Pharmacokinetics of ketoconazole in normal subjects

Daneshmend, T. K.; Warnock, David W.; Turner, Andrew M.; Roberts, CJ

doi:10.1093/jac/8.4.299

Cited by 82 publications

(41 citation statements)

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“…The t1/2 of ketoconazole has shown some variation in single-dose and multiple-dose studies (2,3,5,6,8,13,14). Some of the more extreme values (9) are difficult to explain, even after allowing for the different methods used.…”

Section: Resultsmentioning

confidence: 99%

“…More recently, a reduction in ketoconazole absorption was found when single doses were taken with meals (2), but this was not significant compared with the fasting state. However, another study (14) found that breakfast significantly reduced the absorption of ketoconazole, and another study (6) suggested a possible improvement in ketoconazole absorption when given with food.…”

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confidence: 99%

“…The single-dose pharmacokinetics of ketoconazole in normal subjects have previously been reported (6,8,14) and have also been investigated in patients with different fungal infections (2,3,7,8) and in immunocompromised patients (9, 13).…”

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confidence: 99%

“…A feature of ketoconazole kinetics noted in single-dose studies in humans is the relationship between ketoconazole dose and elimination: the half-life of ketoconazole increases as the dose is increased. In addition, the area under the serum concentration-time curve increases disproportionately with the increase in dose (6,8). We therefore examined the kinetics of ketoconazole over a wide dose range to determine whether food altered absorption even at high doses and to determine whether the previously observed relationship between dose and elimination was present at doses above 400 mg.…”

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Influence of food on the pharmacokinetics of ketoconazole

Daneshmend¹,

Warnock²,

Ene³

et al. 1984

Antimicrob Agents Chemother

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Eight healthy adults were given single oral doses of ketoconazole (200, 400, 600, and 800 mg) in the fasting state and with a standard breakfast at weekly intervals according to a balanced block design. Concentrations in serum were measured up to 32 h after the dose. Food did not reduce ketoconazole absorption or significantly alter peak ketoconazole concentrations in serum, though there was a food-related delay in achieving peak concentrations. At the 400-and 600-mg doses, food appeared to enhance absorption, but this effect was not seen at the 800-mg dose. With an increase in dose, the half-life and area under the serum concentration-time curve increased disproportionately, suggesting that the pharmacokinetics of ketoconazole may be dose dependent. Up to the 800-mg dose, the elimination of ketoconazole did not appear to be saturable. Administration of the drug with food is unlikely to be a cause of therapeutic failure.Ketoconazole is a new imidazole derivative which is active against both superficial and deep fungal infections after oral administration (11,12). The single-dose pharmacokinetics of ketoconazole in normal subjects have previously been reported (6,8,14) and have also been investigated in patients with different fungal infections (2,3,7,8) and in immunocompromised patients (9, 13).It is recommended by the manufacturers that the drug be given with food to improve absorption. This recommendation is based on the higher ketoconazole concentrations found 1 and 2 h postdose in the sera of 30 patients with onychomycosis when the drug was given with food (7). More recently, a reduction in ketoconazole absorption was found when single doses were taken with meals (2), but this was not significant compared with the fasting state. However, another study (14) found that breakfast significantly reduced the absorption of ketoconazole, and another study (6) suggested a possible improvement in ketoconazole absorption when given with food.In animal studies, ketoconazole kinetics appear to be dose dependent (1). A feature of ketoconazole kinetics noted in single-dose studies in humans is the relationship between ketoconazole dose and elimination: the half-life of ketoconazole increases as the dose is increased. In addition, the area under the serum concentration-time curve increases disproportionately with the increase in dose (6, 8). We therefore examined the kinetics of ketoconazole over a wide dose range to determine whether food altered absorption even at high doses and to determine whether the previously observed relationship between dose and elimination was present at doses above 400 mg. MATERIALS AND METHODSThree male and five female healthy adults aged 20 to 31 years (mean, 23 years) and weighing between 50 and 75 kg (mean, 64 kg) gave informed consent to inclusion in this study, which was approved by the medical ethics committee. A full blood count, plasma and urea electrolyte concentrations, and standard liver function tests were performed before treatment and 1 day after each dose of ketoconazole. No subje...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Influence of food on the pharmacokinetics of ketoconazole

