Marc Lefebvre

Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects

Almeida L, Nunes T, Sicard E, Rocha J‐F, Falcão A, Brunet J‐S, Lefebvre M, Soares‐da‐Silva P. Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects. 
Acta Neurol Scand: 2010: 121: 257–264.
© 2009 The Authors Journal compilation

Pharmacokinetic interaction study between eslicarbazepine acetate and topiramate in healthy subjects

Abstract Objective: Combination therapy is frequently required in the management of epilepsy. The primary objective of this study was to investigate the pharmacokinetic interaction between eslicarbazepine acetate (ESL) 1200 mg once daily and topiramate (TPM) 200 mg once daily in healthy subjects. Methods: Multiple-dose, open-label, one-sequence study in two parallel groups of 16 healthy male volunteers. After an 8-day treatment with ESL (Group A) or TPM (Group B), ESL and TPM were co-administered for 19 days. A bioequivalence approach based on a within-subject comparison was used to investigate a potential drug–drug interaction. End/start of treatment geometric mean ratios (GMR, %) and 90% confidence intervals (90% CI) were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve over the dosing interval at steady-state (AUCss) of eslicarbazepine (ESL major active metabolite), R-licarbazepine (ESL minor active metabolite) and TPM at Day 8 and Day 27. Results: In Group A, eslicarbazepine GMR (90% CI) was 86.79% (81.06%; 92.94%) for Cmax and 92.70% (89.21%; 96.32%) for AUCss. In Group B, TPM GMR (90% CI) was 81.50% (77.48%; 85.89%) for Cmax and 81.81% (79.69%; 84.00%) for AUCss. The 90% CI of eslicarbazepine Cmax and AUCss fell within the pre-specified bioequivalence range (80.00%; 125.00%), allowing it to be concluded that the extent of systemic exposure to eslicarbazepine was unaffected by the concomitant administration of TPM. The 90% CI for topiramate AUCss was borderline in relation to the pre-specified bioequivalence range and topiramate Cmax fell outside the pre-specified bioequivalence range. Therefore, the extent of systemic exposure to TPM following co-administration with ESL was not formally bioequivalent to the extent of systemic exposure to TPM when TPM was administered alone. However, there was no difference between TPM elimination half-life following TPM co-administered with ESL and TPM administered alone (24.0 and 24.3 h, respectively). The bioavailability of R-licarbazepine was essentially bioequivalent. Two subjects discontinued due to adverse events. No clinical interaction appeared to be present in terms of adverse events when both drugs were given concomitantly. Conclusion: Concomitant administration of eslicarbazepine acetate 1200 mg once daily and topiramate 200 mg once daily showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required.

Determination of naproxen using DBS: evaluation & pharmacokinetic comparison of human plasma versus human blood DBS

BACKGROUND Dried blood spots (DBS) sampling is a well-known technology for qualitative determination such as DNA analysis and screening of newborn metabolic disorders. The scientific community has recently expressed interest in applying the DBS technique for quantitative determination of drugs in biological fluid. RESULTS Two new bioanalytical assays were developed and validated for the determination of naproxen in human plasma and in DBS samples using liquid chromatography coupled with tandem MS. Furthermore, plasma and DBS clinical samples were collected from four subjects enrolled as part of a bioequivalence study. Concentration data for plasma and DBS samples were determined and pharmacokinetic (PK) profiles in plasma and in DBS samples were compared. CONCLUSIONS A strong correlation between PK data obtained by the DBS and conventional plasma method was observed, which makes DBS a valuable technique for further naproxen bioavailability and PK investigations and studies.

Influence of omeprazole on bioavailability of bismuth following administration of a triple capsule of bismuth biskalcitrate, metronidazole, and tetracycline.

The objective of this study was to determine the impact of omeprazole on bismuth (Bi) bioavailability when given in a three‐in‐one capsule containing bismuth biskalcitrate, metronidazole, and tetracycline. Thirty‐four healthy volunteers were randomly assigned to receive three capsules (each containing bismuth biskalcitrate 140mg+ metronidazole 125 mg+ tetracycline 125 mg) qid alone × 6 days or the same treatment + omeprazole (OM) 20 mg bid. Blood was drawn at intervals for 24 hours after the last dose. After the last dose, mean (CV) Cmin for plasma bismuth was 2882 pg/mL (36%) and 1195 pg/mL (23%) (p < 0.001), with and without OM, respectively. Mean (CV)Cmax was 25,493 pg/mL (69%) and 8061 pg/mL (28%) (p < 0.001) with and without OM, respectively. AUC0‐24 increased by 2.9 in presence of OM (p < 0.001). Adverse events in both groups were usually mild and of a gastrointestinal nature, and all had resolved by the end of the trial. This study confirms an interaction between Bi biskalcitrate and OM. Risk of Bi toxicity, seen after long‐term use of Bi compounds, is minimal here because plasma levels of Bi remained well below the toxic levels of 50 μg/L, and the treatment period with this triple capsule + OM is only 10 days, a substantially lower number of days compared to that which might produce Bi toxicity.

