Effect of food on oral pharmacokinetics of edaravone coamorphous dispersion containing bile salts as coformers - Part II.

OBJECTIVES: Edaravone (EDR) is an effective neuroprotective agent in various neurological diseases; however, its use is restricted due to poor oral absorption. Bile salts are known for improving solubility and inhibiting drug crystallization in supersaturated conditions of the gastrointestinal tract (GIT). In our previous work, we prepared coamorphous dispersion (COAM) of EDR with sodium taurocholate (NaTC) using spray drying. The optimized EDR COAM exhibited superior in vitro performance compared to plain EDR. EDR is well absorbed in fasted-over-fed conditions. METHODS: The present work, we conducted a pharmacokinetic study for EDR and EDR COAM in fasted and fed conditions to check effect of food on its oral absorption. The LC-MS/MS-based method was developed and validated to determine the amount of EDR in plasma. RESULTS: The results suggested that EDR COAM did not show a significant difference in Cmax (P=0.3544) and AUC (P=0.1696) of fasted and fed states. On the other hand, plain EDR showed 2-fold and 3-fold reduced Cmax (P<0.0001) and AUC (P=0.0094) in the fed condition, respectively. The Cmax and AUC of EDR COAM were improved in fasted (AUC: 2.56-fold) and fed states (AUC: 5.74-fold) than plain EDR, suggesting better oral absorption of COAM than crystalline EDR without having the effect of food. CONCLUSIONS: The unique structural attributes of NaTC had the potential to inhibit the recrystallization of EDR in GIT, while concurrently reducing the impact of food on the oral absorption of EDR.

Validated LC/MS method for simultaneous determination of elbasvir and grazoprevir in human plasma.

A sensitive and accurate LC/MS method for the determination of elbasvir (ELB) and grazoprevir (GZP) in human plasma was established using daclatasvir (DCT) as an internal standard. The analytes were separated on a Waters Spherisorb phenyl column (150mm×4.6mm ID, 5µm particle size) maintained at 40°C±2°C. Gradient elution, at a flow rate of 0.8mLmin-1, was used. The mobile phase consists of 90% of acetonitrile mixed to 10% of a 5mM ammonium formate buffer (+0.1% v/v of trimethylamine, pH was adjusted to 3.2 by formic acid) as phase A and 10% of acetonitrile mixed to 90% of the same buffer as phase B. Liquid-liquid extraction with ethyl acetate solvent was used to recuperate compounds from plasma. The method was validated over a concentration range of 2 and 100ng/mL for GZP and between 1 and 50ng/mL for ELB. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD)<15%, and the accuracy values ranged from 94.2 to 107.8%. The robustness of the method was established using a two-level full factorial design.

Effects of students' peer teaching in a new pharmacokinetics teaching format.

INTRODUCTION: The aim of this work was to evaluate the impact of a teaching method in pharmacokinetics (PK) in terms of satisfaction and performance in the final test of students. MATERIAL AND METHODS: This method consisted of the development of a practical problem and a peer-tutored solution by small groups of three or four students. Students enrolled in the second year of pharmaceutical studies had to generate a PK practical problem, to propose a solution and to conduct a peer-tutored solution of the practical problem completed by another student group in a learning-connected classroom. Student's performance was assessed by individual semi-structured interviews and by comparing the scores obtained in the final test with those obtained in previous years. RESULTS: More than 70% of the students were highly satisfied with the new format of the PK course, especially concerning the development and the design of a practical problem. More than 94% of the students considered that the content of the lecture-based teaching was at least adapted and in accordance with the objectives of the PK course. Students reported very constructive discussions and interactions with peers and the teacher. In addition, students significantly increased their score at the final PK test compared to previous years (53.27±19.10% in 2015-2017 vs. 71.30±13.47% in 2018-2019, P<.0001). CONCLUSION: This new method including peer teaching was applied in PK and allowed to significantly increase the performance and the satisfaction of the students in PK.

Improved oral bioavailability of febuxostat by liquid self-micro emulsifying drug delivery system in capsule shells.

