Laurence Bonhomme-Faivre

Publications of Laurence Bonhomme-Faivre

• Therapeutic efficiency of everolimus and lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation.

  Authors: Céline Chu, Marie-Sophie Noël-Hudson, Valérie Boige, Diane Goéré, Sylvie Marion, Mélanie Polrot, Ludovic Bigot, Patrick Gonin, Robert Farinotti, Laurence Bonhomme-Faivre

  Fundamental & clinical pharmacology. 03/2012;

  KRAS mutation is a negative predictive prognostic factor during metastatic colorectal cancer treatment with antiepidermal growth factor receptor antibodies. For affected patients, new therapeuticsKRAS mutation is a negative predictive prognostic factor during metastatic colorectal cancer treatment with antiepidermal growth factor receptor antibodies. For affected patients, new therapeutics must be explored. Our objective was to study efficacy of two drugs with different mechanisms of action, everolimus (mTOR inhibitor) and lapatinib (tyrosine kinase inhibitor), in a mouse xenograft model. We chose a model obtained after engraftment of a tumor originating from a human tumor collection. The patient was affected by a metastasis colorectal carcinoma resistant to cetuximab with KRAS mutation. From a previous study in mice, we know that everolimus is a P-glycoprotein (P-gp) substrate and that a lapatinib pretreatment increases significantly (2.6-fold) everolimus AUC by inhibiting its intestinal P-gp efflux. We hence tested the effect of these drugs alone or combined. Mice bearing the xenografts were divided in four groups: control, lapatinib, everolimus, and L/E group (L/E: 2 days of lapatinib 200 mg/kg and then 3 days of everolimus 1 mg/kg). Tumor volumes and treatment toxicities were evaluated. Sixteen days after treatment initiation, the group L/E was the first one in which tumor volume average was significantly lower than the one of control group (193 ± 90 vs. 395 ± 171 mm(3) ; P = 0.0025). After 4 weeks of treatment, inhibition of tumor growth in lapatinib, everolimus, and L/E groups reached, respectively, 49, 53, and 57%. Each drug showed significant antitumor activity. Only moderate hematologic toxicity signs were observed. These results lead to new perspectives for new oral drugs in metastatic KRAS-mutated colorectal cancer resistant to standard chemotherapy.

• Cytotoxics compounded sterile preparation control by HPLC during a 16-month assessment in a French university hospital: importance of the mixing bags step.

  Authors: Vincent Castagne, Hélène Habert, Chadi Abbara, Eric Rudant, Laurence Bonhomme-Faivre

  Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 09/2011; 17(3):191-6.

  The Centralized Chemotherapy Reconstitution Unit (CCRU) of Paul Brousse Hospital Pharmacy Department assessed the reliability of its Cytotoxics Compounded Sterile Products (CCSP) preparation methodThe Centralized Chemotherapy Reconstitution Unit (CCRU) of Paul Brousse Hospital Pharmacy Department assessed the reliability of its Cytotoxics Compounded Sterile Products (CCSP) preparation method in order to improve its CCSP quality assurance system. Five cytotoxic drugs - gemcitabine, 5-fluorouracil, docetaxel, paclitaxel, and oxaliplatin - were assayed by high performance liquid chromatography (HPLC) to determine CCSP concentration. During the observation period, 23,892 CCSP were prepared. Overall, 12,964 preparations contained one of the five analyzed drugs; 7382 (56.9%) out of 12,964 CCSP were analyzed by HPLC; 646 (8.8%) out of 7382 concentrations were outside ± 20% of the prescribed dose; 544 (84.2%) out of 646 were post-administration results and could not be verified. Out of 102 (15.8%) pre-administration results that were re-tested after re-shaking, 94 (92.2%) were found to be acceptable upon re-testing, and 8 (7.8%) were confirmed to be unacceptable and needed to be re-compounded. The 8.8% of tested CCSP were outside ± 20% of the prescribed dose, but extrapolating the results on re-tested CCSP, we can say that our CCSP preparation is reliable with an estimation of only 0.7% of 7382 CCSP analyzed, confirmed as being ± 20% outside the prescribed dose. Nevertheless, this ± 20% magnitude of error should be reduced. Based on pre-administration results, the primary cause of concentration errors appeared to be insufficient mixing of the finished product. Most CCSP dosages occurred after it had been administered, the organization should, therefore, be improved to include testing all CCSP prior to administration. Pharmaceutical companies should endeavor to manufacture compounded injectible drugs in a 'ready to use' form and provide vehicles in accurate volumes in order to improve compounding precision.

