Publications by authors named "Christophe Bardin"

18 Publications

  • Page 1 of 1

.

Mol Pharmacol 2021 May 14. Epub 2021 May 14.

Centre de Recherche des Cordeliers, INSERM UMRS1138, France

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multi-target inhibitor sorafenib is a first-line treatment for patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the anti-diabetic drug metformin have a survival disadvantage compared to patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg/d) could influence the antitumoral effects of sorafenib (15 mg/kg/d) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, concomitant sequential dosing regimens. We observed that the administration of metformin six hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. When drugs are administrated sequentially, metformin alters the anti-tumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMPK pathway as well as major transcriptomic changes are associated with the loss of the anti-tumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were co-treated with metformin and sorafenib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/molpharm.120.000223DOI Listing
May 2021

Identifying options for oncology therapy regimen codification to improve standardization-combined results of an expert panel and a review.

J Clin Pharm Ther 2021 Mar 9. Epub 2021 Mar 9.

Department of Clinical Pharmacy & Pharmacology, Amsterdam University Medical Center (AUMC), Amsterdam, The Netherlands.

What Is Known And Objective: Chemotherapy drugs are often administered in combinations with predefined interdependent doses and cycle intervals. As yet, there is no global standardization system to describe these complex regimens in a universally comprehensive manner. The aim of this review is to identify which efforts for standardization have been undertaken and which recommendations for databases and nomenclature of chemotherapy regimens are available.

Methods: A literature review was performed to identify all peer-reviewed full-text articles about oncology therapy regimen codification. In addition, the results of this search were evaluated and consensus recommendations from a European expert panel were subsequently added.

Results: This review gives an overview of attempts to standardize chemotherapy nomenclature described in the literature, as well as of previously published identified gaps in regimen codification. In addition, we summarized the suggestions for improvement of chemotherapy codification found in the available literature, combining them with the expertise from a European expert panel of oncology pharmacists.

What Is New And Conclusions: We believe that one of the most important error-prevention measures is standardization. However, there is a paucity of data how it may be achieved. Currently available data suggest that standardization has a positive impact on usability for data networks, prescription software, safety and the measurement of the quality of cancer care delivery. Standardization is also a strong pre-requisite for all discussions including oncology pharmacists and oncologists when evaluating chemotherapy regimen in countries in Europe but also all over the world. The recommendations compiled in this review can help to support overdue standardization efforts in this important therapeutic area.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcpt.13402DOI Listing
March 2021

Cancer, immune suppression and Coronavirus Disease-19 (COVID-19): Need to manage drug safety (French Society for Oncology Pharmacy [SFPO] guidelines).

Cancer Treat Rev 2020 Aug 23;88:102063. Epub 2020 Jun 23.

Department of Pharmacy, Groupement Hospitalier Sud - Hospices Civils de Lyon, Lyon, France; EA 3738 CICLY, UCBL1 Université de Lyon, Lyon, France. Electronic address:

The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctrv.2020.102063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308737PMC
August 2020

Providing Oncology Pharmacy Services During the Coronavirus Pandemic: French Society for Oncology Pharmacy (Société Francaise de Pharmacie Oncologique [SFPO]) Guidelines.

JCO Oncol Pract 2020 11 15;16(11):e1282-e1290. Epub 2020 Jun 15.

French Society for Oncology Pharmacy, Paris, France.

Purpose: Patients with cancer are at higher risk for contracting the COVID-19 infection and are more likely to have higher morbidity and mortality. This is a big challenge for oncology teams that have to treat patients to avoid contamination by SARS-CoV-2. The aim of the current work is to present oncology pharmacy practice guidelines during the COVID-19 pandemic to secure the pharmaceutical care of patients with cancer.

Methods: The bureau of the French Society for Oncology Pharmacy proposed these recommendations according to the French High Authority of Health following the Guidelines of Good Practice, slightly modified according to the pandemic crisis situation. These guidelines were developed by a working group of 7 experts in oncology pharmacy practice. Furthermore, the guidelines were assessed by 31 independent reviewers.

Results: One hundred percent of reviewers approved the guidelines and 90% of them suggested some improvements. The final version incorporates the best comments and consists of 26 recommendations organized in 8 different sections.

Conclusion: These guidelines allow secure pharmaceutical management of patients with cancer during the COVID-19 pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/OP.20.00295DOI Listing
November 2020

Effect of a Roux-en-Y gastric bypass on the pharmacokinetics of oral morphine using a population approach.

Clin Pharmacokinet 2014 Oct;53(10):919-30

Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris, France,

Background And Objectives: Obesity and opioid use for chronic pain in obese individuals are both important public health concerns. The pharmacokinetics of oral morphine after Roux-en-Y gastric bypass (RYGB) are unknown. Therefore, we aimed to study the pharmacokinetics of oral morphine in morbidly obese patients before and after RYGB surgery, to identify the effects of RYGB and the subsequent reversal of morbid obesity on the pharmacokinetic parameters of morphine.