PURPOSE: Febuxostat is a non-purine xanthine oxidase inhibitor which belongs to the BCS class II. Main aim of this study is to enhance dissolution and bioavailability of a drug by formulating a liquid self-micro emulsifying drug delivery system (SMEDDS) in different capsule shells. METHOD: Compatability of gelatin and cellulose capsule shells was checked with different oils, surfactants and co-surfactants. Solubility studies were then carried out in selected excipients. Capryol 90, labrasol, and PEG 400 were used in a liquid SMEDDS formulation based on phase diagram and the drug loading. Further SMEDDS was characterized for zeta potential, globule size and shape, thermal stability and in vitro release. Based on the in vitro release, pharmacokinetic study was carried out using SMEDDS in gelatin capsule shells. RESULT: The diluted SMEDDS had globule size of 157.9±1.5d.nm, zeta potential of -16.2±0.4mV and they were thermodynamically stable. The formulation was found stable for 12 months in capsule shells. When tested in different media (0.1N HCl and pH 4.5 acetate buffer), the in vitro release of newly produced formulations differed substantially from that of commercially available tablets, while the release rate in alkaline medium (pH 6.8) was comparable and the highest. According to in vivo findings in rats, a threefold increase in plasma concentration, a fourfold increase in AUC0-t, and a reduction in oral clearance increased fuxostat's oral bioavailability. CONCLUSION: This investigation revealed that the novel liquid SMEDDS formulation sealed in capsules has considerable potential as a vehicle for enhancing the bioavailability of febuxostat.

Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models.

Despite numerous therapeutic options, multidrug resistance (MDR) remains an obstacle to successful breast cancer therapy. Jadomycin B, a natural product derived from Streptomyces venezuelae ISP5230, maintains cytotoxicity in MDR human breast cancer cells. Our objectives were to evaluate the pharmacokinetics, toxicity, anti-tumoral, and anti-metastatic effects of jadomycin B in zebrafish larvae and mice. In a zebrafish larval xenograft model, jadomycin B significantly reduced the proliferation of human MDA-MB-231 cells at or below its maximum tolerated dose (40 µm). In female Balb/C mice, a single intraperitoneal dose (6 mg/kg) was rapidly absorbed with a maximum serum concentration of 3.4 ± 0.27 µm. Jadomycin B concentrations declined biphasically with an elimination half-life of 1.7 ± 0.058 h. In the 4T1 mouse mammary carcinoma model, jadomycin B (12 mg/kg every 12 h from day 6 to 15 after tumor cell injection) decreased primary tumor volume compared to vehicle control. Jadomycin B-treated mice did not exhibit weight loss, nor significant increases in biomarkers of impaired hepatic (alanine aminotransferase) and renal (creatinine) function. In conclusion, jadomycin B demonstrated a good safety profile and provided partial anti-tumoral effects, warranting further dose-escalation safety and efficacy studies in MDR breast cancer models.

Antibiotic therapy for infectious hemodialysed patients in Bamako: Pharmacokinetic analyses and first improvement suggestions.

Infection which occurs in renal kidney failure patient have to be therapeutically managed immediately and the treatment must be aggressive to be quickly efficient. In Bamako (Mali). Posology adaptation cause a problem in nephrology, especially for the most common used antibiotics to care these infections. Drug dosage is not routinely performed in Bamako. The main objective of this work is to compare anthropometric, clinical and pharmacokinetic profiles and the clinical future between infected hemodialysis patients following an antibiotic therapy in Bamako and Lyon (hospital used as a reference). To reach these objectives, a preliminary punctual study of clinical pharmacokinetic of vancomycin were set up at Bamako, following the personalization therapeutics model from Lyon. Bamako patients' samples were imported to France and dosage analysis were performed at Lyon. BestDose software was used to view and compare complete pharmacokinetic profile. It includes for the first time, in routine, the 50 ml/mn of the renal function during dialyses for 58 patients: 31 for Bamako and 21 for Lyon. The residual concentration at the beginning of the dialysis session was compared. In Bamako, patients are younger, the renal failure is more severe and arteriovenous fistula are never set up, treatments are limited in dose and in duration; the residual concentration before the dialyses are too low; as a consequence, infections are rarely quickly reduced and more especially the death linked to these infections are more important (9 in Bamako versus 1 in Lyon). Urgent corrective measures have to be proposed: propose a conciliation between therapeutic requirements formulated within Lyon protocols and the financial ability of the patient, to promote arteriovenous fistula creation as soon as possible, and develop first dose strategy (unfortunately there is often only one dose): a more aggressive dose estimated from simulation profile performed in this study.

