Ch. Crevoisier

Stereoselective passage of mefloquine through the blood-brain barrier in the rat.

The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)‐mefloquine and (–)‐mefloquine.

Comparative Single-Dose Pharmacokinetics of Clonazepam following Intravenous, Intramuscular and Oral Administration to Healthy Volunteers

The objective was to assess the single-dose pharmacokinetics of clonazepam following i.m., p.o. and i.v. administration. In an open-label, three-way crossover study, 12 healthy volunteers were randomized to receive a single dose of 2 mg clonazepam either by the i.m., p.o. or i.v. route. Serial blood samples were collected up to 120 h after drug administration. Plasma concentrations of clonazepam were determined by electron-capture gas-liquid chromatography. The absorption rates of clonazepam after i.m. and p.o. administration of clonazepam were significantly different from each other, as reflected by the respective mean values of maximum plasma concentration (Cmax 11.0 vs. 14.9 ng·ml–1) and time to reach maximum concentration (tmax 3.1 vs. 1.7 h). Secondary plasma peaks of clonazepam were observed in 9 volunteers after i.m. injection (Cmax 9.9 ng·ml–1; tmax 10.4 h). A comparison of the area under the plasma concentration-time curves (AUC) shows that the i.m. route is equivalent to the oral route (AUC0–∞ 620 vs. 561 ng·h·ml–1). Clonazepam was almost completely absorbed after i.m. and p.o. administration, as shown by the mean absolute bioavailability of 93 and 90%, respectively. No significant differences existed between the elimination half-lives (i.v. 38.0 h; i.m. 43.6 h; p.o. 39.0 h). The average clearance and volume of distribution (VZ) were 55 ml·min–1 and 180 liters, respectively. In conclusion, the observed differences in Cmax and tmax after i.m. and p.o. administration were consistent with a slower absorption rate of clonazepam after i.m. injection. The systemic exposure to clonazepam was not affected by the route of extravascular administration. Statistical evaluation of these kinetic data showed differences in the absorption rate, so that clonazepam given by the i.m. route is not bioequivalent to the oral route. On the basis of the results of this study, we would recommend the same i.m. and p.o. dose in epileptic patients, but therapeutic response would be expected to be less predictable and to occur later in the case of i.m. administration.

Bioavailability of L-Dopa after Madopar HBS Administration in Healthy Volunteers

Eight healthy male and fasted volunteers received alternatively either one HBS capsule of Madopar 125 or two HBS capsules of Madopar 125 or one standard capsule of Madopar 125 at weekly intervals with and without benserazide pretreatment (50 mg t.i.d. for 6 days). In this trial the Madopar formulations were administered 9.5 h after the last dose of benserazide. Serial blood samples were collected at various time intervals up to 12 h after Madopar dosing. Levodopa plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection. After Madopar HBS without benserazide pretreatment the peak concentration (Cmax) of levodopa was lower and occurred at later times (tmax) than after standard Madopar. The mean values for tmax were 2.4, 2.8 and 0.8 h, whereas those for Cmax were 0.25, 0.56 and 1.38 micrograms/ml for one HBS capsule, two HBS capsules and standard Madopar, respectively. The mean relative bioavailability (versus standard Madopar) was 58 and 67% (value normalized to dose) for one and two HBS capsules, respectively. The parameter of half-value duration (= time span where plasma concentrations are equal to or higher than the half Cmax) was on average 3.5, 3.8 and 0.8 h for one HBS capsule, two HBS capsules and standard Madopar, respectively. Following benserazide pretreatment the mean tmax values for levodopa were 2.8, 2.3 and 0.8 h and the mean Cmax values were 0.35, 0.60 and 1.33 micrograms/ml, respectively, for one HBS capsule, two HBS capsules and standard Madopar. The relative bioavailability (versus standard Madopar) was 57 +/- 14 and 63 +/- 21% (value normalized to dose) for one and two HBS capsules, respectively. The mean values of the half-value duration were 3.6, 4.2 and 1.3 h for one HBS capsule, two HBS capsules and standard Madopar, respectively. For most of the parameters measured, the interindividual variability after Madopar HBS was less pronounced than after standard Madopar. In conclusion, according to these kinetic data, Madopar HBS shows the characteristics of a controlled-release formulation. The reduced bioavailability of the HBS form (60% of that of the standard form) suggests that a higher daily dose of Madopar HBS should be used for clinical practice.