Methods: The pharmacokinetics of oral morphine (30 mg) were studied in 30 obese patients before (Visit 1) and then 7-15 days (Visit 2) and 6 months (Visit 3) after RYGB. A population pharmacokinetic model was used to describe the time course of the plasma morphine concentration, to study the effect of RYGB on morphine pharmacokinetics and to estimate inter-patient variability.

Results: The oral morphine time to maximum plasma concentration (t max) was twofold lower and maximum plasma concentration (C max) was 1.7 times higher at Visit 2, and t max was 7.5 times lower and C max 3.3 times higher at Visit 3 than at Visit 1. The mean oral morphine area under the plasma concentration-time curve (AUC) increased significantly (1.55-fold) between Visits 1 and 3. Changes in body mass index (BMI) after RYGB were clearly associated with decreased apparent oral morphine clearance and apparent central and peripheral morphine volumes of distribution. None of the other anthropometric parameters explained the inter-subject variability in morphine exposure better than BMI.

Conclusion: RYGB and the BMI reduction that followed it dramatically increased the rate of morphine absorption and slightly increased morphine exposure. The dose of immediate-release forms of morphine may be divided in obese patients after RYGB to prevent adverse events due to early and high morphine plasma peaks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-014-0163-0DOI Listing
October 2014

Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies.

Eur J Cancer 2014 Aug 10;50(12):2020-36. Epub 2014 Jun 10.

Department of Pharmacy, CNRS-UMR 7054, School of Medicine Paris 12, Henri Mondor University Hospitals, Créteil, France.

Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2014.04.015DOI Listing
August 2014

Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics.

Eur J Cancer 2014 Aug 2;50(12):2010-9. Epub 2014 Jun 2.

EA4553 Institut Claudius-Regaud, Université Paul-Sabatier, Toulouse, France.

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2014.04.014DOI Listing
August 2014

Therapeutic drug monitoring in cancer--are we missing a trick?

Eur J Cancer 2014 Aug 27;50(12):2005-9. Epub 2014 May 27.

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Stotervaart Hospital, Amsterdam, The Netherlands.

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2014.04.013DOI Listing
August 2014

Drug interactions with solid tumour-targeted therapies.

Crit Rev Oncol Hematol 2014 Jan 28;89(1):179-96. Epub 2013 Aug 28.

Centre d'Étude et de Recours aux Inhibiteurs de l'Angiogénèse, Paris, France; Service d'Oncologie Médicale, Groupement des Hôpitaux Paris Centre, AP-HP, Paris, France.

Drug interactions are an on-going concern in the treatment of cancer, especially when targeted therapies, such as tyrosine kinase inhibitors (TKI) or mammalian target of rapamycin (mTOR) inhibitors, are being used. The emergence of elderly patients and/or patients with both cancer and other chronic co-morbidities leads to polypharmacy. Therefore, the risk of drug-drug interactions (DDI) becomes a clinically relevant issue, all the more so as TKIs and mTOR inhibitors are essentially metabolised by cytochrome P450 enzymes. These DDIs can result in variability in anticancer drug exposure, thus favouring the selection of resistant cellular clones or the occurrence of toxicity. This review provides a comprehensive overview of DDIs that involve targeted therapies approved by the FDA for the treatment of solid tumours for more than 3 years (sorafenib, sunitinib, erlotinib, gefitinib, imatinib, lapatinib, everolimus, temsirolimus) and medicinal herb or drugs. This review also provides some guidelines to help oncologists and pharmacists in their clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2013.08.007DOI Listing
January 2014

Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes.

BMC Pharmacol Toxicol 2013 Aug 5;14:40. Epub 2013 Aug 5.

Background: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes.

Methods: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix.

Results: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days.

Conclusions: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/2050-6511-14-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750485PMC
August 2013

Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus.

Eur J Clin Pharmacol 2012 Jun 25;68(6):961-8. Epub 2012 Jan 25.

Pharmacy-Pharmacology-Toxicology Department, Hôtel-Dieu, 1 Place du Parvis Notre-Dame, Paris Cédex 04, France.

Purpose: The objective of this study was to develop a population pharmacokinetic model and investigate the effect of several demographic covariates on metformin pharmacokinetics in patients with type 2 diabetes mellitus, over a wide range of weights.

Methods: A total of 105 patients received different metformin regimens, and pharmacokinetic sampling included a minimum of two concentrations per patient. Plasma determination of metformin was assayed by high performance liquid chromatography. Population pharmacokinetics was modelled using a nonlinear mixed effects model program (Monolix version 3.1 s).

Results: An open one-compartment model adequately described metformin data. Lean body weight was a better size descriptor than actual body weight or ideal body weight for clearance (CL/F) and volume (V/F) parameters. CL/F was negatively related to age and serum creatinine (SCr). The estimation of specific coefficients for these effects gave better results than the use of renal function descriptors (Cockroft or MDRD). A dose effect in the relative bioavailability was demonstrated.

