Adverse event potentially due to an interaction between ibrutinib and verapamil: a case report.

WHAT IS KNOWN AND OBJECTIVE: Ibrutinib is a recently approved oral anticancer agent with pharmacokinetics that is very sensitive to metabolic inhibition. We report a serious side effect of ibrutinib potentially attributable to interaction with the moderate CYP3A4 inhibitor verapamil. CASE DESCRIPTION: A patient with mantle cell lymphoma was admitted to our emergency department with severe diarrhoea. During a prescription review, the clinical pharmacist identified a potential drug interaction between ibrutinib and verapamil present in a branded combination product also containing trandolapril. Ibrutinib was discontinued for 5 days, and verapamil was stopped. Lercanidipine 10 mg daily was prescribed as an alternative antihypertensive drug. The patient was discharged after 3 days with symptomatic treatment for his diarrhoea. Three months later, the patient maintained control with ibrutinib and olmesartan, but without verapamil. WHAT IS NEW AND CONCLUSION: This is the first description of a serious side effect of ibrutinib likely due to an interaction with the CYP3A4 inhibitor verapamil. Prescriptions of ibrutinib must be carefully checked to identify possible interactions with CYP3A4 inhibitors and patients monitored accordingly.

[Feedback on the evaluation of clinical pharmacy activities developed in surgery]. / Retour d'expérience sur l'évaluation des activités de pharmacie clinique développées en chirurgie.

INTRODUCTION: Our current development strategy integrates clinical pharmacy activities prioritized in surgical services. Patients in these services are typically risk patients: transfers, multiple prescribers, frequent medication change, pharmacotherapeutic risk classes. PATIENTS AND METHODS: Three clinical pharmacy activities (admission reconciliation, pharmaceutical analysis, participation doctors round) have been developed in orthopaedic surgery and neurosurgery. Pharmacists prospectively recorded data describing their activities: number of reconciliations and analyzed requirements and time required to achieve them. Data on pharmaceutical interventions were recorded on the basis ActIP®. The clinical significance of interventions was retrospectively rated by a team of two pharmacists and two physicians on the scale adapted Hatoum et al. RESULTS: Four thousand five hundred pharmaceutical analysis and 248 reconciliations were conducted. One hundred and fifty-six pharmaceutical interventions were issued. The average acceptance rate was 80%. A total of 5.8% of pharmaceutical interventions have been listed with a very significant clinical importance and 48.1% with at least significant clinical importance. The activities and documentation required pharmaceutical average daily time (senior pharmacist, resident and external pharmacist) about 6 hours. DISCUSSION AND CONCLUSION: Other studies, including comparative and medico-economic, must be conducted to support these results. Nevertheless, the indicators obtained attend a better readability of the clinical importance of the activities performed by clinical pharmacists and this particularly in surgical services, both by prescribers and authorities.

[Clinical pharmacy and surgery: Review]. / Pharmacie clinique et chirurgie : revue de la littérature.

Clinical pharmacy has been developed and evaluated in various medical hospital activities. Reviews conducted in this area reported a higher value of this discipline. In surgical services, evenly adverse drug events may occur, so clinical pharmacy activities must also help to optimize the management of drug's patient. The objectives of this literature review is to determine the profile of clinical pharmacy activities developed in surgical services and identify indicators. The research was conducted on Pubmed(®) database with the following keywords (2000-2013), "surgery", "pharmacy", "pharmacist", "pharmaceutical care", "impact" and limited to French or English papers. Studies dealing on simultaneously medical and surgical areas were excluded. Twenty-one papers were selected. The most frequently developed clinical pharmacy activities were history and therapeutic drug monitoring (antibiotics or anticoagulants). Two types of indicators were identified: activity indicators with the number of pharmaceutical interventions, their description and clinical signification, the acceptance rate and workload. Impact indicators were mostly clinical and economic impacts. The development of clinical pharmacy related to surgical patients is documented and appears to have, as for medical patients, a clinical and economical value.