Comt inhibition by tolcapone further improves levodopa pharmacokinetics when combined with a dual-release formulation of levodopa/benserazide: A novel principle in the treatment of Parkinson's disease

The objective of the study reported here was the investigation of the effect of catechol-O-methyl transferase (COMT) inhibition by tolcapone on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new dual-release formulation (dual-RF) of levodopa/benserazide (200/50). The study had a double-blind, placebo-controlled, randomized, crossover design and was conducted in 18 healthy young subjects. On the 2 treatment days, separated by a washout period of 7 days, the dual-RF was administered in combination (blinded) with tolcapone (200 mg) or placebo. Both treatment combinations were well tolerated. Tolcapone increased the bioavailability (AUC0–∞) and apparent elimination half-life (t½) of levodopa by 80 and 40%, respectively, compared to placebo. The maximal plasma concentration (Cmax) was slightly elevated by tolcapone. In the presence of tolcapone, formation of 3-OMD was substantially reduced. In conclusion, the effect of tolcapone on levodopa pharmacokinetics after administration of the dual-RF is similar to the one observed after immediate- and slow-RFs and leads to a marked improvement in levodopa pharmacokinetics and subsequently to an optimization of levodopa therapy.

Plasma tenoxicam concentrations after single and multiple oral doses

SummaryThe pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76±0.48 μg/ml (mean±s.d.) and the time to reach Cmax (Tmax) was 5.0±3.0 h. The area under the plasma concentration-time curve (AUCo-∼) after a single administration of tenoxicam was 242.5±73.5 μg x h/ml. The elimination half-life (t 1/2 ) was 66.3±15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84±0.33 μg/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63±3.33 μg/ml and Tmax remained 5.0±3.0 hours. AUC within a dosing interval at steady-state was 262.2±67.0 μg x h/ml, Cminss was 9.67±3.25 μg/ml, and t 1/2 averaged 74.2±13.3 h. The average fluctuation during multiple-dose administration was 26.8±8.0% and the accumulation ratio was 5.82±0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy subjects

A multiple-dose study was performed to assess the pharmacokinetic profile of a new levodopa/benserazide dual-release formulation (DRF) in comparison with a conventional slow-release formulation (SRF). The study was of an open label, randomized, two-way cross-over design and was conducted in 18 subjects. Assessment of the two formulations was at day 1 (single-dose) and at day 7 after a 5-day t. i.d. pre-treatment (100 mg levodopa and 25 mg benserazide) in fasting state. The pharmacokinetic parameters reflecting bioavailability, accumulation and metabolism of levodopa were determined. The levodopa pharmacokinetics of the new DRF showed rapid absorption (tmax=1.1 h), followed by sustained levodopa plasma concentrations, similar to the SRF. Following multi-dose administration, the peak plasma concentration of the new DRF was 90% higher compared to the SFR (Cmax=2.1 and 1.1 microg/ml, respectively). The bioavailability was significantly increased by 40% (AUC0-infinity=6.1 and 4.3 microg x h/ml, respectively). The new DFR was well tolerated as shown by the low incidence of mild side effects. In conclusion, the results of this study confirmed the levodopa dual-release properties of this new levodopa/benserazide formulation.

Pharmacokinetic Studies with a Dual-Release Formulation of Levodopa, a Novel Principle in the Treatment of Parkinson’s Disease

The objectives of the two studies reported here were the investigation of the influence of tablet breaking and food on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new levodopa/benserazide formulation with a biphasic drug delivery profile (Madopar® DR). Both studies had an open-label, randomised, two-way crossover design and were conducted in 12 healthy young subjects. The pharmacokinetics of levodopa and 3-OMD after one intact or two halved tablets were very similar with average Cmax and tmax 1.9 mg·l–1 and 1.2 h, respectively. Administration of the formulation after a standard breakfast did not influence the extent of levodopa absorption but increased the absorption rate. Cmax and tmax were on average 2.1 mg·l–1 and 1.3 h, respectively, in the fed condition and 1.5 mg·l–1 and 2.5 h in the fasted condition. The presence of food did not markedly affect the plateau in levodopa levels between about 1 and 3 h after intake. In conclusion, the release characteristics in healthy subjects of the new levodopa/benserazide formulation are influenced only to a minor extent by concomitant intake of food or by tablet breaking.