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C R Banfield

Publications and source records attributed to C R Banfield.

12 recordsLinked to original sources
PubMed1997

Single and multiple dose pharmacokinetics of felbamate in the elderly.

AIMS: The objective of this study was to compare the pharmacokinetics, safety and tolerability of the antiepileptic drug felbamate in young and elderly healthy vounteers. METHODS: The single and multiple dose pharmacokinetics of felbamate were examined in an open-label two-dose level parallel group study in 24 elderly (66 to 78-year-old) and 11 young (18 to 45-year-old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120 h after administration of single 600 mg or 1200 mg doses, and after multiple doses of 600 mg or 1200 mg administered every 12 h. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events. RESULTS: Single dose felbamate pharmacokinetic parameters differed between young and elderly subjects; compared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1 ml min(-1); 90% CI -11.4 to -0.9; P = 0.02) and a trend towards a greater half-life (18.6 vs 21.0 h; 90% CI -0.6 to 5.4; P = 0.11). Mean AUC and C(max) values were also higher in elderly subjects. No gender differences were noted for weight-adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. This may be due to age-related pharmacokinetic differences, to the rapid dose titration schedule used in this study, and/or to altered sensitivity to felbamate's pharmacodynamic effects. CONCLUSIONS: These findings imply that elderly subjects require lower initial dosing and slower dose titration of felbamate than non-elderly subjects.

Adolescent↗
PubMed1997

Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation.

This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism. In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions. Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it had been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate. Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of beta-oxidation. No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate's drug:drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.

Anticonvulsants↗
PubMed1996

The effect of age on the apparent clearance of felbamate: a retrospective analysis using nonlinear mixed-effects modeling.

The effects of age on felbamate apparent clearance were examined through a retrospective analysis of plasma concentration data from 700 pediatric and adult epileptic patients (age range, 2-74 years) enrolled in six clinical studies. Patients received felbamate as monotherapy or in combination with either the antiepileptic drugs (AEDs) carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA). Data were analyzed using a nonlinear mixed-effects pharmacostatistical modeling technique (NONMEM). Factors in the model included age, body weight, and concomitant AEDs. Apparent clearance was highest in the very young and decreased during the early teenage years, with minimal changes observed beyond 13 years. Mean apparent clearance values were approximately 40% higher in children (2-12 years) compared with those in adults (13-65 years). This pattern and its magnitude were consistent whether felbamate was administered alone or coadministered with CBZ, PHT, or VPA. The increase in clearance is minimal compared with other AEDs including PHT, CBZ, and phenobarbital. Enzyme-inducing AEDs (CBZ and PHT) increased felbamate apparent clearance by 32-38% relative to monotherapy, whereas coadministration with VPA had a minimal effect on felbamate apparent clearance. Dose/concentration linearity was observed at all ages during mono- or polytherapy. These findings suggest that felbamate dosing should be relatively uncomplicated in children relative to that in adults.

Adolescent↗
PubMed1996

Effect of felbamate on valproic acid disposition in healthy volunteers: inhibition of beta-oxidation.

We assessed the effects of felbamate (FBM) on the disposition of valpr oic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2-4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2-en, 4-en, and 3-oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3-oxo and 4-hydroxy metabolites in urine were measured by gas chromatography/mass spectrometry (GC/MS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 mu g/ml (1,200 mg dose) to 76.8 mu g/ml (3,600-mg dose). Mean plasma VPA C max values were 32-42 mu g/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4-63.8 mu g/ml). The excretion of 3-oxo-VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at approximately 2400 mg/day. FBM has caused significant inhibition of the beta-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.

Adult↗
PubMed1995

Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension.

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the ¿link¿ model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum effect (Emax), 8.1 mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC50), 0.87 microgram x ml(-1); and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple Emax PD model. PD parameters obtained over the dose range were: Emax, 10.3 mmHg; Eo, 2.0 mmHg; and EC50 0.7 microgram x ml(-1). These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 microgram x ml(-1).

Adult↗
PubMed1995

Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine.