[Medication adverse events: Impact of pharmaceutical consultations during the hospitalization of patients]. / Évènements iatrogènes médicamenteux : impact des consultations pharmaceutiques en cours d'hospitalisation.

The medication iatrogenic events are responsible for nearly one iatrogenic event in five. The main purpose of this prospective multicenter study is to determine the effect of pharmaceutical consultations on the occurrence of medication adverse events during hospitalization (MAE). The other objectives are to study the impact of age, of the number of medications and pharmaceutical consultations on the risk of MAE. The pharmaceutical consultation is associated to a complete reassessment done by both a physician and a pharmacist for the home medication, the hospital treatment (3days after admission), the treatment during chemotherapy, and/or, the treatment when the patient goes back home. All MAE are subject to an advice for the patient, additional clinical-biological monitoring and/or prescription changes. Among the 318 patients, 217 (68%) had 1 or more clinically important MAE (89% drug-drug interaction, 8% dosing error, 2% indication error, 1% risk behavior). The patients have had 1121 pharmaceutical consultations (3.2±1.4/patient). Thus, the pharmaceutical consultations divided by 2.34 the risk of MAE (unadjusted incidence ratio, P≤0.05). Each consultation decreased by 24% the risk of MAE. Moreover, adding one medication increases from 14 to 30% as a risk of MAE on the population. Pharmaceutical consultations during the hospital stay could reduce significantly the number of medication adverse effects.

Assessment of high-priced systemic antifungal prescriptions.

OBJECTIVES: To assess compliance with international guidelines for costly antifungal prescriptions and to compare these results with a first study performed in 2007. METHODS: Retrospective study including all costly antifungal prescriptions made in surgical and medical intensive care units and in a hepatobiliary, pancreatic, and digestive surgery unit. Prescriptions were assessed in terms of indication, dosage, and antifungal de-escalation. RESULTS: Seventy-four treatments were analyzed. Treatments were prescribed for prophylactic (1%), empirical (22%), pre-emptive (16%), or targeted therapy (61%). Caspofungin accounted for 68% of prescriptions, followed by voriconazole (20%) and liposomal amphotericin B (12%). Indication was appropriate in 91%, debatable in 1%, and inappropriate in 8%. Dosage was appropriate in 69%, debatable in 8%, and inappropriate in 23%. Prescriptions were inappropriate for the following reasons: lack of dosage adjustment in light of the hepatic function (10 cases), underdosage or excessive dosage by>25% of the recommended dose in seven cases. De-escalation to fluconazole was implemented in 40% of patients presenting with a fluconazole-susceptible candidiasis. CONCLUSION: The overall incidence of appropriate use was higher in 2012 compared with 2007 (62% and 37% respectively, P=0.004). Nevertheless, costly antifungal prescriptions need to be optimized in particular for empirical therapy, dosage adjustment, and potential de-escalation to fluconazole.

Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography.

The pharmacokinetics and metabolism of Navelbine (NVB) were investigated in 20 patients by a specific high performance liquid chromatographic methodology allowing the monitoring of NVB, deacetyl-NVB, and N-oxide NVB. After the i.v. (15 min) administration of 30 mg/m2 of drug, blood and urine samples were collected for, respectively, 144 and 48 h. NVB is characterized by a three compartmental kinetics, with a Cmax of 1130 +/- 139 (SEM) ng/ml. The total body clearance and apparent volume of distribution, as defined by high performance liquid chromatography, are 1.26 +/- 0.09 liter/h/kg (48.6 +/- 4.1 liters/h/m2) and 75.6 +/- 9.2 liters/kg (2918.4 +/- 307.2 liters/m2). No metabolite could be detected in serum; the urinary excretion of NVB represented 11% of the administered dose. Deacetyl-NVB could be identified as a minor urinary metabolite when no N-oxide NVB appeared in the urine samples. Two additional peaks appeared in most of urinary chromatograms as trace amounts. Thus, the major pathway of NVB, as for other Vinca alkaloids, should be hepatic clearance, as biliary elimination and/or hepatic biotransformation.

