Interest Of Therapeutic Drug Monitoring Research Articles

Sensing of Catecholamine in Human Urine Using a Simple Colorimetric Assay Based on Direct Melanochrome and Indolequinone Formation.

We used the first enzyme-free synthesis and stabilization of soluble melanochrome (MC) and 5,6-indolequinone (IQ) derived from levodopa (LD), dopamine (DA), and norepinephrine (NE) oxidation to develop a simple colorimetric assay for catecholamine detection in human urine, also elucidating the time-dependent formation and molecular weight of MC and IQ using UV-Vis spectroscopy and mass spectrometry. The quantitative detection of LD and DA was achieved in human urine using MC as a selective colorimetric reporter to demonstrate the potential assay applicability in a matrix of interest in therapeutic drug monitoring (TDM) and in clinical chemistry. The assay showed a linear dynamic range between 5.0 mg L-1 and 50.0 mg L-1, covering the concentration range of DA and LD found in urine samples from, e.g., Parkinson's patients undergoing LD-based pharmacological therapy. The data reproducibility in the real matrix was very good within this concentration range (RSDav% 3.7% and 6.1% for DA and LD, respectively), also showing very good analytical performances with the limits of detection of 3.69 ± 0.17 mg L-1 and 2.51 ± 0.08 mg L-1 for DA and LD, respectively, thus paving the way for the effective and non-invasive monitoring of dopamine and levodopa in urine from patients during TDM in Parkinson's disease.

A critical review of ustekinumab for the treatment of active ulcerative colitis in adults

ABSTRACT Introduction Ustekinumab is a humanized monoclonal antibody, targeting the p40 subunit common to both human interleukin 12 and 23, approved by the European Medicines Agency and US Food and Drug Administration for the treatment of moderate-to-severe ulcerative colitis. Areas covered In this review, the results of the phase 3 UNIFI and the real-world studies assessing the efficacy and safety of ustekinumab in moderate-to-severe ulcerative colitis are discussed, as well as limitations of these studies. Predictive factors of response, the interest of therapeutic drug monitoring and the positioning of ustekinumab in specific situations are also addressed. Finally, in the light of data presented, the positioning of ustekinumab in the therapeutic algorithm of ulcerative colitis will also be considered. Expert opinion Ustekinumab has been shown to be effective to induce and maintain clinical, endoscopic and histologic remission in moderate-to-severe ulcerative colitis both in phase 3 and real-world studies, with a favorable safety profile. Overall, its favorable risk–benefit ratio, its efficacy on extra-intestinal manifestations and in biologics failure patients make ustekinumab an ideal candidate as first, second, or third-line therapy in ulcerative colitis.

Has the Time Come for Systematic Therapeutic Drug Monitoring of First-Line and WHO Group A Antituberculosis Drugs?

Tuberculosis (TB) is a major global health issue, with approximately 10 million people being infected each year, and is the leading cause of mortality from infectious disease, with 1.5 million deaths a year. Optimal TB treatment requires a combination of drugs for an adequate treatment duration owing to persistent organisms, hardly accessible infection sites, and a high risk of resistance selection. Long-term therapy increases the risk of patients' loss of adherence, adverse drug reactions, and drug-drug interactions, potentially leading to treatment failure. The high interpatient variability of TB drug exposure is another point eliciting interest in therapeutic drug monitoring (TDM) to optimize treatment. Studies reporting clinically relevant exposure thresholds, which might be proposed as targets toward treatment personalization, are discussed. Practical TDM strategies have also been reported to circumvent issues related to delayed drug absorption and the need for multiple samples when evaluating the area under the curve of drug concentrations. The need for treatment individualization is further emphasized because of the development of multidrug-resistant TB or extensively drug-resistant TB. Finally, the willingness to shorten the treatment duration while maintaining success is also a driver for ensuring adequate exposure to TB drugs with TDM. The aim of the present review was to underline the role of TDM in drug-susceptible TB and World Health Organization group A TB drugs.

Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study.

Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients. BRAFV600mut metastatic melanoma patients initiating standard doses of dabrafenib 150mg BID plus trametinib 2mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC0-τ and Ctrough) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed. Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib Ctrough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE. In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.

Therapeutic Drug Monitoring of Second- and Third-Generation Antiepileptic Drugs.

