Pharmacokinetics of ketoconazole in patients with neoplastic diseases

Maksymiuk, Andrew W.; Levine, Howard B.; Bodey, G P

doi:10.1128/aac.22.1.43

Cited by 23 publications

(10 citation statements)

References 11 publications

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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%

“…Some of the more extreme values (9) are difficult to explain, even after allowing for the different methods used. Most studies have shown that t1j2 increases with chronic dosing (3,5,13). However, in one study the t112 of ketoconazole in patients with leukemia was found to be less than 1 h (9).…”

Section: Resultsmentioning

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%

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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%

Section: Resultsmentioning

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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“…Less than 1% is free in the plasma. The blood half-life, which is dose dependent, ranges from 1 to 11 h (9). After a single oral dose of 200 mg in humans, detectable levels have been found in the cerebrospinal fluid, urine, saliva, cerumen, and sebum (5).…”

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confidence: 99%

Orally administered ketoconazole: route of delivery to the human stratum corneum

Harris¹,

Jones²,

Artis³

1983

Antimicrob Agents Chemother

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Delivery of ketoconazole to human stratum corneum was studied. Thirteen healthy volunteers, three patients with chronic fungal disease and one patient with palmar-plantar hyperhidrosis were given 400 mg of ketoconazole daily for various lengths of time. The ketoconazole content of palmar stratum corneum, eccrine sweat, sebum, and serum was measured by high-pressure liquid chromatography (sensitivity, 0.005 to 0.010 microgram/ml). Palmar stratum corneum obtained after 7 and 14 days of daily administration contained up to 14 micrograms of ketoconazole per g. Ketoconazole was not found in sebum after 7 or 14 days of daily ingestion of the antimycotic agent. Sebum from three patients with chronic fungal infection treated for greater than 9 months contained ketoconazole (means, 4.7 micrograms/g). Thermogenic whole body eccrine sweat contained a mean of 0.059 microgram/ml on day 7 and 0.084 microgram/ml on day 14 of daily administration. Ketoconazole appeared in thermogenic whole body eccrine sweat and palmar hyperhidrotic sweat within 1 h after a single oral dose. Partition studies of ketoconazole containing eccrine sweat demonstrated a 10-fold greater concentration in the sediment phase (desquamated keratinocytes) compared with the clear supernatant phase. In vitro studies with [3H]ketoconazole-supplemented supernatant sweat revealed preferential binding to stratum corneum, hair, and nails and its partitioning to lipid-rich sebum. We conclude that eccrine sweat rapidly transports ketoconazole across the blood-skin barrier, where it may bind or partition to keratinocytes and surface lipids.

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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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Pharmacokinetics of ketoconazole in patients with neoplastic diseases

Cited by 23 publications

References 11 publications

Influence of food on the pharmacokinetics of ketoconazole

Influence of food on the pharmacokinetics of ketoconazole

Orally administered ketoconazole: route of delivery to the human stratum corneum

Systemic absorption of ketoconazole from vaginal pessaries.

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