Clinical pharmacokinetics of vinorelbine.

Vinorelbine (5'-noranhydrovinblastine) is a recently developed semisynthetic anticancer drug which belongs to the Catharanthus alkaloid family. Its mechanism of action is only partially known but it is assumed that it acts, like vinblastine and vincristine, as an antimicrotubule agent arresting cell division in mitosis. Clinically, vinorelbine has mainly shown activity in the treatment of advanced non-small-cell lung cancer and the treatment of metastatic breast cancer. Early pharmacokinetic data were obtained with radioactive assays (radio-immunoassay or 3H-labelled vinorelbine), then with more selective high performance liquid chromatographic techniques. Vinorelbine is usually administered intravenously but there has also been some experimentation with an oral formulation. The bioavailability of a liquid filled gelatin capsule ranges between 12 and 59% with a mean value of 27% [standard deviation (SD) 12%]. Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. In vitro, vinorelbine is mainly distributed into the blood cells, especially platelets (78%) and lymphocytes (4.8%) The unbound blood fraction is around 2%. In lung tissue vinorelbine concentrations are much higher than in serum, by up to 300-fold 3 hours after administration. Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. Urinary excretion of vinorelbine is low, accounting for less than 20% of the dose. Faecal elimination has been demonstrated in 2 patients who were administered 3H-labelled vinorelbine; the amount of radioactivity recovered in the faeces was 33.9 and 58.4% for the 2 patients, respectively. The pharmacokinetic profile of vinorelbine is often described as a 3-compartment model characterised by a long terminal half-life (t1/2) that varies between 20 and 40 hours and a large apparent volume of distribution (Vd) of around 70 L/kg. Systemic clearance ranges between 72.54 and 89.46 L/h (1209 and 1491 ml/min) when determined by high performance liquid chromatography and is higher than that reported by radioimmunoassay [46.2 L/h (770 ml/min)]. This could be due to the greater specificity of the chromatographic method. Vinorelbine has been administered by continuous intravenous infusion over 4 days. Steady-state was reached and the concentrations obtained were above the in vitro IC50 (concentration of drug causing 50% inhibition). The effect of liver disease on vinorelbine pharmacokinetics has been studied in patients with breast cancer. Patients with massive secondary liver disease had a lower systemic clearance than those who have no liver disease or a lesser invasion. In children, vinorelbine seems to display a shorter t1/2 (14.7 hours) than that found in adults. In addition, the systemic clearance is highly variable [from 12 to 93.96 L/h/m2 (200 to 1566 ml/min/m2)]. Vinorelbine is often co-administered with cisplatin in the treatment of advanced non-small-cell lung cancer. The disposition of the alkaloid is not altered by concurrent administration of cisplatin.

Clinical pharmacokinetics of vinorelbine alone and combined with cisplatin.

Vinorelbine (NVB) is a new anticancer drug belonging to the vinca alkaloid family that shows activity as a single-agent treatment in advanced non-small cell lung cancer (NSCLC). Preliminary results show a better response rate with a combination of cisplatin (CDDP) and NVB than with NVB alone. To assess whether this increased activity is secondary to a pharmacokinetic interaction, the authors compared the pharmacokinetic profiles of NVB alone and combined with CDDP in previously untreated inoperable NSCLC patients. Five patients received NVB (30 mg/m2) by short intravenous infusion, and four patients received CDDP (80 mg/m2) 1 hour after the NVB infusion (30 mg/m2). Serum NVB was assayed using a specific high-performance liquid chromatography method. The mean serum concentrations in both groups were similar. In addition, the areas under the curve calculated from 1 hour (beginning of CDDP administration) to 72 hours were 414 ng.hour/mL (standard deviation [SD]: 94) (group NVB alone) and 407.1 ng.hour/mL (SD: 32.9) (group NVB + CDDP). In conclusion, the increased activity observed with the combination NVB + CDDP is not the result of a pharmacokinetic interaction.

Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer.

