Laboratoire Of Pharmacocinetique Et Toxicologie

Toulouse, France

Laboratoire Of Pharmacocinetique Et Toxicologie

Toulouse, France

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Delobel P.,Service des Maladies Infectieuses et Tropicales | Delobel P.,French Institute of Health and Medical Research | Saliou A.,French Institute of Health and Medical Research | Nicot F.,French Institute of Health and Medical Research | And 12 more authors.
PLoS ONE | Year: 2011

The impact of minor drug-resistant variants of the type 1 immunodeficiency virus (HIV-1) on the failure of antiretroviral therapy remains unclear. We have evaluated the importance of detecting minor populations of viruses resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) during intermittent antiretroviral therapy, a high-risk context for the emergence of drug-resistant HIV-1. We carried out a longitudinal study on plasma samples taken from 21 patients given efavirenz and enrolled in the intermittent arm of the ANRS 106 trial. Allele-specific real-time PCR was used to detect and quantify minor K103N mutants during off-therapy periods. The concordance with ultra-deep pyrosequencing was assessed for 11 patients. The pharmacokinetics of efavirenz was assayed to determine whether its variability could influence the emergence of K103N mutants. Allele-specific real-time PCR detected K103N mutants in 15 of the 19 analyzable patients at the end of an off-therapy period while direct sequencing detected mutants in only 6 patients. The frequency of K103N mutants was <0.1% in 7 patients by allele-specific real-time PCR without further selection, and >0.1% in 8. It was 0.1%-10% in 6 of these 8 patients. The mutated virus populations of 4 of these 6 patients underwent further selection and treatment failed for 2 of them. The K103N mutant frequency was >10% in the remaining 2, treatment failed for one. The copy numbers of K103N variants quantified by allele-specific real-time PCR and ultra-deep pyrosequencing agreed closely (ρ = 0.89 P<0.0001). The half-life of efavirenz was higher (50.5 hours) in the 8 patients in whom K103N emerged (>0.1%) than in the 11 patients in whom it did not (32 hours) (P = 0.04). Thus ultrasensitive methods could prove more useful than direct sequencing for predicting treatment failure in some patients. However the presence of minor NNRTI-resistant viruses need not always result in virological escape. © 2011 Delobel et al.


Guilhaumou R.,Aix - Marseille University | Guilhaumou R.,Laboratoire Of Pharmacocinetique Et Toxicologie | Guilhaumou R.,Laboratoire Of Pharmacologie Medicale Et Clinique | Solas C.,Aix - Marseille University | And 8 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: The aim of this study was to investigate the impact of plasma and intracellular exposure and CYP3A4, CYP3A5, and ABCB1 polymorphisms on vincristine neurotoxicity. We subsequently assessed the impact of ABCB1 polymorphisms on intracellular vincristine accumulation. Methods: Children treated for solid tumors were enrolled in the study (n = 26) and received 1.5 mg/m2 of vincristine per course. Individual pharmacokinetic parameters and CYP3A4, CYP3A5, and ABCB1 genotypes were available from a previous analysis. A global toxicity score (pain, peripheral neurotoxicity, and gastrointestinal toxicity) was collected at each course. Vincristine in plasma and PBMCs were quantified by LC-MS/MS. Results: Vincristine plasma and intracellular concentrations ranged from 0.40 to 89.6 ng/ml and from 0.00225 to 1.85 ng/10 6 cells over a 24-h interval, respectively. The global toxicity score ranged from 0 to 6 and was not correlated with individual pharmacokinetics parameters. Neurotoxicity events (global score ≥3) were observed in 8 patients but the incidence was not influenced by the different studied polymorphisms. The global toxicity score was correlated with age, body surface area, and dose in mg. A trend to higher intracellular/plasma ratio of vincristine was found for patients with heterozygous diplotype (CGC-TTT) of ABCB1. Conclusions: None of the different genetic covariates nor plasma and intracellular exposure was predictive of the observed neurotoxicity in our pediatric population. Nevertheless, the heterozygote diplotype of ABCB1 appears to influence the intracellular accumulation of vincristine. Owing to the small sample size, further evaluations are needed in a larger patient cohort. © 2011 Springer-Verlag.