• Ultra-resistant schizophrenia is not associated with the multidrug-resistant transporter 1 (MDR1) gene rs1045642 variant.

  Authors: Fayçal Mouaffak, Oussama Kebir, Véronique Picard, Laurence Bonhomme-Faivre, Bruno Millet, Jean Pierre Olié, Michel Reynaud, Marie-Odile Krebs, Amine Benyamina

  Journal of clinical psychopharmacology. 04/2011; 31(2):236-8.

• Interleukin-2 treatment effect on imatinib pharmacokinetic, P-gp and BCRP expression in mice.

  Authors: Benoît Hosten, Chadi Abbara, Marion Cibert, Benoît Petit, Robert Farinotti, Patrick Gonin, Laurence Bonhomme-Faivre

  Anti-cancer drugs. 12/2009;

  The aim of this study was to investigate the effect that recombinant interleukin-2 (rIL-2) (0.16 MUI/injection) had on the pharmacokinetics of imatinib (IM) in plasma. In this study, IM was givenThe aim of this study was to investigate the effect that recombinant interleukin-2 (rIL-2) (0.16 MUI/injection) had on the pharmacokinetics of imatinib (IM) in plasma. In this study, IM was given orally to mice at a dose of 150 mg/kg once a day for 11 days (from day 1 to 11) either alone or in combination with intraperitoneal injections of rIL-2 twice a day from day 8 to 11. Pharmacokinetic parameters were determined using WinNonLin software. Areas under the curve were compared using Bailer's method. The repeated administration of the rIL-2+IM combination was shown to have two pharmacokinetic advantages compared with repeated IM doses alone. In addition to the pharmacodynamic interest of this treatment, we found that the combined treatment significantly increased the IM Cmax (P<0.05) and significantly increased the IM trough concentration (C24 h) (P<0.01), which was always above the minimum therapeutic IM concentration (1 mumol/l) in plasma. Those pharmacokinetic modifications may be explained, in part, by a decrease in the P-glycoprotein expression in the three intestinal segments of the mice (duodenum, P<0.01; jejunum, P<0.05; and ileum, P<0.05) and a decrease in BCRP expression in the duodenum segment (P<0.05) due to rIL-2. In another experiment, we found a significant induction of intestinal P-glycoprotein expression in mice that had been given IM orally (150 mg/kg) twice a day for 11 days. It would be interesting to further investigate the IM disposition associated with rIL-2 treatment for clinical applications.

• MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer.

  Authors: Bernard Paule, Vincent Castagne, Véronique Picard, Raphaël Saffroy, René Adam, Catherine Guettier, Robert Farinotti, Laurence Bonhomme-Faivre

  Medical oncology (Northwood, London, England). 10/2009;

  The aim of the study was to evaluate the influence of the MDR1 C3435T polymorphism on the therapeutic response in 23 patients treated with cetuximab plus irinotecan for irinotecan refractory liverThe aim of the study was to evaluate the influence of the MDR1 C3435T polymorphism on the therapeutic response in 23 patients treated with cetuximab plus irinotecan for irinotecan refractory liver metastatic colorectal cancer considering their KRAS status. Indeed, irinotecan and its active metabolite (SN-38) are both substrates of P-glycoprotein (P-gp) encoded by MDR1. Patients received cetuximab and irinotecan up to progression. The overall survival was 55% at 10 months. Overall, four patients had an undetermined KRAS status and two patients with mutated KRAS were in progression disease. The response to treatment was observed after 3 months among the 17 wild-type KRAS patients. Two patients presented a progressive disease (1 TT and 1 CT), eight patients had a stable disease (5 CC and 3CT) and five patients had a partial response (3 CC and 2 CT). Importantly, 2 patients (2 TT) were in complete response and still alive 5 years after starting the treatment, which suggests that the combination of wild-type KRAS and MDR1 3435 TT may be a factor of good prognosis. These results suggest that EGFR inhibition by cetuximab may overcome this irinotecan resistance by abrogating drug efflux depending on MDR1 3435 polymorphism. Among patients resistant to irinotecan, it is still possible to use the association of cetuximab plus irinotecan to obtain a complete resection of hepatic metastases that is necessary to improve their survival.

• Enfuvirtide: a safe and effective antiretroviral agent for human immunodeficiency virus-infected patients shortly after liver transplantation.

  Authors: Elina Teicher, Chadi Abbara, Jean-Charles Duclos-Vallée, Teresa Antonini, Laurence Bonhomme-Faivre, Delphine Desbois, Didier Samuel, Daniel Vittecoq

  Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 10/2009; 15(10):1336-42.

  The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virusThe aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV)-coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir-exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence.

• Effect of the ABCB1 3435C>T polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients.

  Authors: Laurence Bonhomme-Faivre, Véronique Picard, Faouzi Saliba, Chadi Abbara, Madjid Fodil, Mélanie Chaunoy, Robert Farinotti

  American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 09/2009; 66(18):1645-51.

  PURPOSE: The effect of ABCB1 3435C>T on tacrolimus concentrations in liver transplant recipients was studied. Tacrolimus is a substrate for P-glycoprotein, the product of the ABCB1 gene. To determinePURPOSE: The effect of ABCB1 3435C>T on tacrolimus concentrations in liver transplant recipients was studied. Tacrolimus is a substrate for P-glycoprotein, the product of the ABCB1 gene. To determine whether the ABCB1 single-nucleotide polymorphism (SNP) 3435C>T was associated with variation in the tacrolimus concentration:dose ratio (C:D) in 42 liver transplant recipients during three months after transplantation. METHODS: Forty-two Caucasian patients who underwent an orthotopic liver transplantation from cadaveric donors received a basic immunosuppressive regimen containing tacrolimus and corticosteroids; mycophenolate mofetil was added in 18 cases. The SNP 3435C>T in exon 26 was investigated by MboI restriction-enzyme digestion, leading to the identification of CC, TT, or CT status at nucleotide 3435. Results obtained for the three genotypes were compared for each of three values: daily weight-adjusted tacrolimus dose, blood trough tacrolimus concentration, and C:D. RESULTS: The wild-type genotype (3435CC) was observed in 10 patients (24%); 23 patients (55%) were heterozygous (3435CT) and 9 patients (21%) were homozygous for the mutation (3435TT). One to three days after liver transplantation, the mean +/- S.D. C:D was significantly higher in subjects homozygous for the mutation compared with subjects with the wild-type allele (236 +/- 119 ng . kg/mL . mg versus 104 +/- 74 ng . kg/mL . mg, respectively; p = 0.0167). Subjects with the heterozygous allele had an intermediate mean +/- S.D. C:D (131 +/- 108 ng . kg/mL . mg). One or three months after transplantation, no significant difference in the tacrolimus C:D was evident among the three groups. CONCLUSION: The ABCB1 3435C>T polymorphism influenced the tacrolimus C:D in the first days after liver transplantation.

• Association between ABCB1 C3435T polymorphism and increased risk of cannabis dependence.

  Authors: Amine Benyamina, Laurence Bonhomme-Faivre, Valérie Picard, Audrey Sabbagh, Damien Richard, Lisa Blecha, Hassan Rahioui, Laurent Karila, Michael Lukasiewicz, Robert Farinotti, Véronique Picard, Catherine Marill, Michel Reynaud

  Progress in neuro-psychopharmacology & biological psychiatry. 08/2009;

  Prolonged cannabis use has a significant impact on health and well-being. Genetic factors are known to influence cannabis dependence, but few specific genetic markers have been identified. ABCB1Prolonged cannabis use has a significant impact on health and well-being. Genetic factors are known to influence cannabis dependence, but few specific genetic markers have been identified. ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T polymorphism may represent an independent genetic marker for cannabis dependence risk. An open bi-centric association study was conducted in two French Addiction Centres. Caucasian patients diagnosed with isolated cannabis dependence were compared with healthy age-matched controls for socio-demographic, clinical and genetic data using chi-square test, Fisher's exact test, or Mann-Whitney U test. Independent association between ABCB1 C3435T SNP marker and cannabis dependence was evaluated using multiple logistic regression analysis. Versus controls (n=40), patients with cannabis dependence (n=40) had a significantly higher 3435C allele frequency (62.5% versus 43.8% respectively, P=0.017) and CC genotype (50% versus 20%, P=0.005, OR=4.00 [1.50-10.60]). Multiple logistic regression analysis of the C3435T SNP and variables identified in univariate analyses indicated that the CC genotype was independently associated with cannabis dependence (P=0.045, OR=6.61 [1.05-46.58]). This is the first time a significant specific genetic marker has been shown in cannabis dependence. ABCB1 polymorphisms may alter Delta9THC distribution, its psychoactive effects and individual vulnerability to dependence. These results pave the way to a new pharmacogenetic hypothesis in cannabis dependence.

