Increased Gastric pH and the Bioavailability of Fluconazole and Ketoconazole Robert A. Blum, PharmD; David T. D'Andrea; Becky M. Florentino, BA; John H. Wilton, PhD; Donald M. Hilligoss, PharmD; Mark J. Gardner, PhD; Eugenia B. Henry, PhD; Harvey Goldstein, MD; and Jerome J. Schentag, PharmD Annals of Internal Medicine. 1991;114:755-757. Two orally active antifungal agents are currently available, ketoconazole and fluconazole. However, the absorption of ketoconazole depends on gastric pH for tablet disintegration and dissolution (1, 2). Reduced serum concentrations of ketoconazole have been reported in patients with achlorhydria and in patients receiving concomitant treatment with antacids or cimetidine (1-3). Our study was done to determine the effects of cimetidine-induced increases in gastric pH on the relative bioavailability of fluconazole and ketoconazole. Methods Twenty-four healthy male volunteers, 19 to 43 years of age, gave written informed consent to participate in the study. The study protocol was approved by the Millard Fillmore Hospital Institutional Review Board. All subjects were judged to be healthy on the basis of a From Millard Fillmore Hospital and State University of New York at Buffalo, Buffalo, New York; and Pfizer, Inc., Groton, Connecticut. For current author addresses, see end of text. 1 May 1991 • Annals of Internal Medicine • Volume 114 • Number 9
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normal physical examination and normal clinical laboratory studies. In a randomized, four-way crossover study, subjects received oral fluconazole, 200 mg, and oral ketoconazole, 400 mg, (Nizoril [Lot 98G126], Janssen Pharmaceutica, Piscataway, New Jersey) with and without cimetidine (Tagamet [Lot 4018T22], Smith Kline & French, Philadelphia, Pennsylvania). During each study period, volunteers had continuous gastric pH monitoring using a tethered Heidelberg radiotelemetry capsule (Heidelberg International Corporation, Norcross, Georgia). Two 300-mg intravenous doses of cimetidine were given before oral antifungal dosing, one dose 60 minutes before and the other 30 minutes before antifungal dosing. Three 100-mg supplemental bolus doses were administered if gastric pH fell below 6.0 during the first 5 hours of the study. Fluconazole and ketoconazole were administered 1 hour after the initial cimetidine infusion. Serial serum samples were collected over a 24-hour period after ketoconazole administration and over a 144-hour period after fluconazole administration. Fluconazole and ketoconazole concentrations in serum were determined by a reverse-phase, high-pressure liquid chromatography assay method. The dynamic range was 0.1 /xg/mL to 20.0 /xg/mL for fluconazole and 0.15 /x,g/mL to 12.0 iJLg/mL for ketoconazole. Individual serum concentration-time profiles were analyzed, and the maximum concentration, the time of peak concentration, and the area under the concentration-time curve were determined for each subject. The area under the serum concentration-time curve was estimated using a linear trapezoidal rule. Comparisons of fluconazole and ketoconazole regarding normalized area under the curve and maximum concentration values were done using a two-way, repeatedmeasures analysis of variance to test for sequence, treatment, and period effects. The 95% CIs on the two comparisons done for each antifungal with and without cimetidine were calculated using the Bonferroni Mest
technique. Ketoconazole and fluconazole treatments were compared using the Student f-test technique. Results The mean serum concentrations of fluconazole and ketoconazole were plotted over time under conditions of normal and elevated gastric pH (Figure 1). The disposition of fluconazole was unaffected by the cimetidine-induced elevations in gastric pH. However, the disposition of ketoconazole was markedly affected by concomitant cimetidine administration. The mean (± SD) area-under-the-curve values were reduced 95%, from 34.1 ± 12.0 /xg • h/mL without cimetidine to 1.7 ± 1.5 xtg • h/mL with cimetidine. The mean maximum concentration values were significantly reduced to a similar extent, from 7.01 ± 2.21 /xg/mL to 0.48 ± 0.37 /xg/mL. The mean time to maximum concentration estimates were unaffected by concomitant cimetidine administration. For fluconazole, mean maximum concentration values with and without concomitant cimetidine therapy were 3.43 ± 0.57 /xg/mL and 3.43 ± 0.67 /xg/ mL, respectively. The corresponding mean time to maximum concentration estimates were 4.0 hours and 4.7 hours. The mean area-under-the-curve value was 161.5 ± 29.4 /xg • h/mL for fluconazole without cimetidine and 161.7 ± 26.4 /xg • h/mL for fluconazole with cimetidine. For normalized maximum concentration and area-under-the-curve values, there was a statistically significant difference between the ketoconazole with cimetidine treatment group and the ketoconazole without cimetidine treatment group (P < 0.001 for both variables), but no statistically significant difference between the fluconazole with cimetidine treatment group and the fluconazole without cimetidine treatment group (P > 0.2). The 95% CIs for the comparison between ketoconazole with and without cimetidine and fluconazole with and without cimetidine indicated a statistically significant difference (P < 0.05).
