The influence of gastric acidity on the bio-availability of ketoconazole

Meer, J.W.M. van der; Keuning, J.J.; Scheijgrond, H.; Heykants, J.; Cutsem, J. Van; Brugmans, J

doi:10.1093/jac/6.4.552

Cited by 140 publications

(41 citation statements)

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“…Several factors may account for the differences in our two studies. First, we anticipated wide variability in the absorption of ketoconazole (2,18,28) (14). In contrast, they did not observe a sucralfate-induced increase in gastric pH as predicted by our in vitro data and reported by previous investigators (3,19,21,23), despite the multiple-dose sucralfate regimen employed in their study.…”

Section: Discussionsupporting

confidence: 59%

“…Thus, ketoconazole is virtually insoluble in neutral or slightly acidic solutions (4, 30). Predictably, absorption of ketoconazole is impaired in subjects with an increased gastric pH due to the administration of antacids, H2-receptor antagonists, or the presence of achlorhydria (2,16,17,25,28).Frequently, patients receiving ketoconazole also require therapy for the treatment or prevention of acid-peptic disorders. Because sucralfate does not increase gastric pH as efficiently as antacids or antisecretory agents, it provides an attractive alternative in this setting (10, 22).…”

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confidence: 99%

“…increased gastric pH due to the administration of antacids, H2-receptor antagonists, or the presence of achlorhydria (2,16,17,25,28).…”

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confidence: 99%

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In vivo interaction of ketoconazole and sucralfate in healthy volunteers

Carver

Berardi

Knapp

et al. 1994

Antimicrob Agents Chemother

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Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 ± 12.20 versus 59.32 ± 13.61 ,ug * h/ml and 12.34 ± 3.07 versus 8.92 ± 2.57 ,ug/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h.Ketoconazole is a dibasic oral antifungal agent with a pKal of 6.51 and a PKa2 of 2.94. Thus, ketoconazole is virtually insoluble in neutral or slightly acidic solutions (4, 30). Predictably, absorption of ketoconazole is impaired in subjects with an increased gastric pH due to the administration of antacids, H2-receptor antagonists, or the presence of achlorhydria (2,16,17,25,28).Frequently, patients receiving ketoconazole also require therapy for the treatment or prevention of acid-peptic disorders. Because sucralfate does not increase gastric pH as efficiently as antacids or antisecretory agents, it provides an attractive alternative in this setting (10, 22). However, simultaneous administration with sucralfate results in a significant decrease in the oral bioavailability of phenytoin or fluoroquinolone antibiotics (11,13,27,29). The interaction between sucralfate and ciprofloxacin can be minimized by administration of ciprofloxacin 2 h prior to or 6 h after administration of sucralfate (29).We studied the in vitro interaction between ketoconazole and sucralfate in acidified solutions with various pHs. A marked decrease in the concentration of ketoconazole was observed following the addition of sucralfate (14). On the basis of these in vitro studies, we undertook a pharmacokinetic study with 12 healthy human v...

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Section: Discussionsupporting

confidence: 59%

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confidence: 99%

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In vivo interaction of ketoconazole and sucralfate in healthy volunteers

Carver

Berardi

Knapp

et al. 1994

Antimicrob Agents Chemother

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“…Also, unlike in a clinical trial, there was no mandate given that ketoconazole be taken on an empty stomach, and no restriction on the use of antacids, anticholinergics, or H2-blockers, although gastric acidity is known to improve absorption. 18 In addition, steroids have been shown to induce PSA responses alone in up to 20% of patients with AIPC, and less than half of the patients in this cohort received steroids. 19 Of note, Grade 3 toxicities were observed in only 2.3% of patients who received LDK.…”

Section: Discussionmentioning

confidence: 86%

Response to low‐dose ketoconazole and subsequent dose escalation to high‐dose ketoconazole in patients with androgen‐independent prostate cancer

Nakabayashi

Xie

Regan

et al. 2006

Cancer

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BACKGROUND.High‐dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen‐independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low‐dose ketoconazole (LDK). To the authors' knowledge, relatively little is known regarding the efficacy of LDK in AIPC. The efficacy of LDK and of subsequent dose escalation from LDK to HDK was evaluated as secondary hormonal therapy in patients with AIPC.METHODS.In a single institution, patients with AIPC treated with LDK (at a dose of 200 mg orally 3 times daily) as secondary hormonal therapy with or without concomitant steroids were retrospectively identified. In addition, patients were identified who received dose escalation to HDK (400 mg orally 3 times daily) after experiencing a rising prostate‐specific antigen (PSA) level.RESULTS.Thirty‐nine of 138 eligible patients (28.3%, 95% confidence interval [95% CI], 20.9–36.6%) treated with LDK experienced PSA declines ≥50%. The median time to disease progression or dose escalation on LDK was 3.2 months (range, 0.1+–61 months). Dose escalation to HDK was subsequently performed in 55 patients (39.9%), 7 of whom (12.7%) demonstrated a subsequent PSA decline ≥50%. A longer duration of primary androgen deprivation therapy and total duration of all previous hormonal therapies was associated with a longer time to progression with LDK (P < .05). The most common reversible adverse effect of LDK was NCI Common Toxicity Criteria Grade 1 or 2 fatigue (12.3%).CONCLUSIONS.LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, but with less toxicity. Although uncommon, additional durable responses occurred in some patients after dose escalation. Cancer 2006. © 2006 American Cancer Society.

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“…Clinical studies reported that the bioavailability of the drug decreased when the gastric pH increased by administering the drug concomitantly with antacids or H2 blockers (19) .…”

Section: Dissolution and Saturation Solubility In Conventional Mediamentioning

confidence: 99%

The impact of food components on the intrinsic dissolution rate of ketoconazole

Ghazal

Dyas

Ford

et al. 2014

Drug Development and Industrial Pharmacy

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Ghazal, HS, Dyas, AM, Ford, JL and Hutcheon, GAThe impact of food components on the intrinsic dissolution rate of ketoconazole http://researchonline.ljmu.ac.uk/2650/ Article LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain.The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription. 2 AbstractTo accurately predict the in vivo performance of drugs from an in vitro dissolution test, the dissolution conditions used are supposed to be similar to those present in the gastrointestinal milieu. Post-prandial gastric fluid contains partially digested food mixtures consisting of fat, protein and carbohydrate. Despite this, the compendial dissolution medium recommended to simulate the gastric fluid is still composed of simple solution of hydrochloric acid and sodium chloride with or without the addition of pepsin. Therefore, in this investigation, biorelevant dissolution media were developed to evaluate the impact of food constituents; milk with different fat contents, egg albumin, gelatin, casein, gluten, carbohydrates and amino acids on the intrinsic dissolution behaviour of ketoconazole. Most of the food additives that were evaluated enhanced the apparent solubility of the drug but to different extents. The greatest enhancement in dissolution was observed in media containing either neutral amino acids or media based on milk mixtures. The formation of complexes between the drug and the additives most likely accounted for the solubilising effect and in milk-containing media the effect was attributed to the whole complex structure of milk rather than simply its fat content.These results highlight the potential effect of the type of ingested meal on drug dissolution and subsequent bioavailability.3

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The influence of gastric acidity on the bio-availability of ketoconazole

Cited by 140 publications

References 0 publications

In vivo interaction of ketoconazole and sucralfate in healthy volunteers

In vivo interaction of ketoconazole and sucralfate in healthy volunteers

Response to low‐dose ketoconazole and subsequent dose escalation to high‐dose ketoconazole in patients with androgen‐independent prostate cancer

The impact of food components on the intrinsic dissolution rate of ketoconazole

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