• Effect of interleukin-2 pretreatment on Paclitaxel absorption and tissue disposition after oral and intravenous administration in mice.

  Authors: Benoît Hosten, Chadi Abbara, Benoît Petit, Angélique Dauvin, Fanchon Bourasset, Robert Farinotti, Patrick Gonin, Laurence Bonhomme-Faivre

  Drug metabolism and disposition: the biological fate of chemicals. 09/2008; 36(8):1729-35.

  The aim of the present study was to investigate the effects of recombinant interleukin (rIL)-2 treatment on paclitaxel (PLX) pharmacokinetics in the plasma and tissue of Lewis lung carcinoma-bearingThe aim of the present study was to investigate the effects of recombinant interleukin (rIL)-2 treatment on paclitaxel (PLX) pharmacokinetics in the plasma and tissue of Lewis lung carcinoma-bearing mice (lung tissues and s.c. tumors). PLX pharmacokinetics studies were conducted after oral and i.v. administration of 15 and 4 mg/kg, respectively, either alone or after 3 days of rIL-2 pretreatment. The noncompartmental approach was used to determine the mean pharmacokinetic parameters using WinNonlin software (Pharsight, Mountain View, CA). The influence of rIL-2 pretreatment on physiological P-glycoprotein (P-gp) expression in lung and intestine was investigated by Western blot analysis. After oral administration of PLX, areas under the curve (AUC) in plasma, lung, and s.c. tumors were significantly higher (2.98, 2.66, and 3.41-fold, respectively) in the rIL-2 + PLX group as compared with the PLX group. However, no significant effect of rIL-2 pretreatment was observed in plasma or lung following i.v. administration of PLX. PLX AUC in s.c. tumors was significantly higher (1.37-fold) with rIL-2 pretreatment as compared with the PLX-alone group after i.v. injection. Pretreatment with rIL-2 appeared to have no effect on PLX plasma terminal half-life when PLX was administered orally or i.v. However, prolongation of PLX terminal half-life estimated from lung and s.c. tumors data had been observed. Increased PLX tissue absorption in the rIL-2-pretreated group may be explained by a decrease of P-gp expression in the intestines and lung or decreased functionality due to rIL-2. Oral administration allowed the targeted tissues a much higher PLX exposure as compared with i.v. administration.

• Disposition of Delta(9) tetrahydrocannabinol in CF1 mice deficient in mdr1a P-glycoprotein.

  Authors: Laurence Bonhomme-Faivre, Amine Benyamina, Michel Reynaud, Robert Farinotti, Chadi Abbara

  Addiction biology. 04/2008;

  P-glycoprotein (P-gp) plays a major role in drug efflux. All the transported substrates are more or less hydrophobic and amphiphatic in nature. Being lipophilic, Delta(9) tetrahydrocannabinol (THC),P-glycoprotein (P-gp) plays a major role in drug efflux. All the transported substrates are more or less hydrophobic and amphiphatic in nature. Being lipophilic, Delta(9) tetrahydrocannabinol (THC), the main cannabis component, could be a potential P-gp substrate. The aim of this project was to determine the contribution of the mdr1a gene product to THC disposition. Therefore, oral THC and digoxin (substrate test for P-gp) pharmacokinetics have been investigated in the intestinal epithelium and in the brain capillary endothelium of CF1 mdr1a (-/-) mice (mice naturally deficient in P-gp). These pharmacokinetics were compared to THC and digoxin oral pharmacokinetics in wild type mice mdr1a (+/+) (not P-gp deficient). The application of Bailer's method showed that THC total exposure measured by the area under the plasma concentration time curve was 2.17-fold higher in CF1 mice naturally deficient in P-gp than in wild type mice after oral administration of 25 mg/kg of THC, and 2.4-fold higher after oral administration of 33 microg/kg of digoxin. As a consequence, the oral bioavailability of THC and digoxin was higher in naturally P-gp-deficient mice. We concluded that P-gp limits THC oral uptake and mediates direct drug excretion from the systemic circulation into the intestinal lumen.