Inhibitory effect of resveratrol on the pharmacokinetics of ticagrelor in vivo and in vitro.

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human cytochrome P450 (CYP) 3A4 (CYP3A4) and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50 mg/kg resveratrol), and group C (150 mg/kg resveratrol). After 30 min administration of resveratrol, a single dose of ticagrelor (18 mg/kg) was administered orally. The in vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated ultra high-performance liquid chromatography - tandem mass spectrometer methods. For the in vivo study, the area under the concentration-time curve and mean peak plasma concentrations of ticagrelor in group B and C appeared to be significantly higher than the control group, while volume of distribution in terminal phase and apparent clearance of ticagrelor in group B and C were significantly decreased. For the in vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The half-maximal inhibitory concentration values of resveratrol were 56.75 µM, 69.07 µM, and 14.22 µM, respectively. Our results indicated that resveratrol had an inhibitory effect on the metabolism of ticagrelor in vitro and in vivo. Further research should focus on the clinical combination of resveratrol with ticagrelor, and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

[Off label uses of tigecycline]. / Les utilisations hors-autorisation de mise sur le marché de la tigécycline.

INTRODUCTION: Tigecycline is a relatively new antibiotic that have very limited valid indications. When no other alternative is available, this drug is widely used off label with promising results. The objective of this study is to summarize the different off label uses of tigecycline so that we can decide when and how to prescribe it in the absence of guidelines. MATERIAL AND METHODS: This study a revue of the literature collecting all the articles concerning the off label uses of tigecycline. RESULTS: Tigecycline was widely prescribed, off label, to treat infections with controversial results. Randomised clinical trials were conducted to evaluate its use to treat pneumonia. The results for this indication have a respectable level of evidence. For the other indications, the data collected was insufficient to support tigecycline prescription. In fact, different protocols were used which makes it hard to evaluate the efficacy and to conclude to the best treatment regimen. A tendency to prescribe high doses of the molecule was noted in different studies. When prescribed off label, tigecycline prescriptions were associated with a higher mortality and incidence of side effects. CONCLUSION: The tigecycline remains a valid option for the treatment of infections dues to multi-resistant bacteria especially when other alternatives are scarce or in cases of renal failure.

[Pharmacokinetic modifications and pharmacokinetic/pharmacodynamic optimization of beta-lactams in ICU]. / Modifications pharmacocinétiques et optimisation pharmacocinétique/pharmacodynamique des bêta-lactamines en réanimation.

Pharmacokinetic modifications in critically ill patients and those induced by ICU therapeutics raise a lot of issues about antibiotic dose adaptation. Beta-lactams are anti-infectious widely used in ICU. Frequent beta-lactam underdoses induce a risk of therapeutic failure potentially lethal and of emergence of bacterial resistance. Overdoses expose to a neurotoxic and nephrotoxic risk. Therefore, an understanding of pharmacokinetics modifications appears to be essential. A global pharmacokinetic/pharmacodynamic approach is required, including use of prolonged or continued beta-lactam infusions to optimise probability of pharmacokinetic/pharmacodynamic target attainment. Beta-lactam therapeutic drug monitoring should also be considered. Experts agree to target a free plasma betalactam concentration above four times the MIC of the causative bacteria for 100 % of the dosing interval. Bayesian methods could permit individualized doses adaptations.

The effect of gender and ABCB1 gene polymorphism on the pharmacokinetics of azithromycin in healthy male and female Pakistani subjects.

