In vitro metabolism of the specific endothelin-A receptor antagonist ZD4054 and clinical drug interactions between ZD4054 and rifampicin or itraconazole in healthy male volunteers.

ZD4054 is an oral specific endothelin-A receptor antagonist in development for the treatment of hormone-resistant prostate cancer. Both renal and metabolic processes contribute to its overall clearance. Two preclinical in vitro studies investigated the metabolism of ZD4054 using human liver microsomes, individual cytochrome P450 (CYP) isozymes, and flavin-containing monooxygenase isoforms. Two Phase I open-label crossover volunteer studies subsequently investigated in vivo drug interactions between ZD4054 and the CYP450 inducer rifampicin or CYP3A4 inhibitor itraconazole. The most abundant metabolite produced in in vitro incubations accounted for 12.8% of radioactivity after ZD4054 was incubated with CYP3A4. No significant flavin-containing monooxygenase metabolism of ZD4054 was observed. In the in vivo studies, rifampicin co-administration reduced the area under the concentration-time curve and maximum plasma concentration of ZD4054 by 68% and 29%, respectively, whilst co-administration with itraconazole was associated with an increase in ZD4054 area under the curve of approximately 28%. While co-administration of CYP450 inducers might be associated with reduced efficacy of ZD4054, dose reduction is unlikely to be required with concomitant administration of CYP3A4 inhibitors.

Frovatriptan: a review of drug-drug interactions.

OBJECTIVE: To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan. BACKGROUND: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans. METHODS: The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials. RESULTS: In vitro, frovatriptan was principally metabolized by cytochrome P-450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase-A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination. CONCLUSIONS: Because it has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins, it is unlikely that frovatriptan will alter the pharmacokinetics of concomitantly administered drugs. Frovatriptan, therefore, appears to have a low risk of interaction with other drugs, and adjustments of dose are unlikely to be required when it is coadministered with other agents.

Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.

AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.

The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing.

AIMS: The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily. METHODS: Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 microg (n = 8), 1500 microg (n = 8), or 2500 microg (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two-way crossover for each subject and separated by at least a 6 day washout period. RESULTS: Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. Ctrough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (Cmax) and the area under the concentration vs time curve (AUC(0,tau) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. Cmax occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose-dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml-1) than on day 5 (ranging from 9.9 to 12. 8 ms/ng ml(-1). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.

The long-term safety and tolerability of ispaghula husk.

The safety and tolerability of ispaghula husk, which can now be used as an adjunct to diet for the treatment of mild-to-moderate hypercholesterolaemia, was assessed in 93 healthy subjects over a 52-week period. The study looked at the nutritional, biochemical, and haematological effects of ispaghula. Over the study period there were small but statistically significant changes in some measurements of minerals and vitamin levels, and in some haematological and biochemical parameters. However, none of these were of clinical significance, with the possible exception of changes in vitamin B12 levels. A daily dose of 10.5 g ispaghula was well tolerated and the majority of adverse events recorded were minor, of short duration and either unrelated or possibly related to the study treatment. The results suggest that ispaghula husk can be used with confidence for the long-term treatment of mild-to-moderate hypercholesterolaemia.

An open, controlled, crossover study on the effects of cimetidine on the steady-state pharmacokinetics of trovafloxacin.

Twelve healthy male volunteers participated in this open, randomized, placebo-controlled, two-way crossover study to investigate the effects of cimetidine on the steady-state pharmacokinetics of oral trovafloxacin. Volunteers were randomized to receive either 400 mg cimetidine twice daily or placebo for 5 days. From day 3-5, volunteers received 200 mg trovafloxacin once daily in addition to either cimetidine or placebo. After a minimum 7-day washout period, the study was repeated: those volunteers who received placebo during the first study period were administered cimetidine, and vice versa. The maximum observed serum trovafloxacin concentration, the area under the concentration-time curve of trovafloxacin within the dosing interval of 24 h and the earliest time to the maximum serum concentration for trovafloxacin in volunteers receiving concomitant cimetidine were 2.4 microg/ml. 27.8 microg x h/ml and 1.4 h, respectively, compared with 2.5 microg/ml, 27.1 microg x h/ml and 1.5 h, respectively, in volunteers receiving concomitant placebo. Thus. multiple dosing with cimetidine had no significant effect on the absorption or disposition of trovafloxacin at steady state. Co-administration of cimetidine and trovafloxacin was also well tolerated and without serious adverse effects.