Figure 1. Mean serum concentration plotted against time for fluconazole and ketoconazole under conditions of normal (A) and elevated gastric pH ( • ) . 756
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Discussion When normal volunteers were given intravenous cimetidine to titrate pH to 6.0 and above, there was a dramatic effect on the disposition of ketoconazole. Reductions in mean area under the curve and maximum concentration values of more than 90% are consistent with the findings of other investigators (4). The disposition of fluconazole was unaffected by the concomitant administration of cimetidine. Cimetidine and antacids can dramatically reduce ketoconazole absorption (2). A single 400-mg dose of cimetidine administered 2 hours before a 200-mg dose of ketoconazole reduced the maximum concentration from 4.5 jiig/mL to 1.3 ju,g/mL. When this same dose of cimetidine was given with ketoconazole, 200 mg in acidified solution, the maximum concentration increased to 5.6 /xg/mL. When cimetidine and ketoconazole, 200 mg in 0.5 sodium bicarbonate, were administered, the maximum concentration decreased to less than 0.5 ftg/mL. These findings suggest that ketoconazole has dissolution rate-limited absorption and that alkaline pH of the duodenum appears not to affect absorption across the small-bowel mucosa. Our study was the first to compare the effects of rigorously controlled gastric pH on the oral bioavailability of fluconazole. The pKa of fluconazole (1.5) differs from that of ketoconazole (6.5 and 2.9) (5). The relatively low pKa of fluconazole allows for dissolution at a higher pH. These findings have important implications
for oral antifungal therapy in patients who are elderly or have AIDS. Increasing numbers of such patients have been shown to have relative states of gastric hypochlorhydria. Grant Support: In part by a research grant from Pfizer Central Research, Pfizer, Inc., Groton, Connecticut. Requests for Reprints: Robert A. Blum, PharmD, The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209-1194. Current Author Addresses: Drs. Blum, Wilton, and Schentag, Mr. D'Andrea, and Ms. Florentino: The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209-1194. Drs. Hilligoss, Gardner, and Henry: Pfizer Central Research, Pfizer, Inc., Eastern Point Road, Groton, CT 06430. Dr. Goldstein: Department of Medicine, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209.
References 1. Carlson JA, Mann HJ, Canafax DM. Effect of pH on disintegration and dissolution of ketoconazole tablets. Am J Hosp Pharm. 1983;40: 1334-6. 2. Van Der Meer JW, Keuning J J, Scheijgrong HW, Heykants J, Van Cutsen J, Brugmans J. The influence of gastric acidity on the bioavailability of ketoconazole. J Antimicrob Chemother. 1980;6:552-4. 3. Drew RH, Perfect JR, Gallis HA. Use of fluconazole in a patient with documented malabsorption of ketoconazole. Clin Pharm. 1988;7: 622-3. 4. Lelawongs P, Barone JA, Colaizzi JL, et al. Effect of food and gastric acidity on absorption of orally administered ketoconazole. Clin Pharm. 1988;7:228-35. 5. Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinetics. 1988;14:13-34. © 1991 American College of Physicians
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normal physical examination and normal clinical laboratory studies. In a randomized, four-way crossover study, subjects received oral fluconazole, 200 mg, and oral ketoconazole, 400 mg, (Nizoril [Lot 98G126], Janssen Pharmaceutica, Piscataway, New Jersey) with and without cimetidine (Tagamet [Lot 4018T22], Smith Kline & French, Philadelphia, Pennsylvania). During each study period, volunteers had continuous gastric pH monitoring using a tethered Heidelberg radiotelemetry capsule (Heidelberg International Corporation, Norcross, Georgia). Two 300-mg intravenous doses of cimetidine were given before oral antifungal dosing, one dose 60 minutes before and the other 30 minutes before antifungal dosing. Three 100-mg supplemental bolus doses were administered if gastric pH fell below 6.0 during the first 5 hours of the study. Fluconazole and ketoconazole were administered 1 hour after the initial cimetidine infusion. Serial serum samples were collected over a 24-hour period after ketoconazole administration and over a 144-hour period after fluconazole administration. Fluconazole and ketoconazole concentrations in serum were determined by a reverse-phase, high-pressure liquid chromatography assay method. The dynamic range was 0.1 /xg/mL to 20.0 /xg/mL for fluconazole and 0.15 /x,g/mL to 12.0 iJLg/mL for ketoconazole. Individual serum concentration-time profiles were analyzed, and the maximum concentration, the time of peak concentration, and the area under the concentration-time curve were determined for each subject. The area under the serum concentration-time curve was estimated using a linear trapezoidal rule. Comparisons of fluconazole and ketoconazole regarding normalized area under the curve and maximum concentration values were done using a two-way, repeatedmeasures analysis of variance to test for sequence, treatment, and period effects. The 95% CIs on the two comparisons done for each antifungal with and without cimetidine were calculated using the Bonferroni Mest
