A study of topiramate pharmacokinetics and tolerability in children with epilepsy.

The pharmacokinetic and safety profile of topiramate as adjunctive therapy was assessed in pediatric patients with epilepsy in an open-label, 4-week, single-center study. Six children from each of the following age groups were enrolled: 4-7 years, 8-11 years, and 12-17 years. Patients received topiramate 1 mg/kg/day for 1 week, with subsequent progressive weekly increases in dosage to 3, 6, and then 9 mg/kg/day or 800 mg/day, whichever was less. Topiramate oral plasma clearance (CI/F) was independent of dose, and steady-state plasma concentrations increased in proportion to dose. Weight-normalized topiramate CL/F was higher (P = 0.003) in pediatric patients receiving enzyme-inducing concomitant antiepileptic drugs (AEDs) (mean = 70.1 ml/minute/70 kg) than in those not receiving enzyme-inducing AEDs (mean = 33.1 mL/ minute/kg). Topiramate CL/F in children was approximately 50% greater than that observed in adults regardless of the type of concomitant AED therapy. Thus steady-state plasma topiramate concentrations for the same mg/kg dose will be approximately 33% lower in pediatric patients than in adult patients. The most frequently reported treatment-emergent adverse events considered related to topiramate therapy included anorexia, fatigue, and nervousness, and no patient discontinued therapy. This study indicates that, in children 4-17 years of age, topiramate has linear pharmacokinetics, 50% higher clearance than in adults, and is generally well tolerated.

Topiramate pharmacokinetics in infants.

PURPOSE: This study's goal was to provide preliminary data on the pharmacokinetics of topiramate (TPM) in a cohort of infants (younger than 4 years) participating in an open-label trial of TPM in refractory infantile spasms. METHODS: The pharmacokinetics of TPM were assessed in infants receiving a stable TPM dose for >7 days during the extension phase of this trial. Blood samples were drawn just before and 0.5. 1, 1.5, 2, 4, 6, 8, and 12 h after the morning TPM dose. TPM plasma concentrations were determined by fluorescence polarization immunoassay. The noncompartmental analysis module of WinNonlin was used to calculate individual patient pharmacokinetics profiles. RESULTS: Five infants (ages, 23.5-29.5 months) formed the study cohort. These infants had been given TPM for a median of 9 months (range, 6-11 months) and were currently receiving between 11 and 38.5 mg/kg/day TPM. One was receiving TPM monotherapy, whereas four were taking concomitant antiepileptic medications (AEDs; n = 2, enzyme-inducing agents; n = 2, non-enzyme-inducing drugs). TPM pharmacokinetics in infants appears to be linear. In this cohort, mean TPM plasma clearance (CL/F, 66.6+/-27.4 ml/h/kg) was slightly higher than that reported for children and adolescents and therefore substantially higher than that reported for adults. TPM CL/F was higher and the calculated half-life shorter in the infants receiving concomitant enzyme-inducing AEDs. CONCLUSIONS: Based on this small cohort of patients, it appears that infants may require significantly larger TPM doses, based on weight, than children, adolescents, or adults. Titration to effect and not absolute TPM dose should guide therapy in this age group.

Levofloxacin does not alter cyclosporine disposition.

Certain fluoroquinolones have been shown to elevate the serum concentrations of the immunosuppressant cyclosporine. It is thus important to investigate the potential interaction between levofloxacin, a new fluoroquinolone antimicrobial agent, and the pharmacokinetics of cyclosporine. Twelve healthy subjects (6 men, 6 women) were enrolled in and completed a placebo-controlled, randomized, double-blind, two-phase crossover study. Subjects were given a single oral 10-mg/kg dose of cyclosporine solution during multiple-dose twice-daily oral treatment with placebo or 500 mg of levofloxacin. Blood cyclosporine concentrations were measured for 48 hours after each cyclosporine dose for pharmacokinetic evaluation. Cyclosporine pharmacokinetic parameters were comparable and not significantly different in the absence and presence of levofloxacin. Results of this study suggest that a clinically important pharmacokinetic interaction between levofloxacin and cyclosporine is unlikely to occur during concurrent therapy.

Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy.

PURPOSE: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. METHODS: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-microg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200, and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. RESULTS: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100-400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC(0-24)) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p < or = 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p < or = 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T(max)) values determined during topiramate therapy were not significantly different from those at baseline. CONCLUSIONS: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing > or = 35 microg of ethinyl estradiol.

PIP: The efficacy of combined oral contraceptives (OCs) is diminished in women taking enzyme-inducing anti-epileptic drugs such as phenytoin, phenobarbital, and carbamazepine. In preliminary in vitro studies, a new anti-epileptic drug derived from D-fructose, topiramate, produced no clinically relevant inhibitory effects on the metabolism of such drugs as barbiturates, classic neuroleptics, and tricyclic antidepressants. To assess this new drug, 12 women with documented histories of epilepsy took an OC containing 1 mg norethindrone and 35 mcg ethinyl estradiol as well as topiramate (100-400 mg every 12 hours) for 4 menstrual cycles. Serial blood samples were obtained on day 20 of the 4 cycles. None of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate. Ethinyl estradiol serum levels were reduced by an average of 30% from baseline. The mean area under the concentration-versus-time curve over the 24-hour period values for ethinyl estradiol were 18-30% lower in cycles 2-4 than the baseline cycle and mean oral serum clearance values were 14.7-33.0% higher. This compares favorably with the 40-72% reductions in progestin and estrogen levels recorded in women taking a levonorgestrel-containing OC and enzyme-inducing anti-epileptics. Although topiramate's modest interaction with OCs is not likely to interfere with contraceptive efficacy, the reduction in serum estrogen concentrations has the potential to increase the incidence of breakthrough bleeding, indicating the OC should contain at least 35 mcg of estrogen.

Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug.

Topiramate, a new antiepileptic drug effective in controlling partial-onset seizures, was administered to humans for the first time as single oral doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg in a phase I safety and pharmacokinetic study. Model-independent pharmacokinetic data analysis was performed on plasma concentration and renal excretion data for topiramate. Maximum plasma concentrations (Cmax) were observed between 1.4 and 4.3 hours after administration. Mean values for plasma Cmax and area under the concentration-time curve (AUC) increased linearly with dose; however, a greater-than-proportional increase in both parameters was observed, probably due to saturable binding of the drug to erythrocytes. Mean oral clearance (Cl/F) was 22.5 to 36.1 mL/min and mean volume of distribution (Vd/F) was 38.5 to 58.0 L. Approximately 50% of the dose was excreted renally and cumulative urinary excretion increased linearly and proportionally over the 200 mg to 1,200 mg dose range. Elimination half-life (t1/2) values calculated from plasma (21.5 hrs) and urinary data (18.5 hrs) were consistent and independent of dose. Intersubject variability was low for all parameters. Renal clearance was 13.9 mL/min, suggesting that renal tubular reabsorption may be prominently involved in the renal handling of topiramate. The elimination profile of topiramate indicated that longer sampling times are necessary in future studies to more accurately determine the t1/2. Food effect studies indicated a slight reduction in the rate (approximately 10% decrease in mean Cmax and mean tmax approximately 2 hours later) but not the extent of absorption when topiramate was given with food. Topiramate demonstrates a number of favorable pharmacokinetic features, including linear and predictable dose-concentration relationships, excretion mainly as unchanged drug by the kidney, a dose-independent t1/2, low intersubject variability in pharmacokinetic parameters, and lack of clinically significant effect of food on bioavailability.

Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy.

PURPOSE: We studied the steady-state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ). METHODS: We enrolled 12 patients with partial epilepsy receiving chronic stable doses of CBZ 300-800 mg every 8 h. In a 6-week period, TPM was added and doses were increased at approximately 2-week intervals from 100 to 200 to 400 mg every 12 h and stabilized at the highest tolerated dose to as high as 400 mg every 12 h. CBZ was tapered in the next 4 weeks when possible, and TPM was maintained as monotherapy at the highest stabilized dose for 2 more weeks. Plasma and urine samples were collected before TPM dosing, after each TPM dose increase, and during TPM monotherapy. RESULTS: Dose-normalized results (n = 10) for TPM area under the curve from 0 to 12 h (AUC(0-12)), Cmin(0), and Cavg indicated that TPM exhibits linear plasma pharmacokinetics over the dose range of 100- to 400-mg every 12 h when administered with CBZ. Mean TPM AUC(0-12), Cmax, Cmin(0), and Cavg values were approximately 40% lower during CBZ treatment as compared with those during TPM monotherapy (n = 3). TPM oral and nonrenal clearance rates were approximately two- to threefold higher, whereas TPM renal clearance was unchanged during concomitant CBZ treatment (n = 3). There were no significant changes in total and unbound CBZ and CBZ-epoxide (CBZ-E) pharmacokinetics during TPM administration (n = 10). TPM pharmacokinetics during concomitant CBZ treatment were significantly different from those during TPM monotherapy, suggesting that metabolic clearance of TPM increases when CBZ is coadministered. CONCLUSIONS: When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.

Effects of meals and meal composition on the bioavailability of fenretinide.

The effects of meals and meal composition on the bioavailability of fenretinide, N-(4-hydroxyphenyl) retinamide, a synthetic retinoid undergoing clinical trials, were examined in two separate studies using an open, randomized, crossover design. In the first study, 13 healthy male volunteers received 300-mg doses of fenretinide (1) while fasting and (2) after a high-fat breakfast. In a subsequent study, 15 subjects received 300 mg fenretinide after each of three different test meals (high-fat, high-protein, and high-carbohydrate) separated by a 1-week washout period. Plasma specimens obtained over a 72-hour period after each treatment were assayed by high-pressure liquid chromatography to characterize the effects of a meal and meal composition on the bioavailability of fenretinide. Results from the initial study demonstrated a significant increase in the bioavailability of fenretinide after a high-fat meal. In the follow-up study, the bioavailability of fenretinide, as assessed by total area under the plasma concentration curve, was three times greater after the high-fat meal than after the high-carbohydrate meal. This supported the findings of the first study. Although to a lesser extent, the high-protein meal also produced a greater area under the curve than the high-carbohydrate meal. These combined findings demonstrate that the bioavailability of fenretinide is markedly influenced not only by administration with meals but also by the specific composition of such meals.

The bioavailability and pharmacokinetics of oral and depot intramuscular haloperidol in schizophrenic patients.

In a four-segment long-term (greater than or equal to 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5-35 mg/d for oral haloperidol (mean, 17 mg/d), and 75-500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days.(ABSTRACT TRUNCATED AT 250 WORDS)