Françoise Pommier

Pharmacokinetics and Pharmacodynamics of the Novel Daily Rivastigmine Transdermal Patch Compared With Twice‐daily Capsules in Alzheimer's Disease Patients

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226–90, and compared drug exposure between patch and capsule administrations. This was an open‐label, parallel‐group study in Alzheimers disease patients randomized to receive either capsule (1.5–6 mg Q12H, i.e., 3–12 mg/day) or patch (5–20 cm2) in ascending doses through four 14‐day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8‐fold at 20 cm2, 345 versus 191 ng·h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

We conducted 3 open–label, multiple–dose, 3‐period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin‐converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration–time curve from time zero to 24 hours (AUC0–24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80–1.25). Valsartan AUC0–24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Estimation of the Absolute Bioavailability of Rivastigmine in Patients with Mild to Moderate Dementia of the Alzheimer’s Type

ObjectiveTo investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer’s type, at the highest approved single dose of 6mg.Design and settingRandomised, two-period crossover, single-centre, non-blinded, inpatient study.Patients and participantsEleven patients (five females and six males) with mean age 69.5 years.MethodsThe 6mg oral dose was compared with a 2mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method.ResultsFollowing oral administration of a single 6mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 µg/L. By a noncompartmental approach, the absolute bioavailability of the 6mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration.ConclusionA noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics.

Gas chromatographic determination of amantadine hydrochloride (symmetrel) in human plasma and urine

A method for the determination of amantadine hydrochloride at concentrations down to 10 ng/ml in human plasma and urine is described. After addition of a known amount of amphetamine sulphate as internal standard to 1 ml of plasma or urine, amantadine is extracted at basic pH in toluene. Both compounds are derivatized with trichloroacetyl chloride. The derivatives are determined by gas chromatography using a 63Ni electron-capture detector. The technique was applied in a study of the elimination of amantadine after oral administration to man; plasma concentrations are reported.

Steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease not affected by co-administration of memantine: an open-label, crossover, single-centre study.

AbstractBackground and objective: It has been shown that combining memantine and a cholinesterase inhibitor, which each affect different neurotransmitter systems, may offer further improvements in efficacy over either treatment alone in patients with Alzheimer’s disease. The present study was conducted to determine if memantine has any effects on the steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer’s disease. Methods: Rivastigmine-treated Alzheimer’s disease patients who had been maintained on a fixed regimen of twice-daily rivastigmine for ≥2 months were eligible to enter the study. Sixteen patients (seven males and nine females, age range 64–88 years, weight range 51.8–104 kg) were enrolled in this open-label, crossover tudy, which consisted of a 28-day screening period, a 36-hour baseline period, and a 35-day combination treatment phase. The patients spent the baseline period and day 35 at the study centre, where plasma samples for pharmacokinetic evaluation were taken at specified time intervals over a 10-hour time period. In addition, 10-hour (evening pre-dose) memantine plasma samples were taken on days 21, 34 and 35. Results: The combination of memantine (10 mg twice daily) with rivastigmine (1.5–6 mg twice daily) was safe and well tolerated. At each dose level of rivastigmine, the area under the concentration-time curve (AUC) values of rivastigmine and its metabolite as well as the metabolite-to-parent AUC ratios were unaffected by co-administration of memantine, confirming the absence of a meaningful pharmacokinetic drug-drug interaction. Conclusion: Under the study conditions, the extent of systemic exposure to rivastigmine and its metabolite NAP226-90 at steady state did not appear to be affected by concomitant administration of memantine.

Simultaneous determination of imipramine and its metabolite desipramine in human plasma by capillary gas chromatography with mass-selective detection

An analytical method for the simultaneous determination of imipramine (IMI) and its N-desmethyl metabolite, desipramine (DIMI) in human plasma by capillary gas chromatography-mass selective detection (GC-MS), with D4-imipramine (D4-IMI) and D4-desipramine (D4-DIMI) as internal standards, was developed and validated. After addition of the internal standards, the compounds were extracted from plasma at basic pH into n-heptane-isoamyl alcohol (99:1, v/v), back-extracted into acidic aqueous solution and re-extracted at basic pH into toluene. Desipramine and D4-desipramine were converted into their pentafluoropropionyl derivatives. The compounds were determined by gas chromatography using a mass selective detector at m/z 234 for IMI, m/z 238 for D4-IMI, m/z 412 for DIMI and m/z 416 for D4-DIMI. The method was applied to clinical samples.