Study on the bioequivalence of two formulations of eplerenone in healthy volunteers under fasting conditions: data from a single-center, randomized, single-dose, open-label, 2-way crossover bioequivalence study.

BACKGROUND Eplerenone (CAS 107724-20-9) prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease and is indicated, in addition to standard therapy including beta-blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF < or = 40%) and clinical evidence of heart failure after recent myocardial infarction. OBJECTIVE The aim of this study was to assess the bioequivalence of a new eplerenone 50 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product. METHODS This was a single-center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions. Plasma samples were collected up to 24 h post-dosing and plasma eplerenone levels were determined by reversed phase high performance liquid chromatography and by tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated using non-compartmental analysis. Area under the concentration-time curve from time zero to time of last non-zero concentration (AUClast) and maximum observed concentration (Cmax) were the main evaluation criteria. All of the above-mentioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the 1n-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis. RESULTS According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUClast and Cmax were within the predefined ranges (80.00-125.00%). CONCLUSION Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions was concluded according to European guidelines. Both formulations were well tolerated.

Pharmacokinetic bioequivalence, safety and acceptability of Ornibel®, a new polymer composition contraceptive vaginal ring (etonogestrel/ethinylestradiol 11.00/3.474 mg) compared with Nuvaring® (etonogestrel/ethinylestradiol 11.7/2.7 mg)

Abstract Objective: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring® (MSD, Spain). Subjects and methods: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. Ornibel® contains etonogestrel/ethinylestradiol 11.00/3.47 mg and Nuvaring® contains etonogestrel/ethinylestradiol 11.7/2.7 mg, both rings delivering 120/15 µg/day. For the calculation of pharmacokinetic parameters, 37 blood samples were collected up to 840 h after each ring insertion to quantify plasma concentrations of etonogestrel and ethinylestradiol using a validated MS/MS-HPLC. Safety was assessed by adverse events recording, clinical laboratory and vital signs and tolerability by vaginal examination. Acceptability was investigated by a 5-point scale questionnaire. Results: Bioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80–125% acceptance range for both etonogestrel (Cmax: 96.81–112.20%; AUC0-504h: 98.71-108.61%; AUC0-t: 100.14–109.10%) and ethinylestradiol. (Cmax: 105.91–120.62%; AUC0-504h: 105.47–114.59%; AUC0-t: 108.31-117.61%). During the first day of use a burst effect was observed with Nuvaring®, with significantly higher level of ethinylestradiol (Cmax0-24h ratio: 78.34%, 94.12CI: 73.55–83.45%). Both products were well tolerated and accepted, without significant differences between them. Conclusion: Ornibel® is bioequivalent to Nuvaring® in terms of efficacy, safety, tolerability and acceptability. The new polymer composition provides Ornibel® with more stability and gradual hormonal release during the first day of use, particularly for ethinylestradiol.

The impact of new partial AUC parameters for evaluating the bioequivalence of prolonged-release formulations.

To demonstrate bioequivalence (BE) between two prolonged-release (PR) drug formulations, single dose studies under fasting and fed state as well as at least one steady-state study are currently required by the European Medicines Agency (EMA). Recently, however, there have been debates regarding the relevance of steady-state studies. New requirements in single-dose investigations have also been suggested by the EMA to address the absence of a parameter that can adequately assess the equivalence of the shape of the curves. In the draft guideline issued in 2013, new partial area under the curve (pAUC) pharmacokinetic (PK) parameters were introduced to that effect. In light of these potential changes, there is a need of supportive clinical evidence to evaluate the impact of pAUCs on the evaluation of BE between PR formulations. In this retrospective analysis, it was investigated whether the newly defined parameters were associated with an increase in discriminatory ability or a change in variability compared to the conventional PK parameters. Among the single dose studies that met the requirements already in place, 20% were found unable to meet the EMAs new requirements in regards to the pAUC PK parameters. When pairing fasting and fed studies for a same formulation, the failure rate increased to 40%. In some cases, due to the high variability of these parameters, an increase of the sample size would be required to prove BE. In other cases however, the pAUC parameters demonstrated a robust ability to detect differences between the shapes of the curves of PR formulations. The present analysis should help to better understand the impact of the upcoming changes in European regulations on PR formulations and in the design of future BE studies.