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.

Summary: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-yg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle l), topiramate 100, 200f 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,.,,) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p S 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (TmJ 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 2 3 5 yg of ethinyl estradiol. Key Words: Topiramatearal contraceptives-Anticonvulsants-Pharmacokinetics-Drug interactions-Epilepsy.Hepatic drug-metabolizing, enzyme-inducing AEDs, such as carbamazepine, phenytoin, and barbiturates, are known to inhibit the effectiveness of a number of drugs when administered concurrently. An important example of this type of interaction is the concomitant use of AEDs with estrogen/progestin

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.

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (C max) values were generally attained within 2 h postdose. The mean values of C max and area under the concentration-time curve from 0 to 24 h (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean C max and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These C maxand AUC0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (V ss/F), half-life (t 1/2), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F,V ss/F,t 1/2, and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.

Summary:Purpose: The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions.Methods: After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy.Results: All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for 2 2 weeks without VPA. TPM plasma peak concentration (Cmax) and area under the concentration-versus-time curve during a 12-h dosing interval (AUC,,,) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy.