The pharmacokinetics of ketoconazole in severely immunocompromised patients

Hann, Ian; Hg, Prentice; Keaney, M.G.L.; Corringham, Robert; Blacklock, Hilary; Fox, Jonathan; Gascoigne, E.; Custem, J. Van

doi:10.1093/jac/10.6.489

Cited by 30 publications

(12 citation statements)

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“…Ketoconazole absorption is reduced in renal failure (Chapman & Warnock 1983) and in bone marrow transplant recipients after 2 weeks (Hann et al 1982b). In adults with haematological malignancy, absorption may be reduced compared to normals (Stockley et al 1986); the malabsorption may relate to the phase of neutropenia (Donnelly et al 1984) [see section 4.2].…”

Section: Effect Of Disease Statesmentioning

confidence: 99%

Clinical Pharmacokinetics of Ketoconazole

Daneshmend¹,

Warnock

1988

Clinical Pharmacokinetics

203

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Ketoconazole, a synthetic imidazole antifungal, is effective for superficial fungal infections, genital candidosis and chronic mucocutaneous candidosis, and has been used in immunocompromised patients and advanced prostatic carcinoma. Absorption of ketoconazole is variable after oral administration, with large variability in peak serum concentrations. Antacids reduce, and food or dilute hydrochloric acid increase, absorption. Renal failure and bone marrow transplantation are associated with reduced absorption. Ketoconazole is not absorbed systemically after topical administration, and minimally absorbed from the vagina. Distribution of ketoconazole varies according to the tissue sampled, the underlying disease and the dose and duration of treatment. Ketoconazole does not cross the intact blood-brain barrier, and crosses to only a limited extent in fungal meningitis. Urinary concentrations of ketoconazole are usually low, but vaginal and vaginal tissue concentrations correlate with those in serum. Seminal fluid concentrations are inadequate for treatment of epididymitis. Ketoconazole is 83.7% plasma protein (mainly albumin) bound, and 15.3% is erythrocyte bound, resulting in only 1% of free drug. Animal studies indicate strong binding to the cytochrome P-450 mono-oxygenase complex. Extensive metabolism to inactive metabolites occurs, the products being mainly excreted in the faeces. Saturable hepatic first-pass metabolism is probable. The half-life of ketoconazole is dose-dependent, increases during long term treatment, suggesting auto-inhibition of metabolism. The kinetics after oral administration fit a 2-compartment model. Drug interactions of theoretical, if not practical, significance include warfarin, chlordiazepoxide, methylprednisolone, cyclosporin and drugs known to induce microsomal enzymes. In each case, some dosage adjustment for ketoconazole, or the interacting drug, may be required.

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Section: Effect Of Disease Statesmentioning

confidence: 99%

Clinical Pharmacokinetics of Ketoconazole

Daneshmend¹,

Warnock

1988

Clinical Pharmacokinetics

203

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“…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%

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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“…Routine monitoring of the concentration of antifungal agents in serum is not currently recommended, because the therapeutic range for these agents is unclear. However, decreases in the bioavailability of ketoconazole have been correlated with clinical failures in bone marrow transplant patients and in patients with AIDS (12,17,31). Therefore, on the basis of our findings in this study, simultaneous administration of ketoconazole and sucralfate should be avoided.…”

Section: Discussionmentioning

confidence: 99%

“…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 volunteers to assess the in vivo interaction between ketoconazole and sucralfate. The pharmacokinetic parameters of ketoconazole during each phase were compared to determine whether a clinically significant interaction between ketoconazole and sucralfate exists and whether this interaction could be avoided by separation of the doses of ketoconazole and sucralfate by 2 h. Since gastric pH in healthy volunteers varies between 1 and 3 (7, 15), the addition of glutamic acid hydrochloride (GA) ensured that the decreased bioavailability of ketoconazole would not be due to elevated pH.…”

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confidence: 99%

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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The pharmacokinetics of ketoconazole in severely immunocompromised patients

Cited by 30 publications

References 0 publications

Clinical Pharmacokinetics of Ketoconazole

Clinical Pharmacokinetics of Ketoconazole

Influence of food on the pharmacokinetics of ketoconazole

In vivo interaction of ketoconazole and sucralfate in healthy volunteers

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