Ketoconazole Increases Fingolimod Blood Levels in a Drug Interaction via CYP4F2 Inhibition

The sphingosine‐1‐phosphate receptor modulator fingolimod is predominantly hydroxylated by cytochrome CYP4F2. In vitro experiments showed that ketoconazole significantly inhibited the oxidative metabolism of fingolimod by human liver microsomes and by recombinant CYP4F2. The authors used ketoconazole as a putative CYP4F2 inhibitor to quantify its influence on fingolimod pharmacokinetics in healthy subjects. In a 2‐period, single‐sequence, crossover study, 22 healthy subjects received a single 5‐mg dose of fingolimod in period 1. In period 2, subjects received ketoconazole 200 mg twice daily for 9 days and a single 5‐mg dose of fingolimod coadministered on the 4th day of ketoconazole treatment. Ketoconazole did not affect fingolimod tmax or half‐life, but there was a weak average increase in Cmax of 1.22‐fold (90% confidence interval, 1.15–1.30). The AUC over the 5 days of ketoconazole coadministration increased 1.40‐fold (1.31–1.50), and the full AUC to infinity increased 1.71‐fold (1.53–1.91). The AUC of the active metabolite fingolimod‐phosphate was increased to a similar extent by 1.67‐fold (1.50–1.85). Ketoconazole predose plasma levels were not altered by fingolimod. The magnitude of this interaction suggests that a proactive dose reduction of fingolimod is not necessary when adding ketoconazole to a fingolimod regimen. The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring.

Evaluation of a pharmacokinetic interaction between valsartan and simvastatin in healthy subjects

ABSTRACT Objective: The potential for a pharmacokinetic drug interaction between valsartan, an antihypertensive drug, and simvastatin, a lipid-lowering agent, was investigated in this study. This was an open-label, multiple-dose, randomized, three-period, cross over study in 18 healthy subjects. Each subject received one 160 mg valsartan tablet or one 40 mg simvastatin tablet or co-administration of valsartan (160 mg) and simvastatin (40 mg) tablets for 7 days, with a 7‑day inter-dose washout period. The steady-state pharmacokinetics of valsartan, simvastatin β‑hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period. Results: The results were interpreted based on the point estimates and the 90% confidence intervals.italic> These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC(0–24)) of valsartan, simvastatin β‑hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (Cmax) of valsartan and simvastatin β‑hydroxy acid was increased by 10% and 22%, respectively, and the Cmax of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated. Conclusions: Based on the wide therapeutic dosage ranges of valsartan and simvastatin, and the highly variable pharmacokinetics of three analytes, the observed differences in the exposure and Cmax of valsartan, simvastatin β‑hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.

Determination of diclofenac in plasma and urine by capillary gas chromatography—mass spectrometry with possible simultaneous determination of deuterium-labelled diclofenac

A specific and sensitive method for the determination of diclofenac at concentrations down to ca. 1 ng/ml, the limit of detection being 100 pg/ml, in human plasma and urine by gas chromatography-mass spectrometry with 2H4-labelled diclofenac as internal standard is described. The method is also suitable for the simultaneous assay of these two compounds when both are present in samples of human plasma or urine. In this case, 5-chlorodiclofenac is used as internal standard. After toluene extraction from plasma or without extraction for urine, the method involves the formation of a dimethylindolinone derivative by extractive alkylation. The technique was applied to determine low plasma concentrations and urinary excretion of labelled and unlabelled diclofenac after percutaneous applications of Voltaren Emulgel to humans applied simultaneously under occlusive dressing as deuterated diclofenac sodium, and without occlusive dressing as unlabelled diclofenac sodium.

Gas chromatographic determination of phentolamine (Regitine) in human plasma and urine.

A method for the determination of unconjugated phentolamine at concentrations down to 5 ng/ml in human plasma, and of free and total (free plus conjugated) phentolamine down to 25 ng/ml in urine is described. After addition of 2-[N-(p-chlorophenyl)-N-(m-hydroxyphenyl)-aminomethyl]-2-imidazoline as internal standard, both compounds are extracted into benzene-ethyl acetate (1:1, v/v) at pH 10, transferred into an acidic aqueous solution and back-extracted at pH 10 into benzene-ethyl acetate. They are then derivatized with N-heptafluorobutyrylimidazole. The derivatives are determined by gas chromatography using a 63Ni electron-capture detector. In urine, total (free plus conjugated) phentolamine is determined after enzymatic hydrolysis. The technique was applied for the study of the plasma concentrations and urinary elimination after oral administration to man.