The effects of felbamate on the multiple dose pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine were assessed in a placebo-controlled, randomized, double-blind crossover study in 18 healthy male volunteers. Oxcarbazepine, 1200 mg/day, was administered on an open basis in combination with double-blind placebo or 2400 mg/day felbamate for two 10-day treatment periods separated by a 14-day washout period. Pharmacokinetic parameters of monohydroxyoxcarbazepine and dihydroxyoxcarbazepine were determined from plasma and urine samples obtained on the tenth day of each treatment period. Felbamate had no effect on monohydroxyoxcarbazepine plasma or urine pharmacokinetics compared with placebo, but it significantly increased values for dihydroxyoxcarbazepine maximum concentration and area under the curve from 0 to 12 hours, as well as urinary excretion of free and total dihydroxyoxcarbazepine. The mechanism that may account for the observations is the induction of oxidative metabolism of monohydroxyoxcarbazepine. Despite these changes, the relative amount of dihydroxyoxcarbazepine is small in comparison to monohydroxyoxcarbazepine, and antiepileptic activity is associated with monohydroxyoxcarbazepine rather than dihydroxyoxcarbazepine. Therefore we conclude that felbamate has no clinically relevant effects on the pharmacokinetics of oxcarbazepine in humans.

Adolescent↗
PubMed1995

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive.

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 micrograms ethinyl estradiol and 75 micrograms gestodene were assessed in a randomized, double-blind, placebo-controlled parallel-group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration-time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during felbamate treatment.

Adult↗
PubMed1995

Effects of felbamate on the pharmacokinetics of phenobarbital.

The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed in a parallel-group, placebo-controlled, double-blind study, in 24 healthy volunteers. Pharmacokinetic parameters of phenobarbital and parahydroxyphenobarbital were determined from plasma and urine samples obtained after 28 days of daily administration of 100 mg phenobarbital and after a further 9 days of phenobarbital plus 2400 mg/day felbamate or placebo. Felbamate increased phenobarbital values for area under the plasma concentration-time curve from 0 to 24 hours and maximum concentration by 22% and 24%, respectively, whereas placebo had no effect. This increase was caused by a reduction in parahydroxylation of phenobarbital and possibly through effects on other metabolic pathways. Because felbamate inhibits the S-mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in part by this isozyme.

Adult↗
PubMed1992

Dose proportionality of transdermal nitroglycerin.

The FDA Cooperative Efficacy Study of transdermal nitroglycerin utilized a combination of marketed products over a wide dose range. Unfortunately, plasma nitroglycerin concentrations were not determined. The current study was conducted to assess plasma nitrate concentrations after transdermal doses of 15, 30, 60, and 105 mg/24 hr employing the FDA Cooperative Study design. Plasma concentrations of nitroglycerin, 1,3-glyceryl dinitrate, and 1,2-glyceryl dinitrate were determined during the 24 hr of application and for 1 hr after transdermal system removal. Dose proportionality was assessed after normalizing the data by theoretical dose. For nitroglycerin, dose-normalized AUC(0-infinity) and Cmax were higher for the 105 mg/24 hr dose than for the other doses. For the metabolites, 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate, there were no differences in dose-normalized AUC(0-infinity) and dose-normalized Cmax between the dose levels. No differences were seen in Tmax between the dose levels for all three species. Based on the dinitrate metabolites, dose proportionality was seen over the 15 to 105 mg/24 hr dose range. Nitroglycerin, however, was found to be linear only between 15 and 60 mg/24 hr.

Administration, Cutaneous↗
PubMed1992

Saturable tissue binding and imirestat pharmacokinetics in rats.

To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague-Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 +/- 0.103 l and 1.10 +/- 0.228 L, respectively). Clearance was independent of dose over this fourfold range (approximately 15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 micrograms/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 micrograms/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 +/- 20.0 in the imirestat group, 17.7 +/- 1.27 in the statil-coadministered group, and 12.3 +/- 2.59 in the AL3152-coadministered group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