Vinorelbine (Navelbine, NVB) is a new semi-synthetic vinca alkaloid that is currently used in the treatment of advanced breast cancer and advanced non-small-cell lung cancer (NSCLC). In this study we investigated the tumoral and healthy pulmonary tissue concentrations of NVB in previously untreated NSCLC patients undergoing surgery. A total of 13 patients (mean age, 60 years; range, 42-70 years) were included and received NVB (20 mg/m2) at 1 h (mean, 1.1 h; SD, 0.2 h; n = 6 patients) and 3 h (mean, 3.0 h; SD, 0.6 h; n = 7 patients) before tumor resection. A tumoral and adjacent healthy lung-tissue specimen as well as simultaneously sampled serum were analyzed for NVB by high-performance liquid chromatography (HPLC). NVB levels were much higher in tissue than in serum (up to 300-fold). The tissue/serum ratio increased between the 1-h sampling time (range, 0.1-100) and the 3-h time point (range, 10-300). In all patients but two, NVB concentrations were lower in tumors than in healthy lung tissue. The tumor/healthy tissue ratio ranged from 0.06 to 1.3 (median, 0.09) at 1 h and from 0.18 to 1.1 (median, 0.55) at 3 h. This ratio increased between the 1-h sampling time and the 3-h time point as a consequence of increasing tumor levels (median, 50.4 ng/g at 1 h and 278 ng/g at 3 h). In four patients, concentrations could be measured in necrotic and peripheral tumor zones, showing lower values in necrotic areas. Thus, these data indicate that NVB is highly distributed in lung tissue, with the disposition rate being slower in tumor tissue than in healthy parenchyma during the first 3 h.

Biliary elimination and pharmacokinetics of vinorelbine in micropigs.

The biliary elimination and pharmacokinetics of vinorelbine (NVB) were investigated in five conscious micropigs provided with a double-terminal choledocal fistula allowing the collection and reinstillation of bile. After the i.v. administration of NVB (0.5 mg/kg), serum and bile samples were collected over a 48-h period. The concentrations of NVB were measured by high-performance liquid chromatography. The serum concentrations decreased rapidly from a maximal value of 208.6 ng/ml (SD, 111.7 ng/ml). The mean half-life was 10.9 h (SD, 8.6 h) and the mean AUC0-48 h was 292.8 ng ml-1 h (SD, 79.4 ng ml-1 h). The bile concentrations were high, amounting to 16.0 micrograms/ml (range, 5.4-27.7 micrograms/ml). The 0- to 48-h biliary excretion of unchanged NVB accounted for 25.8% (SD, 5.7%) of the injected dose, with 21.5% (SD, 4.0%) being eliminated during the 0- to 8-h period. Desacetyl-NVB was found in an inconstant manner and in very low amounts in bile samples. In addition, no glucuronide of NVB could be detected. Thus, in the micropig, biliary excretion represents an important route of elimination for NVB.

Pharmacokinetics of three new beta-lactams in the Yucatan micropig model administered by intravenous bolus injection and continuous infusion.

The miniature pig is becoming a popular non-rodent animal model in biochemical research because of physiological similarities to humans. In addition, the micropig presents the advantages of large animal species for experimental pharmacokinetics. However, pharmacokinetics of antimicrobial agents are poorly documented in the pig and further work is needed to establish interspecies comparisons. This prompted us to investigate the disposition of three well documented beta-lactams (cefepime, cefpirome and meropenem) in this model and also to evaluate the potential to use it for pharmacodynamic studies. Each drug was given following a single dose both by direct intravenous injection (or short infusion for meropenem) and continuous infusion. Six animals were enrolled in each group. Blood samples were obtained over a 0-12 h period, using a catheter placed in the external jugular vein. All beta-lactams were assayed by high performance liquid chromatography (HPLC). Pharmacokinetics of cefepime and cefpirome given by bolus injection in the microswine were close to those in man receiving equivalent dosage (i.e. 2 g). The terminal half-lives are similar (human: 1.80 h, 1.80 h; pig: 1.46 h, 1.29 h) as is the case for clearance values (human: 1.82, 1.80; pig: 1.90, 1.74 ml/min per kg) for cefepime and cefpirome, respectively. The administration by continuous infusion does not influence the elimination rate of cefepime, cefpirome and meropenem. Meropenem kinetics in the micropig were also similar to those in man. The terminal half-lives are similar (human, 0.83 h; pig, 0.88 h) as in the case for clearance values (human, 4.0 h; pig, 4.90 ml/min per kg) after 30 min intravenous infusion of meropenem. We concluded that the micropig is an adequate model for the study of the pharmacokinetics and probably the pertinent model for ex-vivo pharmacodynamics investigations of cefepime, cefpirome and meropenem.