technique. Ketoconazole and fluconazole treatments were compared using the Student f-test technique. Results The mean serum concentrations of fluconazole and ketoconazole were plotted over time under conditions of normal and elevated gastric pH (Figure 1). The disposition of fluconazole was unaffected by the cimetidine-induced elevations in gastric pH. However, the disposition of ketoconazole was markedly affected by concomitant cimetidine administration. The mean (± SD) area-under-the-curve values were reduced 95%, from 34.1 ± 12.0 /xg • h/mL without cimetidine to 1.7 ± 1.5 xtg • h/mL with cimetidine. The mean maximum concentration values were significantly reduced to a similar extent, from 7.01 ± 2.21 /xg/mL to 0.48 ± 0.37 /xg/mL. The mean time to maximum concentration estimates were unaffected by concomitant cimetidine administration. For fluconazole, mean maximum concentration values with and without concomitant cimetidine therapy were 3.43 ± 0.57 /xg/mL and 3.43 ± 0.67 /xg/ mL, respectively. The corresponding mean time to maximum concentration estimates were 4.0 hours and 4.7 hours. The mean area-under-the-curve value was 161.5 ± 29.4 /xg • h/mL for fluconazole without cimetidine and 161.7 ± 26.4 /xg • h/mL for fluconazole with cimetidine. For normalized maximum concentration and area-under-the-curve values, there was a statistically significant difference between the ketoconazole with cimetidine treatment group and the ketoconazole without cimetidine treatment group (P < 0.001 for both variables), but no statistically significant difference between the fluconazole with cimetidine treatment group and the fluconazole without cimetidine treatment group (P > 0.2). The 95% CIs for the comparison between ketoconazole with and without cimetidine and fluconazole with and without cimetidine indicated a statistically significant difference (P < 0.05).
Figure 1. Mean serum concentration plotted against time for fluconazole and ketoconazole under conditions of normal (A) and elevated gastric pH ( • ) . 756
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Discussion When normal volunteers were given intravenous cimetidine to titrate pH to 6.0 and above, there was a dramatic effect on the disposition of ketoconazole. Reductions in mean area under the curve and maximum concentration values of more than 90% are consistent with the findings of other investigators (4). The disposition of fluconazole was unaffected by the concomitant administration of cimetidine. Cimetidine and antacids can dramatically reduce ketoconazole absorption (2). A single 400-mg dose of cimetidine administered 2 hours before a 200-mg dose of ketoconazole reduced the maximum concentration from 4.5 jiig/mL to 1.3 ju,g/mL. When this same dose of cimetidine was given with ketoconazole, 200 mg in acidified solution, the maximum concentration increased to 5.6 /xg/mL. When cimetidine and ketoconazole, 200 mg in 0.5 sodium bicarbonate, were administered, the maximum concentration decreased to less than 0.5 ftg/mL. These findings suggest that ketoconazole has dissolution rate-limited absorption and that alkaline pH of the duodenum appears not to affect absorption across the small-bowel mucosa. Our study was the first to compare the effects of rigorously controlled gastric pH on the oral bioavailability of fluconazole. The pKa of fluconazole (1.5) differs from that of ketoconazole (6.5 and 2.9) (5). The relatively low pKa of fluconazole allows for dissolution at a higher pH. These findings have important implications
for oral antifungal therapy in patients who are elderly or have AIDS. Increasing numbers of such patients have been shown to have relative states of gastric hypochlorhydria. Grant Support: In part by a research grant from Pfizer Central Research, Pfizer, Inc., Groton, Connecticut. Requests for Reprints: Robert A. Blum, PharmD, The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209-1194. Current Author Addresses: Drs. Blum, Wilton, and Schentag, Mr. D'Andrea, and Ms. Florentino: The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209-1194. Drs. Hilligoss, Gardner, and Henry: Pfizer Central Research, Pfizer, Inc., Eastern Point Road, Groton, CT 06430. Dr. Goldstein: Department of Medicine, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209.
References 1. Carlson JA, Mann HJ, Canafax DM. Effect of pH on disintegration and dissolution of ketoconazole tablets. Am J Hosp Pharm. 1983;40: 1334-6. 2. Van Der Meer JW, Keuning J J, Scheijgrong HW, Heykants J, Van Cutsen J, Brugmans J. The influence of gastric acidity on the bioavailability of ketoconazole. J Antimicrob Chemother. 1980;6:552-4. 3. Drew RH, Perfect JR, Gallis HA. Use of fluconazole in a patient with documented malabsorption of ketoconazole. Clin Pharm. 1988;7: 622-3. 4. Lelawongs P, Barone JA, Colaizzi JL, et al. Effect of food and gastric acidity on absorption of orally administered ketoconazole. Clin Pharm. 1988;7:228-35. 5. Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinetics. 1988;14:13-34. © 1991 American College of Physicians
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