In the current study, the possible outcome of gender difference and genotypic polymorphism of the ABCB1 gene encoding P-glycoprotein on the pharmacokinetics of azithromycin has been evaluated. An open-label, comparative pharmacokinetic study was done in healthy Pakistani volunteers (females (n = 8) and males (n = 8)). They were administered a single 500 mg oral dose of azithromycin. Blood samples (≈5 mL) were collected in heparinized tubes and the HPLC/MS/MS method was used to determine azithromycin plasma levels. ABCB1 polymorphism (single nucleotide polymorphisms) at C3435T, G26SST was performed using the RFLP-PCR method. The Student t test was applied to compare pharmacokinetic parameters of azithromycin between male and female human subjects (at 95% CI) using GraphPad Prism-8. A significant difference was observed in pharmacokinetic parameters between males and females, as Cmax in males (230 ± 80.2 ng/mL) was significantly higher than in females (224.9 ± 75.5 ng/mL), while [Formula: see text] was also significantly higher (p < 0.05) in males (2102 ± 200.3 ng·h-1·mL-1) compared to females (1825.7 ± 225.4 ng·h-1·mL-1). There was a significant variation in Cmax and AUC in three ABCB1 genotyping groups as well. Gender difference and ABCB1 gene polymorphisms have a significant impact on the pharmacokinetics of azithromycin, as they contribute to interindividual variability in therapeutic response.

Pharmacokinetic profile of the selective 5-HT3 receptor antagonist ondansetron in the rat: an original study and a minireview of the behavioural pharmacological literature in the rat.

The availability of agonists and antagonists to modulate the activity of the 5-hydroxytryptamine (5-HT) type 3 (5-HT3) receptor has renewed interest in its role as a therapeutic target. Ondansetron is a highly selective 5-HT3 receptor antagonist that is well tolerated as an anti-emetic for patients undergoing chemotherapy. Preclinical studies in rat have shown the effects of small doses of ondansetron on cognition, behavioural sensitisation, and epilepsy. However, the pharmacokinetic (PK) profile of ondansetron in rat has not been described, which limits the translational relevance of these findings. Here, we aim to determine, in the rat, the PK profile of ondansetron in the plasma and to determine associated brain levels. The plasma PK profile was determined following acute subcutaneous administration of ondansetron (0.1, 1, and 10 µg/kg). Brain levels were measured following subcutaneous administration of ondansetron at 1 µg/kg. Plasma and brain levels of ondansetron were determined using high-performance liquid chromatography - tandem mass spectrometry. Following administration of all three doses, measured ondansetron plasma levels (≈30-3000 pg/mL) were below levels achieved with doses usually administered in the clinic, with a rapid absorption phase and a short half-life (≈30-40 min). We also found that brain levels of ondansetron at 1 µg/kg were significantly lower than plasma levels, with brain to plasma ratios of 0.45 and 0.46 in the motor and pre-frontal cortices. We discuss our findings in the context of a minireview of the literature. We hope that our study will be helpful to the design of preclinical studies with therapeutic end-points.

Pharmacokinetics and tissue distribution study of herpetotriol in rats by ultrahigh-performance liquid chromatography with tandem mass spectrometry.

Herpetotriol, a typical lignan in Herpetospermum pedunculosum Wall's seeds that has long been used to treat icterhepatitis and indigestion and other related diseases in Tibet, is of potential hepatoprotection. This study aims to study the pharmacokinetics features of herpetotriol, including the blood drug concentration - time curve and tissue distribution. The ultrahigh-performance liquid chromatography with tandem mass spectrometry method was established to detect herpetotriol concentration in plasma and tissues, and the method showed good linearity from 10 to 2000 ng/mL (r ≥ 0.9972) and sensitivity (≥10 ng/mL). Our blood drug concentration - time curve indicated that herpetotriol was distributed quickly in rats with a Tmax value at about 0.083 h and eliminated rapidly with a clearance rate at 98.13 ± 8.05 and 137.04 ± 9.48 L·h-1·kg-1 with doses of 5 and 2.5 mg/kg, respectively. Although herpetotriol was detectable in all tested tissues, it has a higher concentration in liver than in heart, lung, spleen, and kidney, which is in line with its hepatoprotection. The pharmacokinetics features uncovered by the present study could provide more information for future pharmacological and toxicological study of herpetotriol.