• Tattooing breast cancers treated with neoadjuvant chemotherapy.

  Authors: Marie-Christine Mathieu, Laurence Bonhomme-Faivre, Roman Rouzier, Monique Seiller, Lise Barreau-Pouhaer, Jean-Paul Travagli

  Annals of surgical oncology. 09/2007; 14(8):2233-8.

  BACKGROUND: In breast carcinomas treated with neoadjuvant chemotherapy, intraoperative identification of residual tumors may be difficult. A well-tolerated, low-diffusion charcoal suspension has beenBACKGROUND: In breast carcinomas treated with neoadjuvant chemotherapy, intraoperative identification of residual tumors may be difficult. A well-tolerated, low-diffusion charcoal suspension has been designed to tattoo breast tumors. In this study, we investigated whether this tattooing technique is efficient for localizing the tumor after treatment with chemotherapy. METHODS: In a series of 109 patients with large breast tumors, a 4% or 10% charcoal suspension was injected at the time of the initial biopsy before preoperative chemotherapy. RESULTS: Tolerance was good. After three or four cycles of chemotherapy, 91 patients underwent conservative treatment, and the surgical specimen was examined intraoperatively. The charcoal was detected in 94% of the cases. The charcoal was seen in the nodule or at the periphery in the surgical specimen without any acute inflammatory reaction or diffusion. CONCLUSIONS: On the basis of these results, this micronized charcoal suspension at a defined granulometry and a concentration of 10% seems to be ideal for tattooing breast carcinomas over a period of 3 months in patients in whom neoadjuvant chemotherapy is planned.

• Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-alpha in rats.

  Authors: Makrem Ben Reguiga, Laurence Bonhomme-Faivre, Robert Farinotti

  The Journal of pharmacy and pharmacology. 03/2007; 59(3):401-8.

  Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha)Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-alpha for 8 days (4MIU kg(-1), once daily) or with pegylated-IFN-alpha (ViraferonPeg; 60 microg kg(-1), Days 1, 4 and 7). The rats were then distributed into sub-groups (n = 5-6) according to the pre-treatment type, and received one dose of [(14)C]DTX (20 mgkg(-1)) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-alpha both increased DTX oral bioavailability parameters: C(max) (17.0+/-4.0 microg L(-1) (P < 0.02) and 18+/-5.5 microg L(-1) (P < 0.05), respectively, vs 7.4+/-2.5 microg L(-1) for the control) and AUC (0.036+/-0.010 microg h mL(-1) (P < 0.01) and 0.033+/-0.009 microg h mL(-1) (P < 0.01), respectively, versus 0.012+/-0.004 microg h mL(-1) for the control). IFN-alpha also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-alpha did not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [(14)C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-alpha modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.

• Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study.

  Authors: Elina Teicher, Isabelle Vincent, Laurence Bonhomme-Faivre, Chadi Abbara, Aurélie Barrail, Alain Boissonnas, Jean-Charles Duclos-Vallée, Anne-Marie Taburet, Didier Samuel, Daniel Vittecoq

  Clinical pharmacokinetics. 01/2007; 46(11):941-52.

  OBJECTIVE: To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant. DESIGN: AnOBJECTIVE: To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant. DESIGN: An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods. METHODS: Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced. RESULTS: When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required. CONCLUSION: The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

• Development and validation of a method for the quantitation of Delta9 tetrahydrocannabinol in human plasma by high performance liquid chromatography after solid-phase extraction.

  Authors: Chadi Abbara, Romain Galy, Amine Benyamina, Michel Reynaud, Laurence Bonhomme-Faivre

  Journal of pharmaceutical and biomedical analysis. 07/2006; 41(3):1011-6.

