John H. Cavanaugh

Effect of Zileuton on Theophylline Pharmacokinetics

SummaryIn controlled trials involving asthma patients, zileuton — a selective 5-lipoxygenase inhibitor — has significantly improved pulmonary function and reduced symptoms. Since theophylline is frequently prescribed for asthma, we designed a placebo-controlled randomised crossover trial to examine the influence of zileuton on theophylline pharmacokinetics.16 healthy adult males were given theophylline (Slo-Phyllin® ) 200mg 4 times daily for 5 days and either zileuton 800mg twice daily or a matching placebo. After a 15-day washout period, theophylline was resumed and the other study drugs reversed. During coadministration with zileuton, mean peak theophylline levels rose from 12.14 to 20.99 mg/L (p < 0.001), while the apparent plasma clearance dropped from 3.74 to 1.91 L/h (p < 0.001). The time to the peak theophylline concentration was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. 14 volunteers reported 44 mild or moderately severe adverse events, possibly or probably related to coadministration of zileuton, and 8 volunteers reported 8 such events with placebo coadministration. Three volunteers receiving theophylline plus zileuton withdrew from the trial prematurely.Thus, a pharmacokinetic interaction that may produce theophylline toxicity exists between zileuton and theophylline. Accordingly, theophylline dosages in patients receiving zileuton should be adjusted to maintain levels within the therapeutic range. Upon initiation of zileuton, the typical asthma patient may require dosage reductions of one-half, and monitoring of plasma theophylline concentrations is recommended.

Pharmacokinetics of Valproate After Multiple‐Dose Oral and Intravenous Infusion Administration: Gastrointestinal‐Related Diurnal Variation

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady‐state pharmacokinetics of valproate after multiple 250‐mg oral and intravenous infusion doses after an intravenous 750‐mg loading dose. Multiple blood samples were collected throughout each 168‐hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within‐regimen comparisons indicated statistically significant differences for mean steady‐state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration‐versus‐time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed‐release tablet preparation. Between‐regimen steady‐state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax (Tmax), Cmax, Cmin, AUC, and total body clearance for respective day‐4 dosing intervals, but not for the entire day 4, except for Cmin and Tmax. Mean elimination rate constant and half‐life did not significantly differ between the regimens. The regimens were bio‐equivalent at steady state, as assessed by 90% confidence intervals (two one‐sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation {(Cmax‐Cmin)/Caverage}. Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady‐state plasma concentration‐versus‐time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 μg/mL.

The Pharmacokinetics of Zileuton in Healthy Young and Elderly Volunteers

SummaryThe effects of age and gender on the single and multiple dose pharmacokinetics of zileuton have been examined in a phase I nonblinded study. A total of 27 healthy volunteers were evaluable, 9 in the young group (age range 20 to 40 years; 5 males and 4 females) and 18 in the elderly group (range 65 to 81 years; 9 males and 9 females). A single oral dose of zileuton 600mg was given to all volunteers on day 1 of the study and at 6-hour intervals from days 3 to 7.Analysis of variance showed slight but significant decreases in the mean apparent clearance of total and free drug in the healthy elderly population after a single zileuton dose, but no significant age-related differences after multiple 6-hourly doses. Similarly, zileuton peak and trough plasma concentrations, and values for half-life, volume of distribution and protein binding were not significantly affected by age after either a single dose or multiple administration. Moreover, gender effects on the pharmacokinetics were also absent after correction for bodyweight differences.From the results of the present study, it is concluded that there is no pharmacokinetic basis for alteration of zileuton dosage schedules in elderly patients.

The Pharmacokinetics of Single Oral Doses of Zileuton 200 to 800mg, its Enantiomers, and its Metabolites, in Normal Healthy Volunteers

SummaryThe pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(−) enantiomers, and its Af-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers.Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of zileuton racemate appeared to be linear. The mean dosenormalised area under the concentration-time curve from zero to infinity (AUC0-∞) remained constant, while the mean dose-normalised peak plasma concentration (Cmax) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses.The R(+) and S(−) enantiomers of zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(−) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC-∞ of each enantiomer increased proportionately with dose.The pharmacokinetics of the N-dehydroxylated metabolite of zileuton were highly variable, with a more than dose-proportional increase in the mean dosenormalised Cmax and area under the concentration-time curve from zero to 24 hours.The elimination of the glucuronide metabolites of the R(+) and S(−) enantiomers of zileuton was formation rate-limited. The mean percentage of the administered zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearances of the glucuronide metabolites of zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.

Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.