The effect of food on the pharmacokinetics of the bicalutamide ('Casodex') enantiomers.

'Casodex' (bicalutamide) is an orally active, non-steroidal, pure antiandrogen; it is a racemate with antiandrogenic activity residing predominantly in the (R)-enantiomer. Healthy male volunteers (n = 15) were administered single oral doses of bicalutamide (50 mg) after food and after fasting as part of a three-treatment, three-period, randomized cross-over study, with a 9 week washout. After fasting, plasma concentrations of (R)-bicalutamide were much higher than those of (S)-bicalutamide; the mean (R)-enantiomer Cmax (734 ng mL-1) was about nine times higher than the (S)-enantiomer value (84 ng mL-1). The corresponding tmax values were 19 and 3 h for (R)- and (S)-bicalutamide, respectively. Elimination of (R)-bicalutamide from plasma was monoexponential and slow (t1/2 = 5.8 d). Elimination of (S)-bicalutamide was biphasic in some volunteers but monophasic in others (terminal t1/2 =1.2 d; n = 11). There was no significant effect of food on AUC, tmax, or t1/2 data for either enantiomer. The observed slightly higher values of Cmax for (R)-bicalutamide (14%) and (S)-bicalutamide (19%), when dosing with food, achieved statistical significance. However, differences of this magnitude are unlikely to to be of any clinical relevance. These data indicate that 'Casodex' can be taken without reference to meal times; this may be of particular relevance for its indication in a disease of the elderly.

Absence of effect of sertraline on time-based sensitization of cognitive impairment with haloperidol.

UNLABELLED: This double-blind, randomized, placebo-controlled study evaluated the effects of haloperidol alone and haloperidol plus sertraline on cognitive and psychomotor function in 24 healthy male subjects. METHOD: All subjects received placebo on Day 1 and haloperidol 2 mg on Days 2 and 25. From Days 9 to 25, subjects were randomly assigned to either sertraline (12 subjects) or placebo (12 subjects); the sertraline dose was titrated from 50 to 200 mg/day from Days 9 to 16, and remained at 200 mg/day for the final 10 days of the drug administration period. Cognitive function testing was performed before dosing and over a 24-hour period after dosing on Days 1, 2, and 25. RESULTS: Impairment of cognitive function was observed 6 to 8 hours after administration of haloperidol on Day 2 but was not evident 23 hours after dosing. When single-dose haloperidol was given again 25 days later, greater impairment with earlier onset was noted in several tests in both treatment groups, suggesting enhancement of this effect. There was no indication that sertraline exacerbated the impairment produced by haloperidol since an equivalent effect also occurred in the placebo group. Three subjects (2 on sertraline and 1 on placebo) withdrew from the study because of side effects. Ten subjects in each group reported side effects related to treatment. The side effect profiles of sertraline and of placebo were similar. CONCLUSION: Haloperidol produced a clear profile of cognitive impairment that was not worsened by concomitant sertraline administration.

Pharmacokinetics and tolerance of a new fluoroquinolone antimicrobial drug after single oral doses in healthy volunteers.

1. The pharmacokinetics and tolerance of DV-7751a were investigated in healthy male Caucasian volunteers after single oral doses (100, 200, 400 and 800 mg). 2. DV-7751a was rapidly absorbed in the fasted state. The mean maximum concentration in plasma (Cmax) ranged from 0.27 to 1.98 micrograms/ml for the 100-800-mg dose and the mean time to reach Cmax (tmax) ranged from 1.1 to 1.9 h. The terminal half-life ranged from 8.75 to 10.0 h. A good linear correlation (r = 0.974) was found between doses from 100 to 800 mg and the resulting area under the concentration-time curve (AUC). The plasma protein binding of the drug was in the range of 57-65%. 3. Within 48 h, the cumulative urinary excretion of unchanged drug amounted to 22.0-26.8% of the dose administered. Faecal recovery of the drug up to 72 h after the 400-mg dose was about 12% of the dose given. 4. Adverse events thought to be possibly related to the drug included headache, rash, leg cramp, diarrhoea, abdominal pain, CNS depression and dizziness. DV-7751a, however, was well tolerated with no serious adverse events at any doses and all subjects completed the study. No drug crystals were observed in the urine.