  A high performance liquid chromatography (HPLC) procedure for the determination of Delta9 tetrahydrocannabinol (THC) in human plasma is described. A two-step solid-phase extraction on CN cartridgesA high performance liquid chromatography (HPLC) procedure for the determination of Delta9 tetrahydrocannabinol (THC) in human plasma is described. A two-step solid-phase extraction on CN cartridges was coupled with a reversed phase HPLC system. THC was eluted using a mobile phase composed of methanol, acetonitrile and tetrabutylammonium perchlorate solution (0.005 M, pH 3.2), through a C18 Nucleosil column and detected at a wavelength of 215 nm. Calibration curve was linear over the range 5-100 ng/ml with a lower limit of quantification validated at 5 ng/ml. Extraction recovery using the developed extraction procedure was higher than 85%. This method is presently used for the quantification of THC in plasma samples from regular cannabis smokers.

• Recombinant interleukin-2 pre-treatment increases anti-tumor response to paclitaxel by affecting lung P-glycoprotein expression on the Lewis lung carcinoma.

  Authors: Benoît Hosten, Désiré Challuau, Sophie Gil, Céline Bouquet, Sylvie Marion, Michel Perricaudet, Mario Di Palma, Robert Farinotti, Laurence Bonhomme-Faivre

  Anti-cancer drugs. 03/2006; 17(2):195-9.

  The aim of the present study was to examine modifications of anti-tumor activity and toxicity of paclitaxel (PLX) when given p.o. after recombinant interleukin-2 (rIL-2) to Lewis lungThe aim of the present study was to examine modifications of anti-tumor activity and toxicity of paclitaxel (PLX) when given p.o. after recombinant interleukin-2 (rIL-2) to Lewis lung carcinoma-bearing mice. PLX was given orally to mice at the dose of 15 mg/kg on day 8 and 30 mg/kg on day 15, either alone or after 16.5 microg of rIL-2 given i.p. twice a day either 1 or 3 days before. The anti-tumor activity was higher and PLX hematological toxicity not increased if orally administered PLX was given after a 3-day rIL-2 pre-treatment rather than if given alone. Lung metastasis was significantly lower and s.c. tumors were smaller in the PLX+rIL-2 group than in the PLX or rIL-2 or non-treated groups. In addition, a decrease in lung P-glycoprotein expression (investigated by Western blot analysis) was observed 1 h after the last administration of rIL-2 on day 7.

• Modification of the P-glycoprotein dependent pharmacokinetics of digoxin in rats by human recombinant interferon-alpha.

  Authors: Makrem Ben Reguiga, Laurence Bonhomme-Faivre, Simone Orbach-Arbouys, Robert Farinotti

  Pharmaceutical research. 12/2005; 22(11):1829-36.

  PURPOSE: This study was conducted to investigate in vivo the impact of interferon-alpha (IFN)-alpha on P-glycoprotein (P-gp) activity in rats by studying how its administration modifies thePURPOSE: This study was conducted to investigate in vivo the impact of interferon-alpha (IFN)-alpha on P-glycoprotein (P-gp) activity in rats by studying how its administration modifies the bioavailability of digoxin, a fairly pure P-gp substrate. METHODS: Human recombinant IFN-alpha was given to rats (n = 5-7 per group) daily for 8 days at different doses (IntronA) 10(6), 2.10(6), or 4.10(6) IU kg(-1), s.c.), whereas pegylated-IFN-alpha (ViraferonPeg), 29 microg kg(-1)) was given s.c. three times a week. Rats were then given digoxin (32 microg kg(-1)) i.v. or orally. The pharmacokinetics of digoxin was studied. Intestinal P-gp expression was also examined. RESULTS: The pharmacokinetics of i.v. administered digoxin was not modified by IFN-alpha, but a dose-dependent increase in areas under the curve (AUCs) was observed in the orally administered digoxin parameters in rats (AUCs: 392 +/- 83 min microg L(-1), p < 0.01 and 550 +/- 97 min microg L(-1), p < 0.001, respectively, vs. 286 +/- 111 min microg L(-1) for control). A decrease in P-gp expression in the ileum (relative intensities: 0.70 +/- 0.19 for 4 Million International Unit (MIU) kg(-1) IFN-alpha-treated animals vs. 1.00 +/- 0.13 for controls, p < 0.05) and mainly in the jejunum (relative intensities: 0.46 +/- 0.13 for 4 MIU kg(-1) IFN-alpha-treated animals vs. 1.00 +/- 0.08 for controls, p < 0.001) was observed. CONCLUSION: IFN-alpha induces in vivo a significant dose-dependent inhibitory effect on intestinal P-gp activity related to a local decrease in its expression, thereby predicting important clinical consequences when IFN-alpha and other P-gp substrates are associated.