SummaryA double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers.Serial blood samples were collected for assessment of prothrombin times and R- and S- warfarin plasma concentrations.Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds.Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

The Pharmacokinetic and Pharmacodynamic Interactions between the 5-Lipoxygenase Inhibitor Zileuton and the Cyclo-Oxygenase Inhibitor Naproxen in Human Volunteers

SummaryThe potential pharmacokinetic and pharmacodynamic interactions between zileuton, a 5-lipoxygenase inhibitor, and naproxen, a nonsteroidal anti-inflammatory drug that acts as a cyclo-oxygenase inhibitor, have been investigated in 24 healthy volunteers. Coadministration of these 2 drugs had no effect upon the plasma concentration-time curves of either zileuton (800mg) or naproxen (500mg) when compared with each drug administered alone. Both naproxen plasma concentrations during the elimination phase and area under the plasma concentration-time curve values were statistically significantly raised upon coadministration with zileuton, when compared with naproxen alone. However, these differences in these 2 values were sufficiently small to be of no clinical significance.There was no evidence that the combination of zileuton and naproxen had an effect on leukotriene B4 levels that was different from the inhibitory effect of zileuton alone, or had an effect on serum thromboxane B2 levels that was different from the effect of naproxen alone. Moreover, inhibition of the 5-lipoxygenase pathway by zileuton did not appear to aggravate the gastrointestinal adverse events commonly associated with naproxen administration. It is concluded that zileuton and naproxen may be coadministered with minimal risk of a clinically significant interaction.

Pharmacokinetic Interactions between Zileuton and Prednisone

SummaryA randomised double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 times daily on the pharmacokinetics of prednisolone after a single 40mg oral dose of prednisone. The effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated.Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentrationtime curve from 0 to infinity (AUC0-∞) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t½) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance.Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0–6) [from 23 to 20 mg/L·h] and a reduction in tmax (from 2.3 to 1.7 hours), these results were not considered to be clinically significant.Therefore, it is concluded that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.

The Effect of Mild or Moderate Hepatic Impairment (Cirrhosis) on the Pharmacokinetics of Zileuton

SummaryThe pharmacokinetics of zileuton and its R(+) and S(−) glucuronide metabolites were determined after single and multiple (400mg every 8 hours) oral dose administration in healthy subjects (n=5) and patients with mild or moderate hepatic impairment (cirrhosis; n=8). The clearance of total zileuton (unbound plus bound to plasma proteins) in patients with hepatic impairment (approximately 350 ml/min) was approximately half that in healthy subjects (approximately 670 ml/min), with similar values in patients with mild or moderate cirrhosis. However, the clearance of unbound zileuton in patients with moderate hepatic impairment was nearly half that in patients with mild hepatic impairment, and one quarter that in healthy subjects. On the basis of these findings, it may be necessary to reduce the dose in patients with impaired hepatic function to maintain levels similar to those in healthy subjects.

The effect of zileuton on antipyrine and indocyanine green disposition

The effects of single and multiple oral doses of zileuton on the pharmacokinetics of antipyrine and indocyanine green were studied in 16 healthy, nonsmoking adult men by means of a double‐blind, randomized, parallel placebo‐controlled design. Indocyanine green disposition was not significantly altered by zileuton. Plasma antipyrine clearance declined by 20% (p < 0.0005) and 52% (p < 0.0005) after single and multiple dose zileuton exposure, respectively. Total urinary recovery of unchanged antipyrine and metabolites decreased with zileuton exposure. Selective declines from baseline of 16% (p = 0.007) and 20% (p = 0.003) after single‐dose zileuton and 30% (p < 0.0005) and 43% (p < 0.0005) after multiple‐dose zileuton were detected in recovery of 4‐hydroxyantipyrine and 3‐hydroxymethylantipyrine, respectively. Urinary recovery of the N‐demethylantipyrine metabolite norantipyrine and percent of conjugation of 3‐hydroxymethylantipyrine were unchanged by zileuton. In conclusion, zileuton therapy has no detectable effect on indocyanine green disposition but exerts marked effects on antipyrine plasma and urine metabolite disposition.

The effect of food on the pharmacokinetics of zileuton

SummaryThe present study was undertaken to assess the effect of food on the pharmacokinetic parameters of zileuton. In a nonblinded crossover study, 18 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of zileuton 600mg in the presence or absence of food consisting of a standardised breakfast on the following morning. The mean zileuton peak plasma concentration (Cmax) increased significantly by 27% after food intake, while the mean area under the plasma concentration versus time curve increased by only 1.4%, a difference that was not statistically significant. The mean time to Cmax was unaffected by the presence of food, as were the other pharmacokinetic parameters assessed.Overall, the results suggest that food has a relatively small effect on the rate of zileuton absorption compared with the fasting state, while the bioavailability of the drug appears to be unaffected. Thus, it is concluded that it is appropriate to administer zileuton with or without food.