Guilhaumou R.,French Institute of Health and Medical Research | Guilhaumou R.,Laboratoire Of Pharmacocinetique Et Toxicologie | Guilhaumou R.,Laboratoire Of Pharmacologie Medicale Et Clinique | Simon N.,Laboratoire Of Pharmacologie Medicale Et Clinique | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: The interindividual variability of vincristine pharmacokinetics is quite large, but the origins of this variability are not properly understood. The aim of this study was to develop a population pharmacokinetic model of vincristine in a paediatric population treated for solid tumour disease and evaluate the impact of different ABCB1, CYP3A4 and CYP3A5 polymorphisms on the different pharmacokinetic parameters. Methods: We assessed vincristine pharmacokinetics in 26 children treated for various solid tumour diseases. Genotypes were determined by real-time PCR with a LightCycler™ and ABCB1 haplotypes calculated using the software program Phase 2.1. Vincristine plasma concentrations were determined by LC-MS/MS, and a population approach was performed on 184 samples by the NONMEM computer program. Demographic, therapeutic and genotypic covariables were evaluated on vincristine pharmacokinetic parameters. Results: The frequency of CYP3A4*1A/*1A and*1A/*1B genotypes were 87.5 and 12.5%, respectively. CYP3A5*1/*3 and*3/*3 were observed in 20.8 and 79.2% of the patients, respectively. The three major haplotypes were (allelic frequencies) CGC (50%), CGT (14.6%) and TTT (23.2%). Vincristine pharmacokinetics was well described by a two-compartment model. Large interindividual and interoccasion variability were observed. The different polymorphisms studied did not improve the model prediction. Conclusions: CYP3A4, CYP3A5 and ABCB1 polymorphisms did not significantly affect in vivo vincristine pharmacokinetics. Our results demonstrate that vincristine pharmacokinetic variability cannot be explained by these genetic polymorphisms. © 2010 Springer-Verlag.


Guilhaumou R.,Laboratoire Of Pharmacocinetique Et Toxicologie | Guilhaumou R.,French Institute of Health and Medical Research | Solas C.,Laboratoire Of Pharmacocinetique Et Toxicologie | Solas C.,French Institute of Health and Medical Research | And 6 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Vincristine is a natural vinca alkaloid widely used in paediatric cancer treatment. Vincristine pharmacokinetics has been already studied, but few data are available in paediatric populations. A sensitive and specific liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed for the quantification of vincristine in plasma in order to investigate pharmacokinetics in a paediatric population. Two hundred microliters of plasma was added to vinblastine, used as internal standard. Chromatographic separation was achieved on a C8 HPLC column (Phenomenex Luna 50 mm × 2.0 mm, 3.0 μm) with a mobile phase gradient at a flow rate of 0.2 ml/min. Quantification was performed using the transition of 825.4 → 765.4 (m/z) for vincristine and 811.4 → 751.4 (m/z) for vinblastine. Chromatographic separation was achieved in 8 min. The limit of quantification was 0.25 ng/ml with a precision of 10.2% and an accuracy of 99.6%. The calibration curve was linear up to 50.0 ng/ml. Intra-day precision and accuracy ranged from 6.3% to 10% and from 91.9% to 100.8%, respectively. Inter-assay precision and accuracy ranged from 3.8% to 9.7% and from 93.5% to 100.5%, respectively. No significant matrix effect was observed for vincristine. A rapid, specific and sensitive LC/MS/MS method for quantification of vincristine in human plasma was developed and is now successfully applied for pharmacokinetic studies in paediatric patients. © 2009 Elsevier B.V. All rights reserved.


Solas C.,Laboratoire Of Pharmacocinetique Et Toxicologie | Gagnieu M.-C.,Federation de Biologie
Therapie | Year: 2011

The efavirenz, a non nucleoside reverse transcriptase inhibitor of HIV-1, presents a marked pharmacokinetics variability related to an intense hepatic metabolism. Efavirenz is also a potent inducer. Central nervous system (CNS) toxicity associated with efavirenz therapy is a major cause of non adherence and therefore treatment failure. The literature has been analyzed to evaluate the level of evidence of the interest of a therapeutic drug monitoring for efavirenz. Several studies have reported that an efavirenz plasma concentration >1000 ng/mL is a predictive factor of the viral response. Efavirenz plasma concentrations >4000 ng/mL were associated to an increase frequency of CNS side effects. CNS toxicity was also more frequent in patients carrying the 516G > T mutation (CYP2B6*6 allele), associated with a significantly greater efavirenz plasma exposure. Non-randomized studies have reported the interest of efavirenz therapeutic drug monitoring to optimize viral response and prevent CNS toxicity, allowing to suggest a level of evidence "recommended" for efavirenz. © 2011 Société Française de Pharmacologie et de Thérapeutique.


Solas C.,Laboratoire Of Pharmacocinetique Et Toxicologie | Pare M.,Laboratoire Of Pharmacocinetique Et Toxicologie | Quaranta S.,Laboratoire Of Pharmacocinetique Et Toxicologie | Stanke-Labesque F.,Joseph Fourier University | Stanke-Labesque F.,French Institute of Health and Medical Research
Therapie | Year: 2011

Ribavirin in combination with pegylated interferon alpha is the current treatment for chronic hepatitis C (HCV). Ribavirin presents a wide inter-individual pharmacokinetic variability and adequate exposure seems crucial for achieving sustained virologic response. Severe anaemia frequently occurred under ribavirin treatment and is a dose-dependent limiting side effect. Several studies have been carried out in HVC-infected or HIV-HCV co-infected patients to evaluate the pharmacokinetic-pharmacodynamic relationships of ribavirin. Achievement of a sustained virologic response, defined as undetectable HCV-RNA six months after the end of treatment, have been significantly associated with ribavirin concentration. A cut-off for the trough concentration of ribavirin ranging between 2-3 μg/ml at week 4 has been proposed. A significant correlation has also been reported between ribavirin concentration and the extent of haemoglobin decline. A ribavirin concentration >2 μg/ml is significantly associated to an increase risk of severe anaemia. Non randomized studies have shown that therapeutic drug monitoring of ribavirin improve the management of therapeutic response and haematologic toxicity. Therefore, the level of evidence of the therapeutic drug monitoring of ribavirin is recommended. © 2011 Société Française de Pharmacologie et de Thérapeutique.