Therapeutic drug monitoring has traditionally been widely used for first-generation antiepileptic drugs (AEDs) such as carbamazepine and phenytoin. The last 2 decades have seen the introduction of second- and third-generation AEDs (eg, lamotrigine, levetiracetam, and topiramate) into clinical practice. To use data from the College of American Pathologists Therapeutic Drug Monitoring, Extended Proficiency Testing Survey to determine the performance of assays used for therapeutic drug monitoring of newer AEDs, including comparison of enzyme immunoassay and chromatographic techniques. Six years of proficiency testing surveys were reviewed (2013-2018). Steady growth was seen in participant volumes for newer AEDs. The analytical performance of automated enzyme immunoassays for lamotrigine, levetiracetam, and topiramate was similar to that of chromatographic methods, consistent with published literature using patient samples for comparisons. The majority of participating laboratories now use enzyme immunoassays to measure levetiracetam. Survey results reflect steadily growing interest in therapeutic drug monitoring of newer AEDs. The increasing availability of robust immunoassays for new AEDs should facilitate their clinical utility, especially for clinical laboratories that do not perform chromatographic assays for therapeutic drug monitoring.

Abstract PS5-16: Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring

Abstract Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy for the management of metastatic breast cancer patients. Like most oral targeted drug, therapeutic drug monitoring may be used for personalize their dosage. Using a recently published dosing technique (LC-MS/MS), we aimed at evaluating the correlation between first-cycle palbociclib plasma exposition and co-medications in order to evaluate drug-drug interaction (DDI) impact under palbociclib treatment.Methods: This is an open-label phase 4 study conducted in female subjects with first-line metastatic breast cancer (NCT04025541) treated with a palbociclib-aromatase inhibitor association. Plasma concentration of palbociclib was assessed at 24 hours postdose (plasma trough concentration Ctrough) at day 15 of first cycle of treatment. A dedicated pharmacist consultation allowed the determination of clinical covariates of interest, such as weight, body surface area, ethnicity, food intake, co-medications use and DDI before Palbociclib initiation and retrospectively at the end of clinical trial. Patients were classified then according to their risk of DDI potentially leading to inhibition of CYP3A4 and/or P-glycoprotein and gastric pH increase by gastric acid-suppressive (GAS) agents (such as proton pump inhibitors, histamine H2-receptor blockers or alginic acid). Relevant drug known to have an inhibition of CYP3A4 and/or P-glycoprotein or pH-modification activity were checked in databases (e.g. DDI predictor®, Drugs.com®, Pubmed®). Results: To date, after Ctrough analysis of the 35 first cases, the geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 79.5 ng/ml (± 26.1% [43.6 ng/mL - 133 ng/mL]) at day 15, similar to what reported in the PALOMA trials. No correlation between plasma concentration and body weight, body area or also age of the patients was found in our cohort. Regarding ethnicity, all the included patients were from Caucasian origin. 31% of patients (11/35) were identified of taking drugs that could cause DDI CYP3A4 and P-glycoprotein inhibition mediated (amlodipine n=3, simvastatin n=3, losartan n=2, fluconazole n=1, atorvastatin n=1, ivabradine n=1). These potential DDI interactions were associated with a significantly higher palbociclib concentration DDI subgroup (102 ng/mL vs 69 ng/mL) (p=0.000272) (Table 1). No CYP3A4 and/or P-glycoprotein inductor were reported in cohort. 1.4% of patients (5/35) were identified of taking GAS agents (pantoprazole n=2, ranitidine n=2, alginic acid n=1). We found a significantly reduction of palbociclib concentration (59.2 ng/mL vs 79.8 ng/mL) (p=0.048) in patients taking GAS medications (Table 1). Conclusion : These preliminary results, in real-life settings, obtained with our recently-published HPLC-MS/MS method, give important information on palbociclib monitoring and pharmacokinetic variability. DDI appear to have a significant impact on palbociclib plasma exposure, GAS agents are already know to modified palbociclib absorption. Additional studies are needed to characterize palbociclib plasma concentration variations between patients, and their clinical impact on efficacy and safety. The study is ongoing and will evaluate additional potential clinical and biological impact of DDI on neutropenia occurrence, on a larger population of patients. Table 1: Patients’ plasma palbociclib concentration (day 15 of cycle 1 of treatment).Plasma palbociclib concentrations (ng/ml), global cohort (n=35)Geometric mean (CV%) (min;max)79.5 (26.1%) (43.6;133)Plasma palbociclib concentrations (ng/ml), cohort with DDI CYP3A4 and P-gp mediated (n=11)Geometric mean (CV%)102 (24.3%)Plasma palbociclib concentrations (ng/ml), cohort without DDI CYP3A4 and P-gp mediated (n=24)Geometric mean (CV%)69 (19.8%)Plasma palbociclib concentrations (ng/ml), cohort with GAS treatment (n=5)Geometric mean (CV%)59.2 (15.9%)Plasma palbociclib concentrations (ng/ml), cohort without GAS treatment (n=30)Geometric mean (CV%)82.9 (26.1%) Citation Format: Fanny Leenhardt, Matthieu Gracia, Catherine Perrin, Claudia Muracciole-Bich, Bénédicte Marion, Celine Roques, Marie Alexandre, Nelly Firmin, Stephane Pouderoux, Litaty Mbatchi, Celine Gongora, William Jacot, Alexandre Evrard. Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-16.