• Pharmacokinetics and neutrophil toxicity of paclitaxel orally administered in mice with recombinant interleukin-2.

  Authors: Candice Jamois, Emmanuelle Comets, France Mentré, Sylvie Marion, Robert Farinotti, Laurence Bonhomme-Faivre

  Cancer chemotherapy and pharmacology. 02/2005; 55(1):61-71.

  PURPOSE: Intrinsic P-glycoprotein (P-gp) expression in the gut limits paclitaxel uptake and, thus, its bioavailability when administered orally. Interleukin-2 has been reported to be a P-gp modulatorPURPOSE: Intrinsic P-glycoprotein (P-gp) expression in the gut limits paclitaxel uptake and, thus, its bioavailability when administered orally. Interleukin-2 has been reported to be a P-gp modulator in vitro and in vivo in mice. In the work described here, the effects of interleukin-2 pretreatment on pharmacokinetics and toxicity of paclitaxel orally administered were investigated. METHODS: For the pharmacokinetic study, 96 mice were allocated to two groups receiving either 10 mg/kg of paclitaxel by the oral route alone or 16.5 microg of human recombinant interleukin-2 (rIL2) by the intraperitoneal route twice daily for 3 days and then paclitaxel. Pharmacokinetic profiles were analysed first by the Bailer method, and then using a compartmental approach. For the toxicity study, 90 Swiss mice were allocated to three groups receiving paclitaxel (10 mg/kg orally), rIL2 alone (16.5 microg i.p. twice daily for 3 days, control group), or both treatments. Haematological parameters were measured and the three groups were compared using the Bailer method. A Bonferroni correction was applied to the test. RESULTS: A complex absorption of paclitaxel was revealed. The Bailer method showed that the mean area under the curve (AUC) values over 0-24 h were not significantly different in the two groups, despite a trend to reduced AUC in the pretreated group. The AUC over 0-0.5 h was significantly higher in the group pretreated with rIL2, but represented only a fraction of total exposure. These results were confirmed by the compartmental analysis. The elimination rate constant remained the same across both groups. rIL2 thus increased paclitaxel absorption for the 15 min following oral intake of the drug but did not enhance the overall exposure. CONCLUSION: We found that a 3-day pretreatment with rIL2 had some in vivo inhibitory effects on P-gp activity for a short period after oral dosing of paclitaxel. Those results encourage further investigation of the effect of rIL2 on the overall exposure of paclitaxel. On the other hand, it seems that the joint administration of the two drugs did not increase the risk of myelosuppression, which might be worth knowing to treat advanced cancers.

• MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.

  Authors: Laurence Bonhomme-Faivre, Aurore Devocelle, Faouzi Saliba, Skander Chatled, Jean Maccario, Robert Farinotti, Véronique Picard

  Transplantation. 08/2004; 78(1):21-5.

  BACKGROUND: Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABCBACKGROUND: Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABC transporter family encoded by the multiple drug-resistant gene MDR1. METHODS: Because MDR1 gene exon 26 C3435T polymorphism influences intestinal P-glycoprotein expression, we investigated whether this polymorphism was correlated with variation in CsA dose requirement and concentration/dose ratio in 44 liver-transplant recipients during 1 month after transplantation. CsA concentration was measured 2 hours after administration (C2), according to international recommendations. RESULTS: The MDR-1 wild-type genotype (3435CC) was observed in 15 patients (34%), whereas 21 (48%) patients were heterozygous (3435CT), and 8 (18%) patients were homozygous for the mutation (3435TT). There was no significant difference between the three groups regarding corticosteroids treatment or renal function during this period. One to 3 days after liver transplantation, when every patient received a similar CsA weight-adjusted dose, the concentration/dose ratio was correlated with exon 26 single nucleotide polymorphism and was significantly higher in subjects homozygous for the mutation (P=0.012). This was confirmed 1 month after transplantation (P=0.049), when the dose was adjusted to maintain the C2 target level of 1,000 microg/L and we observed that TT patients required approximately 50% lower weight-adjusted CsA dose than wild-type patients (P=0,033). CONCLUSIONS: These findings demonstrate that the MDR1 exon 26 C3435T polymorphism is a major determinant of CsA concentration/dose ratio in liver-transplant recipients and is predictive of the dose of CsA to be administered to achieve the target C(2) concentration.