Conclusion: The pharmacokinetics of metformin was influenced by lean body weight on an allometric basis and was related to markers of renal function, age, and serum creatinine in this population of 105 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-011-1207-0DOI Listing
June 2012

A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial).

Ann Rheum Dis 2011 May 20;70(5):747-54. Epub 2010 Dec 20.

Université Paris-Descartes and Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.

Objectives: To assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA).

Methods: A multicentre, randomised, double-blind, placebo-controlled trial was conducted. The primary objective was to compare the efficacy of a 1-month treatment with anakinra (2 mg/kg subcutaneous daily, maximum 100 mg) with a placebo between two groups each with 12 patients with SJIA. Response was defined by a 30% improvement of the paediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared with baseline. After month 1 (M1), patients taking placebo were switched to anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months, and analyses of treatment effect on blood gene expression profiling.

Results: At M1, 8/12 responders were receiving anakinra and 1 responder receiving placebo (p=0.003). Ten patients from the placebo group switched to anakinra; nine were responders at M2. Between M1 and M12, six patients stopped treatment owing to an adverse event (n=2), lack of efficacy (n=2) or a disease flare (n=2). Blood gene expression profiling at enrollment and at 6 months' follow-up showed one set of dysregulated genes that reverted to normal values in the clinical responders and a different set, including interferon (IFN)-inducible genes, that was induced by anakinra.

Conclusions: Anakinra treatment is effective in SJIA, at least in the short term. It is associated with normalisation of blood gene expression profiles in clinical responders and induces a de novo IFN signature.

Trial Registration Number: NCT00339157.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ard.2010.134254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070271PMC
May 2011

Is the recommended once-daily dose of lamivudine optimal in West African HIV-infected children?

Antimicrob Agents Chemother 2010 Aug 1;54(8):3280-6. Epub 2010 Jun 1.

EA 3620, Université Paris-Descartes, Unité de Recherche Clinique, Hôpital Tarnier, 89 Rue d'Assas, 75006 Paris, France.

We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter.h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P=0.01). The target mean AUC of 8.9 mg/liters.h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00306-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916343PMC
August 2010

Pharmacology of morphine in obese patients: clinical implications.

Clin Pharmacokinet 2009 ;48(10):635-51

Unit of Therapeutic Research, Department of Internal Medicine, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Morphine is an analgesic drug used to treat acute and chronic pain. Obesity is frequently associated with pain of various origins (e.g. arthritis, fibromyalgia, cancer), which increases the need for analgesic drugs. Obesity changes drug pharmacokinetics, and for certain drugs, specific modalities of prescription have been proposed for obese patients. However, scant data are available regarding the pharmacokinetics and pharmacodynamics of morphine in obesity. Prescription of morphine depends on pain relief but the occurrence of respiratory adverse effects correlates with obesity, and is not currently taken into account. Variations in the volume of distribution, elimination half-life and oral clearance of morphine, as well as recent advances in the respective roles of drug-metabolizing enzymes, catechol-O-methyltransferase and the mu opioid receptor in morphine pharmacokinetics and pharmacodynamics, may contribute to differences between obese and non-obese patients. In addition, drug-drug interactions may alter the disposition of morphine and its glucuronide metabolites, which may either increase the risk of adverse effects or reduce drug efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2165/11317150-000000000-00000DOI Listing
December 2009

Didanosine population pharmacokinetics in West African human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment.

Antimicrob Agents Chemother 2009 Oct 6;53(10):4399-406. Epub 2009 Jul 6.

EA3620, Université Paris-Descartes, Paris, France.

Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (Cmax), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and Cmax (P < or = 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter x h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01187-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764159PMC
October 2009

Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships.

Crit Care 2007 ;11(1):R5

INSERM U705, CNRS, UMR 7157, Université Paris 7, Assistance Publique--Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Paris, France.

Introduction: Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.

Methods: We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.

Results: Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.

Conclusion: After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/cc5150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151854PMC
May 2007

[The benefits of computerized anticancer drug distribution].

Bull Acad Natl Med 2005 Nov;189(8):1721-32; discussion 1732-3

Service de Pharmacie, Pharmacologie, Toxicologie de l'Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75181 Paris Cedex 04.

Medication errors can lead to treatment failure and adverse drug reactions with potentially life-threatening consequences, especially when the patient is fragile or the drug is highly toxic. Both these latter factors are frequent in the cancer setting. Computers can be used to securitize the prescription (through validated protocols), preparation and administration of anticancer drugs, including experimental drugs, as they can store a wealth of information on both the individual patient and the product. We report our experience at Hotel-Dieu Hospital in Paris, where a computerized anticancer drug distribution system has increased treatment safety, provided major cost savings, and allowed nurses to spend more time with their patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2005