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use.

Protein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed.

Interest of therapeutic drug monitoring of aminoglycosides administered by a monodose regimen

BackgroundAlthough the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG. MethodsWe performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin. ResultsA total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was≤41.66mL/min (OR: 11.29; 95%CI: 7.21–17.61; P<0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26–19.63; P=0.0006). ConclusionOur study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment.

Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?

To date, therapeutic drug monitoring (TDM) is carried out with antiretrovirals and is usually based on total concentrations (Ct ). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir (ATV), a HIV protease inhibitor. As the unbound concentration (Cu ) is the pharmacological active form, the aim of the study was to evaluate the value of Cu and the unbound fraction (fu , fu = Cu /Ct ) for the TDM of ATV. The variability of Cu and the corresponding fu of ATV was explored in 43 patients treated with ATV for an average of 13.5 months. Cu was determined by coupling ultrafiltration and liquid chromatography. As ATV is highly bound to alpha-1 acid glycoprotein (AAG), the correlation between fu and AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total plasma bilirubin and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough Cu and Ct were 37.9 μg/L (Interquartile range (IQR) 20.6-94.9 μg/L) and 628.6 μg/L (IQR 362.7-1078.1 μg/L), respectively. fu , Cu and Ct showed high variability, but the fu variability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response (P = 0.21 and P = 0.65 for Cu and fu , respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (ρ), ρ = 0.22; P = 0.17 for Cu ). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than Ct .

Suivi Thérapeutique Pharmacologique Des Antituberculeux : Quinze Ans d’Expérience

Tuberculosis is a world public health problem. Its treatment is based on a set of drugs that can cause many side effects. Liver toxicity remains one of the most common and severe side effect causing treatment failure. The objective of this study is to demonstrate the interest of therapeutic drug monitoring in the treatment of tuberculosis through the experience of the Laboratory of Toxicology and Pharmacology of the Anti Poison Center. This retrospective study involved 1152 patients who had benefited from a determination of plasma levels of first line antitubureculosis drugs (isoniasid, pyrazinamid, rifampicin) during 15 years. 135 patients had developed hepatotoxicity. The study showed that at therapeutic dose, 71.2% of TB patients had plasma concentrations lower than the therapeutic range, and 57.8% of patients had isoniazid plasma concentrations above the therapeutic range. This interindividual variability justifies the need for therapeutic drug monitoring to assess an inadequate response to tuberculosis treatment and prevent the development of hepatotoxicity.

Simultaneous quantitation of acetylsalicylic acid and clopidogrel along with their metabolites in human plasma using liquid chromatography tandem mass spectrometry.

The interest in therapeutic drug monitoring has increased over the last few years. Inter- and intra-patient variability in pharmacokinetics, plasma concentration related toxicity and success of therapy have stressed the need of frequent therapeutic drug monitoring of the drugs. A sensitive, selective and rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetylsalicylic acid (aspirin), salicylic acid, clopidogrel and carboxylic acid metabolite of clopidogrel in human plasma. The chromatographic separations were achieved on Waters Symmetry Shield(TM) C18 column (150 × 4.6 mm, 5 µm) using 3.5 mm ammonium acetate (pH 3.5)-acetonitrile (10:90, v/v) as mobile phase at a flow rate of 0.75 mL/min. The present method was successfully applied for therapeutic drug monitoring of aspirin and clopidogrel in 67 patients with coronary artery disease.

