Influence of food on the pharmacokinetics of ketoconazole

Abstract

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...

Overview of medically important antifungal azole derivatives

“…VOL. 1, 1988 Serum levels of ketoconazole are markedly decreased by concurrent administration of antacids or H-2 receptorblocking agents due to elevated gastric pH, which impairs absorption of ketoconazole (62). Serum levels of ketoconazole also are decreased by concomitant administration of rifampin, apparently due to accelerated hepatic metabolism (35).…”

A Bayesian Meta-Analysis on Published Sample Mean and Variance Pharmacokinetic Data with Application to Drug–Drug Interaction Prediction

“…• subject-specific PK model: (4) • subject-specific PK parameter model in study k: (5) • study-specific PK parameter model: (6) In (4), y ijkh represents log-transformed drug concentration at time t jkh for subject i in phase h of study k. Here we use a generic notation z jkh to denote available data and constants for a study subject at time t jkh . It includes dosage, dosing route, and fixed constants such as Q h , F I , Km I , fu I , MW I , Km S , fu S , and time point t jkh at which plasma concentration is measured, The mean value f(α,β ik ,z jkh ) is the predicted log-transformed drug concentration for subject i at jth time point from phase h of study k. Basically, f(α,β ik ,z jkh ) corresponds to (part of) a numerical solution at given time points from (1) and (2) by input α, β ik and z jkh .…”

“…The sample variance data at most provide information about between-subject heterogeneity parameter Σ. As a result, models based on (4) - (6) are only suitable when working on subject level data. When only sample mean and sample variance data are available, they need to be modified to make estimation feasible.…”

“…The blood sampling time points were (0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 36) hours after dose for KETO and (0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12) for MDZ. At each KETO dose, its subject specific plasma concentrations were simulated with a two-compartment model (1) and subject specific models (4) - (6). The population PK parameters are β = log(V1 I ,V2 I , CL12 I ,V max I ,ka I,SLF ).…”

“…The measurement error variance is set as 0.10 2 . Similar to the KETO, MDZ plasma concentrations were simulated with a two compartmental PK model (2) and subject specific models (4) - (6). The PK parameters are β = log(V1 S ,V2 S ,Vmax S ,CL12 S ), and the true PK parameters are listed in Table 3 and are chosen to be close to their estimates in the prescribed MDZ data analysis.…”