, D. G. C z n . Pharmucol. Ther. 1975,18,

6.

371390, 18. Daneschmend, T. K.; Warnock, D. W.; Turner, A.; Roberts, C. J. C. J. Antimicrob. Chemother. 1981,8, 299304.

19. Danschmend, T. K.; Warnock, D. W.; Ene, M. D.; Johnson, E.M.; Parker, G.; et al. J. Antimicmb. Chemother. 1983, 12,

185-188. 20. Ginsbur

C. M.; McCracken, G. M.; Olsen, K. Antimicrob. dgen’s &emother. 1983,23,787-789. 21. eel, R. C.; Brogden, R. N.; Carmine, A.; Morley, P. A.; Speight,

T. M.; Avery, G. S. Drugs 1982,23, 1-36.

Acknowledgments The authors thank Mr. Ronald Shank and Mrs. Barbara Johnson for their technical assistance, Miss Cheryl Wild for aesistance in prepann the manuscript, Dr. George Corcoran for his critical review of the manuscript, and Dr. R. Woestenborghs of Janssen Pharmaceutica for the gift of ketoconazole h drochloride and ketoconazole tablets and for providing expert d L C analysis of serum samples.

Journal of Pharmaceutical Sciences / 447 Vol. 75, No. 5, May 1986