Daneshmend¹,

Warnock²,

Ene³

et al. 1984

Antimicrob Agents Chemother

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“…Its pharmacokinetics after oral dosing have been examined in normal subjects (Daneshmend et al, 1981(Daneshmend et al, , 1983Gascoigne et al, 1981;Mannisto et al, 1982), in patients with different fungal infections (Brass et al, 1982;Gascoigne et al, 1981) and in immunocompromised patients (Hann etal., 1982;Maksymiuk et al, 1982). In view of the dysmorphogenic effects of ketoconazole noted in animals (Heel et al, 1982) The poor vaginal absorption of ketoconazole may in part be due to the physicochemical properties of the drug.…”

Section: Introduction Methodsmentioning

confidence: 99%

Systemic absorption of ketoconazole from vaginal pessaries.

Ene¹,

Williamson²,

Daneshmend³

et al. 1984

Brit J Clinical Pharma

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Eight healthy female subjects were each given (a) ketoconazole 400 mg orally, (b) ketoconazole 400 mg as a single vaginal pessary, (c) ketoconazole 800 mg as two vaginal pessaries, and (d) ketoconazole 1200 mg as three vaginal pessaries. The area under the plasma concentration time curve (AUC) after the oral dose was 51.41 +/‐ 10.99 mg l‐1 h (mean +/‐ s.d.) and the half‐life of ketoconazole was 2.98 +/‐ 1.41 h. The AUCs after vaginal administration were 0.27 +/‐ 0.14, 0.52 +/‐ 0.25, and 0.43 +/‐ 0.22 mg‐1 l h following the 400, 800 and 1200 mg pessaries respectively. Systemic absorption of single doses of vaginally administered ketoconazole appears to be negligible in the absence of vaginal infection. There were no local or systemic side effects related to ketoconazole in these healthy volunteers.

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The pathogenesis and clinical significance of cytologically detectable oralCandida in acute leukemia

Rodu

Carpenter

Jones

1988

Cancer

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Using serial examination and oral cytology, 50 adult patients undergoing induction therapy for acute leukemia were studied for oral colonization with candida species. Ninety percent of patients were found to be colonized with Candida, with most of these colonizations present by day 14. The 30 patients exhibiting colonization with pseudohyphae received ketoconazole 400 mg daily by mouth. Of 20 patients in this group treated for 5 or more days, Candida organisms were eradicated in nine. Sixteen patients from the above group with persistent colonization on ketoconazole were treated by independent clinical decision for sustained fever and neutropenia with Amphotericin B, but only one responded by elimination of colonization. Seven of the 15 patients who did not initially receive ketoconazole developed Candida dissemination in contrast to two of 30 who received ketoconazole initially (P = 0.003, Fisher's exact test). No patient who initially had or acquired a negative cytology developed oral or disseminated candidiasis. Clinical oral candidiasis occurred in three patients, all of whom were receiving amphotericin B. Approximately 90% of these patients have or develop oral colonization with Candida organisms as identified by oral cytology. Those with colonization, both with and without pseudohyphae present, are at risk for dissemination. Amphotericin B does not eliminate colonization remaining after treatment with 400 mg of ketoconazole daily. More effective diagnostic and therapeutic strategies are needed to identify and eliminate Candida organisms and to prevent disseminated candidiasis in this population of patients.

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Pharmacokinetics of ketoconazole in normal subjects

Cited by 82 publications

References 0 publications

Influence of food on the pharmacokinetics of ketoconazole

Influence of food on the pharmacokinetics of ketoconazole

Systemic absorption of ketoconazole from vaginal pessaries.

The pathogenesis and clinical significance of cytologically detectable oralCandida in acute leukemia

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