The pharmacokinetics of mycophenolic acid in rats with orotic acid induced nonalcoholic fatty liver disease.

Post-transplantation nonalcoholic fatty liver disease (NAFLD) is common in liver transplant recipients. Changes in the expression levels and activities of drug-metabolizing enzymes and drug transporters have been reported in patients with NAFLD and relevant rodent models. Here, we evaluated whether the pharmacokinetics of mycophenolic acid (MPA), an immunosuppressant, would be altered in rats with NAFLD. NAFLD was induced by feeding a diet containing 1% (w/w) orotic acid for 20 days. The extent of hepatic glucuronidation of MPA to a major metabolite, mycophenolic acid-7-O-glucuronide (MPAG), did not differ between rats with NAFLD and controls. The expression levels of hepatic multidrug resistance-associated protein 2, responsible for biliary excretion of MPAG, were comparable in rats with NAFLD and controls; the biliary excretion of MPAG was also similar in the two groups. Compared with control rats, rats with NAFLD did not exhibit significant changes in the areas under the plasma concentration - time curves of MPA or MPAG after intravenous (5 mg/kg) or oral (10 mg/kg) administration of MPA. However, delayed oral absorption of MPA was observed in rats with NAFLD compared with controls; the MPA and MPAG peak plasma concentrations fell significantly and the times to achieve them were prolonged following oral administration of MPA.

Validated RP-HPLC method for quantification of doxazosin in human plasma: Application in a bioequivalence study.

OBJECTIVES: The aim of the present study was to validate a simple, sensitive, HPLC method of analysis of doxazosin in human plasma with fluorescence detection. METHODS: The validated method employed one-step direct protein precipitation with acetonitrile. Chromatographic separation was attained using a reverse-phase 250mm×4.6mm 5µ Hypersil® BDS C 18 column and the mobile phase consisted of 10mm sodium dihydrogen phosphate dihydrate (pH=3.0) and acetonitrile at a ratio of (65:35 v/v). The method was evaluated in terms of linearity, precision, accuracy, selectivity and stability as per standard guidelines. The total run time was about 4.5min which make this method suitable for high throughput analyses. This method was applied to the bioequivalence study of two doxazosin tablets in healthy human volunteers. RESULTS: Good linear response was achieved over the range of 5.0-200ng/mL. The observed within- and between-day assay precision ranged from 0.64% to 14.73%; accuracy varied between 94.11% and 105%. The 90% confidence intervals for the ratio Cmax, and AUC 0-∞ of the test product over those of reference were within the acceptable range (0.8-1.25) for bioequivalence. CONCLUSION: The developed method was simple and could be applied to therapeutic drug monitoring of doxazosin.

Effect of a nonsystemic, orally administered hydrogel, GS100, on metformin pharmacokinetics.

Overweight and obesity are major health concerns worldwide, and are major predisposing factors for type 2 diabetes. This single-centre, Phase I, randomised, open-label, single-dose, 4-arm crossover, device-drug interaction study on 24 healthy volunteers with a body mass index of 25-40 kg/m2 tested the effect of a novel, nonsystemic, orally administered hydrogel (GS100) on the pharmacokinetics of an oral antidiabetic drug, metformin. When administered in both the fed and fasted states, the effect of GS100 on metformin pharmacokinetic characteristics was found to be similar to that of food. The type, frequency, and intensity of adverse events observed when GS100 was co-administered with metformin were similar to those observed with metformin alone. This study demonstrates that GS100 can be taken by patients receiving metformin, without altering the administration of metformin.

Reversal of P-glycoprotein-mediated multidrug resistance and pharmacokinetics study in rats by WYX-5.