In Memoriam

On February 18, 2014, the international scientific community of Therapeutic Drug Monitoring (TDM) lost our friend and colleague, Offie P. Soldin, PhD, MBA. Offie was a long term member of Therapeutic Drug Monitoring Editorial Board, and the first Review Editor of the Journal. She was a loving mother, grandmother and wife, and in addition to her scientific career she completed an MBA and was a licensed pilot. During her high school years she completed Cume Laude the London Royal Conservatory of Music (piano). The term “impossible” did not exist in her vocabulary. Offie, a Georgetown Lombardi member in DC since 2003, was an associate professor in the Departments of Oncology, Medicine, Physiology and Obstetrics and Gynecology. Her research focused on thyroid disease and tobacco control, and she was equally comfortable and effective working with both clinical and population science colleagues. Publishing 80 peer review papers and well funded by the NIH and other agencies, Offie was a committed educator: she directed two graduate courses; co-directed a pharmacology elective for second-year medical students; and taught thyroid cancer genetics, tumor biology and radiation health within the Department of Oncology. Offie focused her research making excellent innovative contributions regarding the simultaneous quantification of free triiodothyronine and free thyroxine by tandem mass spectrometry. With regard to TDM, Offie Soldin established and published pediatric reference ranges for various clinical chemistry, toxicological and endocrinological parameters. In the field of toxicology, she had a long-standing cooperation with the Hospital for Sick Children in Toronto and the Motherisk program, which focuses on the effects of drugs, chemicals, radiation, and infection in pregnancy and lactation. Of special note, Offie presented an excellent comprehensive review article on developmental neuropathology of environmental agents such as methylmercury, lead, antiepileptic drugs, and ethanol. Dr Steven Lamm of DC, who introduced Offie to the field of thyroid therapeutic monitoring wrote: “Offie made a considerable name for herself in the American Thyroid Association where she brought her keen mind and laboratory skills to establishing trimester-specific thyroid parameters.” As the president of Georgetown Women in Medicine (GWIM), she created a mentorship program for women at the rank of associate professor. Offie also served on the university senate steering committee, was the chair of the American Thyroid Association clinical laboratory services committee, and the Hedwig van Ameringen Executive Leadership in Academic Medicine (ELAM) Program for Women. Most recently, Offie received the GWIM Fall 2013 Estelle Ramey Mentorship Award in honor of her exemplary teaching and mentoring work at Georgetown University Medical Center. She believed that knowledge is transformative and exemplary teaching essential, a belief clearly evidenced in her interactions with her students and mentees. She continuously sought to have a noteworthy impact in multiple communities through her clinical research and proactive work within Georgetown Lombardi Comprehensive Cancer Center. Prior to her arrival in DC, Offie was a member of the Motherisk Program in Toronto, and she continued as a consultant to the Program until her death. In DC, Offie commenced her interest in therapeutic drug monitoring while working with Steven Lamm. This work had initiated her interest in fetal thyroid function, an area she excelled in until her passing. Dr Janine Polifka of Seattle commented: “Offie was a beautiful, talented and extremely bright person. She was a joy to be with and so committed to her work and the people in her life.” When Offie told her close friends that she planned to come to the Summer 2013 scientific meetings, they were surprised, being aware of her grave situation. But she said: “I am on the program talking about thyroid in pregnancy, so I need to be there.” And she was—no one could tell how gravely ill she was. And during the party that evening she was smiling and joking as if everything would be okay. Offie’s legacy will certainly be highlighted by her unique way of doing everything with great passion, combined with talent, creativity and outstanding relationships with colleagues. And above all, an individual for whom the term “impossible” did not exist.

Suivi thérapeutique pharmacologique de la quinine

Quinine is an antimalarial agent whose main mechanism of action on Plasmodium is to inhibit the transformation of toxic haem to polymeric non-toxic haemozoin. After oral and intramuscular administration, quinine is well absorbed, with peak plasma concentration reached in 1 to 3 hours. The pharmacokinetic of quinine differs depending on the severity of the disease: the volume of distribution and the clearance decrease proportionally to the infection, while the half-life increases. Plasma concentrations are approximately 50% higher in patients in the acute phase than in convalescence. Quinine is metabolized primarily by CYP3A4, implying changing the dosage when combined with inhibitors or inducers of CYP. The efficacy of quinine has been proved for residual concentrations above 5 mg/L (15 μmol/L) throughout the duration of treatment. Some side effects are concentration-dependent and a concentration of 20 mg/L (60 μmol/L) is considered as the threshold for toxicity. The 2007 consensus conference of the French Language Infectious Diseases Society calls for daily monitoring of plasma concentrations during the first 3 days of treatment targeting a trough concentration between 10 and 12 mg/L (30-36 μmol/L). For this compound, the level of evidence of the interest of therapeutic drug monitoring has been evaluated and the latter is recommended.