Analysis of recent antimicrobial agents in human biological fluids by high-performance liquid chromatography.

Our previous review on the liquid chromatographic (LC) analysis of anti-bacterial agents was published in 1990 in a special issue of the Journal of Chromatography. Eight years later, some new agents have been registered and numerous other are under clinical experiment. In spite of therapeutic problems encountered with certain bacterial pathogens, the development of novel drug candidates has slowed partially due to the need for identification of new bacterial targets and the cost of the research. The present overview updates the LC methods for the quantitations of recent antimicrobial agents (marketed and in clinical development) in human biological fluids. Consideration has been given to procedures permitting the determination of isomers and metabolites as well as methods regarding tissue extracts or liquid sampled from physiological sanctuaries. LC methods are available for the quantitation of almost all registered or investigated recent anti-infective drugs and some are applicable in routine practice. Nevertheless, few techniques have been validated for the determination in tissue extracts limiting the development of penetration studies.

P-glycoprotein and pharmacokinetics.

P-glycoprotein (P-gp) is a transmembrane protein associated with a phenotype of cross resistance to certain anticancer agents. P-gp is thought to act as an energy dependent pump that expels the anticancer drug out of the tumoral cell, reducing its accumulation and hence its activity. P-gp has been detected in vivo and in vitro in numerous tumor cell types but also in normal tissues and particularly in organs involved in the pharmacokinetic behaviour of xenobiotics. The physiologic functions of P-gp remain unclear but a growing amount of information suggests that it can play an important role at the different steps of pharmacokinetics (i.e., absorption, distribution, elimination). This review gives an update on what is known about the impact of P-gp on the disposition of drugs.

Pharmacodynamics of 5-fluorouracil combined with carboplatin in patients with head and neck cancer.

The objective of our work was to investigate the pharmacodynamics of 5-fluorouracil (5-FU) in 23 patients with head and neck cancer treated with carboplatin (360 mg/m2) followed by 5 day continuous infusion of 5-FU (lg/m2/day). The pharmacokinetic profile of 5-FU was characterized for 36 cycles and was compared with the patient's tolerance. Toxic cycles (> or = grade 1, WHO grading) were associated with higher values of area under the serum concentration-time curve (AUC) than those of non toxic cycles. In addition, AUC values of 37000 ng.h.ml-1 and 21000 ng.h.ml-1 for the entire cycle and the half-cycle respectively were found to be predictive of toxicity. These threshold values are identical to those determined in our previous study with the cisplatin-5-FU regimen. Hence, patients treated with carboplatin and infusional 5-FU might benefit from 5-FU blood level, monitoring using the same dose adjustment diagram.

[Role of pharmacokinetics in anticancer chemotherapy]. / Place de la pharmacocinétique en chimiothérapie anticancéreuse.

This review presents different aspects of oncological pharmacokinetics and emphasizes the clinical applications. Pharmacodynamics, pharmacokinetics in phase I trials, search for kinetic interactions are approached.

[Pharmacology of Catharanthus alkaloids]. / Pharmacologie des Catharanthus alcaloïdes.

Catharanthus alkaloids are antitumoral drugs widely used in the treatment of malignant diseases. This review summarizes different aspects of their pharmacology (mechanism of action, resistance, clinical pharmacokinetics) as well as information on their uses in the clinical setting.