• Effect of recombinant interleukin-2 pretreatment on oral and intravenous digoxin pharmacokinetics and P-glycoprotein activity in mice.

  Authors: Vincent Castagne, Laurence Bonhomme-Faivre, Saik Urien, Makram Ben Reguiga, Mireille Soursac, Francois Gimenez, Robert Farinotti

  Drug metabolism and disposition: the biological fate of chemicals. 03/2004; 32(2):168-71.

  P-glycoprotein (P-gp) is an ATP-dependent efflux membrane transporter involved in many drug pharmacokinetics in humans. Decreasing its expression could enhance the bioavailability of substrates asP-glycoprotein (P-gp) is an ATP-dependent efflux membrane transporter involved in many drug pharmacokinetics in humans. Decreasing its expression could enhance the bioavailability of substrates as digoxin. We have recently found that human recombinant interleukin-2 (rIL2) in vivo decreases P-gp expression in intestine and brain of mice and modifies oral digoxin pharmacokinetics. The aim of the study was to evaluate the involvement of bioavailability in the rIL2 pretreatment effect on digoxin pharmacokinetics by comparing oral and i.v. digoxin pharmacokinetics before and after rIL2 pretreatment (10 microg/kg). We also tried to show the possible effect of a low rIL2 dose (1 microg/kg) pretreatment on oral digoxin pharmacokinetics. First, adult Swiss mice received a single oral or i.v. dose of digoxin (0.03 mg/kg). Two weeks later, the same animals were treated by rIL2 i.p. twice a day (10 microg/kg) for 4 days and received digoxin again at day 5. As well, another group received oral digoxin (0.03 mg/kg) with a 1 microg/kg rIL2 pretreatment. Blood was collected after digoxin administration with and without rIL2 pretreatment. Digoxin pharmacokinetics were described by a one-compartment model. The 10 microg/kg rIL2 pretreatment did not modify i.v. digoxin pharmacokinetics, whereas oral digoxin pharmacokinetics were significantly modified by the 10 microg/kg rIL2 pretreatment and not by the 1 microg/kg rIL2 pretreatment. The decrease of P-gp activity, caused by rIL2 (10 microg/kg), increased digoxin bioavailability. An increase in exposure and intracellular level of drugs is expected from rIL2 pretreatment.

• Enhanced oral bioavailability of paclitaxel by recombinant interleukin-2 in mice with murine Lewis lung carcinoma.

  Authors: Chadi Abbara, Christophe Rouchon, Benoît Hosten, Robert Farinotti, Laurence Bonhomme-Faivre

  Drug metabolism and drug interactions. 02/2004; 20(4):219-31.

  The effect of recombinant interleukin-2 (rIL-2) pretreatment on the pharmacokinetics of paclitaxel was investigated in the murine Lewis lung carcinoma model in C57B1/6 mice. Paclitaxel 15 mg/kg wasThe effect of recombinant interleukin-2 (rIL-2) pretreatment on the pharmacokinetics of paclitaxel was investigated in the murine Lewis lung carcinoma model in C57B1/6 mice. Paclitaxel 15 mg/kg was administrated orally to mice, either alone or after 3 days pretreatment with twice daily dose of 16.5 microg rIL-2. Plasma concentrations of paclitaxel were estimated by reversed phase HPLC. Pharmacokinetic parameters were determined using MicroPharm software. Using Bailer's method, a significant difference was observed in the AUCs of paclitaxel administrated alone and with rIL-2 pretreatment (928.2 +/- 136.8 vs 2549.6 +/- 131.3 ng.h.ml(-1), p <0.0001). Pretreatment with rIL-2 resulted in a 3-fold increase in the oral bioavailability of paclitaxel without altering its elimination half-life (0.798 vs 0.747 h). This could be due to the inhibition of P-glycoprotein (P-gp) mediated transport, thus enhancing paclitaxel intestinal absorption. The combination of these two drugs could be of interest in clinical practice due to their activity in pulmonary cancer.