Multidrug resistance (MDR) is one of the major obstacles confronted in cancer chemotherapy; this obstacle is mainly due to the overexpression of P-glycoprotein (P-gp). Co-administration of anticancer drugs and P-gp inhibitors is a promising approach to overcome MDR. WYX-5, a novel P-gp inhibitor, shows a notable reversal effect with low cytotoxicity in vitro. In this paper, the reversal mechanism and safety of the MDR modulator WYX-5 were explored in vitro, and evaluated for its pharmacokinetics and effects on adriamycin (ADM) metabolism in vivo. The results suggest that WYX-5 is a potent P-gp inhibitor with EC50 in nanomole range (EC50 = 204.3 ± 20.2 nmol·L-1), relative safety (therapeutic index = 446.4), which performs as a substrate of P-gp and retrains its function. Further, WYX-5 (5 mg·kg-1) had relatively ideal pharmacokinetic properties (T1/2 = 6.448 h, F = 96.05%) without interactions with ADM metabolism in vivo. In conclusion, WYX-5 may be a promising candidate for MDR cancer combined-chemotherapy research.

[Pharmacokinetic drug interaction between miconazole mucoadhesive tablet and tacrolimus: About 3 case-reports in transplant patients]. / Interaction pharmacocinétique entre la forme mucoadhésive de miconazole et le tacrolimus : à propos de 3 observations cliniques chez des patients greffés.

Loramyc® is a mucoadhesive tablet of miconazole, indicated for the treatment of oropharyngeal candidiasis in immunocompromised patients. Miconazole, as others azole antifungals, is known for its potent inhibitory properties of cytochromes P450 enzymes and P-glycoprotein (P-gp). Inhibition of cytochromes P450 enzymes and P-gp can produce pharmacokinetic drug interaction. Immunosuppressive agents, such as calcineurin inhibitors (tacrolimus, cyclosporine) are substrates of cytochromes P450 3A4 and P-gp. Nevertheless, the impact of systemic absorption of miconazole mucoadhesive tablet has not been investigated by the laboratory before regulatory approval. No recommendation currently exists in case of co-prescription of Loramyc® and immunosuppressive agents which are counter-indicated as a matter of principle. Herein, we present 3 cases of transplanted patients, requiring miconazole mucoadhesive tablet, who presented a tacrolimus overdose. These cases illustrate that of therapeutic drug monitoring is feasible in order to prevent the occurrence of overdoses and adverse reactions related.

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.

We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.

Effect of CYP2D6 polymorphisms on the pharmacokinetics of propafenone and its two main metabolites.

AIM OF THE STUDY: Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR-PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH-PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated. METHODS: Twelve healthy volunteers, 3 poor metabolizers (PM), 2 intermediate metabolizers (IM) and seven extensive metabolizers (EM) received an oral dose of PPF. Concentrations of PPF and its metabolites were analyzed in serum samples over 27h. RESULTS: The PPF/5OH-PPF ratio distinguished EMs from PMs, but not from IMs. In PMs, the mean transit time (MTT) values were almost the same for PPF and NOR-PPF and much higher than those of EMs and IMs. 5OH-PPF was not detected in EMs. Mean MTT values of 5OH-PPF and NOR-PPF in IMs were 5.27- and 1.52-fold higher than those of EMs. CONCLUSION: A single time point serum PPF-MR approach is a useful tool to identify PMs. CYP2D6 polymorphism significantly affects the pharmacokinetics of PPF and its two metabolites.

[Modeling for clinical trial in psychiatry: rationale, benefits and limitations]. / Quelle place pour la modélisation dans les essais cliniques en psychiatrie ?

Drug development of new compounds implies to define the dosage as well as the conditions of their use (indication, treatment duration, drug interactions, warnings …). This information requires the identification of the time course response. The decisions made during the clinical phases are now based on mathematical models. These models are continuously described and improved during all phases of the drug development using data collected in healthy volunteers and patients. Their objectives are to describe the most precisely, the link between the compound characteristics (pharmacology), the patient demographics and the effects. Further, the natural history of the disease, the placebo effect and the probability of dropping out will be integrated into the model to optimize the evaluation of the compound. These technical improvements are not only statistical, in the sense that they allow a better understanding of the advantages and pitfalls of the new drug. This article presents these methods used in psychiatry and which will become the new standard of drug evaluation.