[Pharmacokinetic monitoring with dosage adjustment of 5 fluorouracil administered by continuous infusion]. / Surveillance pharmacocinétique avec adaptation de posologie du 5-fluorouracile administré en perfusion continue.

Therapeutic drug monitoring of 5-FU was investigated in patients with head and neck cancer treated with cisplatin (100 mg/m2) followed by 5-day continuous infusion of 5-FU (1 g/m2/d). In a first step, the 5-FU pharmacokinetic and pharmacodynamic analysis of 25 cycles for 14 patients revealed that both the time-concentration product (ASC) for the entire cycle and the half-cycle were predictive of cycle toxicity and a dose adjustment diagram was established. In a second experiment, this diagram was used for treatment monitoring in a group of 35 patients (97 cycles). The clinical toxicity and response were compared with those of a retrospective group of 55 patients (184 cycles) treated with the same protocol without dose adjustment. Pharmacokinetic follow-up of 5-FU has proved to be an objective means to significantly reduce haematological and/or digestive tract toxicity (47 to 33%). Moreover, although dose reduction was often performed, the clinical response was not affected (42-44%), neither was the median survival time (8.8 months-14.1 months in control and adapted groups respectively).

[Pharmacokinetic profile of high-dose doxorubicin administered during a 6 h intravenous infusion in breast cancer patients]. / Profil pharmacocinétique de la doxorubicine administrée à haute dose en perfusion de 6 h chez des patientes atteintes d'un cancer du sein.

The purpose of our investigation was to evaluate the pharmacokinetic profile of doxorubicin administered by a new schedule. Nine non-pretreated young women with high risk breast cancer (mean age: 38, range: 29-45) entered this trial and received, cyclophosphamide (600 mg/m2) given as a 30-min infusion followed by doxorubicin (120 mg/m2) as a continuous infusion over 6 h. Chemotherapy was combined with hematopoietic factor support (G-CSF or GM-CSF). Blood was sampled over the 0-54 h period and 14 cycles were studied for pharmacokinetics. Doxorubicin as well as its major metabolite doxorubicinol were assayed in plasma specimen by high performance liquid chromatography. Mean doxorubicin plasma concentration peak was 42.6 ng/ml (standard deviation (SD): 13.3). The mean terminal half-lives were 32.6 h (SD: 22.0) and 39.2 h (SD: 21.6) for doxorubicin and doxorubicinol, respectively. Mean areas under the plasma concentration-time curve (AUC) were 413 ng/h-1 ml (SD: 103) and 1,707 ng/h-1 ml (SD: 815) for doxorubicin and doxorubicinol respectively. Consequently, the ratio of the AUC of doxorubicinol to that of doxorubicin was high (mean: 4.1 (SD: 1.6)) contrasting with previous studies reporting ratios less than 1 in patients with normal liver function. The systemic clearance of doxorubicin was 5.23 l/min/m2 (SD: 1.91). The inter- and intra-patient variability for AUC was low for both drugs. Hence the coefficients of variation were 24.6% for doxorubicin, 26.2% for doxorubicinol (inter-individual variation) and less than 10% for both compounds (intra-individual variation). In conclusion, the pharmacokinetic profile of doxorubicin (120 mg/m2) administered as a 6 h-continuous infusion is characterized by a greater exposure to doxorubicinol. This could be explained by a saturation in the biliary excretion process during the period following the end of the infusion.

[Thrombosis of a valve prosthesis: fatal cerebral embolism during thrombolytic treatment]. / Thrombose de prothèse valvulaire: embolie cérébrale mortelle lors du traitement thrombolytique.

The authors report the first case of lethal cerebral embolism complicating thrombolytic therapy administered for thrombosis of a mitral valve prosthesis. The incidence of systemic embolism during this form of therapy appears to be at least one in five cases. It may be underestimated and should lead to further discussion as to the indications of thrombolytic therapy and surgery for thrombosis of a left heart valve prosthesis.