Solas C.,Laboratoire Of Pharmacocinetique Et Toxicologie | Muret P.,Besancon University Hospital Center
Therapie | Year: 2011

The HIV protease inhibitor atazanavir presents a wide inter-individual variability related to an intense hepatic metabolism. Dose-dependant elevations of bilirubin have been frequently reported with atazanavir. Relative to literature, the atazanavir therapeutic drug monitoring can it be proposed? In naïve HIV-infected patients, the probability of achieving an undetectable HIV viral load at W48 was significantly associated with a plasma trough concentration (Cmin) of atazanavir >200 ng/mL. Studies in HIV-infected pre-treated patients reported that the genotypic inhibitory quotient was a predictive factor of the virologic response with a threshold value around 200 ng/mL/mutation. Concerning the exposure-toxicity relationship, the risk of occurrence of grade 3-4 hyperbilirubinemia was more frequently associated with Cmin > 750-800 ng/mL. Non-randomized studies have reported the interest of atazanavir therapeutic drug monitoring to optimize the virologic response and prevent severe bilirubin elevations. Therefore, the level of evidence of the interest of atazanavir therapeutic drug monitoring is recommended. © 2011 Société Française de Pharmacologie et de Thérapeutique.


Muret P.,Besancon University Hospital Center | Solas C.,Laboratoire Of Pharmacocinetique Et Toxicologie
Therapie | Year: 2011

The human immunodeficiency virus (HIV) protease inhibitor saquinavir displays a large inter-individual variability in its pharmacokinetic parameters, related to a low absorption rate and an important hepatic metabolism. Based on literature, is the saquinavir therapeutic drug monitoring relevant? In naïve HIV-infected patients, the probability of achieving an undetectable HIV viral load at W48 was significantly associated with a saquinavir plasma trough concentration >100 ng/mL. Two studies in HIV-infected pre-treated patients reported that the genotypic inhibitory quotient was a predictive factor of virologic response with a threshold value around 40 ng/mL/mutation. Concerning the exposure-toxicity relationship, the risk of occurrence of grade 3-4 abdominal pains was more frequently associated with high concentrations of saquinavir, but without threshold value determination. Several studies, one of which was randomized, have reported the interest of saquinavir therapeutic drug monitoring to optimize the virologic response. Therefore, the level of evidence of the interest of saquinavir therapeutic drug monitoring is "recommended". © 2011 Société Française de Pharmacologie et de Thérapeutique.


Muret P.,Besancon University Hospital Center | Piedoux S.,Besancon University Hospital Center | Solas C.,Laboratoire Of Pharmacocinetique Et Toxicologie | Quaranta S.,Laboratoire Of Pharmacocinetique Et Toxicologie
Therapie | Year: 2011

Nevirapine, a HIV non nucleosidic reverse transcriptase inhibitor, displays an inter-individual variability in its pharmacokinetics parameters, related to its hepatic metabolism. Based on literature, is the nevirapine therapeutic drug monitoring relevant? In naïve and pre-treated HIV infected patients, the probability of achieving and maintaining an undetectable HIV viral load was significantly associated with a nevirapine plasma trough concentration (C trough) > 4000 ng/mL. The probability of virologic failure was significantly associated with a Ctrough < 3000 ng/mL. Concerning the exposure-toxicity relationship, the emergence of hepatotoxicity was more frequently associated with high Ctrough, especially in case of HCV coinfection. Non-randomized studies have reported the interest of nevirapine therapeutic drug monitoring to optimize the virologic response and, to a lesser extent, to prevent hepatotoxicity. Therefore, the level of evidence of the interest of nevirapine therapeutic drug monitoring is "recommended". © 2011 Société Française de Pharmacologie et de Thérapeutique.


PubMed | Laboratoire Of Pharmacocinetique Et Toxicologie
Type: Journal Article | Journal: Therapie | Year: 2011

The efavirenz, a non nucleoside reverse transcriptase inhibitor of HIV-1, presents a marked pharmacokinetics variability related to an intense hepatic metabolism. Efavirenz is also a potent inducer. Central nervous system (CNS) toxicity associated with efavirenz therapy is a major cause of non adherence and therefore treatment failure. The literature has been analyzed to evaluate the level of evidence of the interest of a therapeutic drug monitoring for efavirenz. Several studies have reported that an efavirenz plasma concentration >1000 ng/mL is a predictive factor of the viral response. Efavirenz plasma concentrations >4000 ng/mL were associated to an increase frequency of CNS side effects. CNS toxicity was also more frequent in patients carrying the 516G > T mutation (CYP2B6*6 allele), associated with a significantly greater efavirenz plasma exposure. Non-randomized studies have reported the interest of efavirenz therapeutic drug monitoring to optimize viral response and prevent CNS toxicity, allowing to suggest a level of evidence recommended for efavirenz.

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