Niveau de preuve du suivi thérapeutique pharmacologique de l’efavirenz

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.

Update on the optimal use of voriconazole for invasive fungal infections

Voriconazole is an extended-spectrum triazole with excellent bioavailability that has now become the treatment of choice for aspergillosis. It has a unique side effect profile compared with other azoles, as well as a number of clinically important drug–drug interactions. These factors, along with a correlation between increased serum levels and improved outcomes, have prompted an interest in therapeutic drug monitoring of this agent. The pharmacology and clinical outcomes data of voriconazole are presented in this review.

Enantioselective Assay for Therapeutic Drug Monitoring of Eslicarbazepine Acetate: No Interference With Carbamazepine and Its Metabolites

As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

Suivi thérapeutique pharmacologique de la gabapentine

Gabapentin is a structural analogue of GABA used in the treatment of the partial epilepsies of adult and child of more than 12 years, in monotherapy or in association with other anticonvulsant drugs. In association, gabapentin presents the advantage of not interfering with the other anticonvulsant drugs. The interindividual pharmacokinetic variability and the saturable absorption are, with the adaptation in case of renal insufficiency, the only arguments in favor of TDM. During clinical studies, the plasma concentrations of gabapentin were generally included between 2 and 20 mg/L. For this molecule, the level of proof of the interest of therapeutic drug monitoring was estimated in: possibly useful.

Pharmacokinetic and pharmacodynamic monitoring of immunosuppressive drugs in solid organ transplant recipients

Current clinical immunosuppressive regimens consist of combinations of drugs, in order to allow a reduction in the individual drug doses as a means to widen the therapeutic interval and to reduce the likelihood of individual drug toxicity. Combining drugs with different mechanisms of action may result in additive or even synergistic effects, potentially allowing dose reduction of individual drugs. Within the field of solid organ transplantation there is an unprecedented interest in therapeutic drug monitoring of immunosuppressive drugs, not only for recently introduced drugs, but also for established agents such as azathioprine and cyclosporine. Pharmacokinetic monitoring usually focuses on reaching certain target drug concentrations. Such ranges have been developed by retrospective review of drug concentration data and their correlation with clinical outcome. Multicenter concentration-controlled clinical trials can provide a basis for designing future prospective TDM investigations. Ideally, added to these trials should be also one or more pharmacodynamic tests, to quantify the biological effect of the drugs applied. Although on theoretical grounds monitoring the pharmacodynamic effect makes more sense than monitoring drug concentrations, in daily practice pharmacodynamic monitoring is not performed. Defining optimal ranges for pharmacokientic and pharmacodynamic drug monitoring of immunosuppressive drugs may lead to further improvement of the safety and efficacy of our immunosuppressive regimens.

Determination of abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine concentration in human plasma by MALDI-TOF/TOF

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. TDM is useful to determine the best dosage regimen adapted to each patient. Here, we apply MALDI-TOF/TOF technology to quantify abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine in the plasma of HIV-infected patients, by standard additions analysis. Regression of standard additions was linear over the whole anti-HIV concentration range explored (1.00 × 10 −2–1.00 pmol/μL). The absolute recovery ranged between 80% and 110%. Values of the drug concentration determined by MALDI-TOF/TOF were in the range of 1.00 × 10 −2–1.00 pmol/μL. The limit of quantification value was 1.00 × 10 −2 pmol/μL for abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine.

Stability of mycophenolic acid and glucuronide metabolites in human plasma and the impact of deproteinization methodology

In recent years there is growing interest in therapeutic drug monitoring of mycophenolic acid (MPA) and its glucuronide metabolites MPAG and AcMPAG. Like other acyl glucuronide metabolites, AcMPAG has a limited stability, but this aspect has received little attention. Plasma sample deproteinization with perchloric acid 2 M (method A) was compared to metaphosphoric acid 15% (method B). Stability of MPA, MPAG and AcMPAG in acidified and non-acidified plasma stored at room temperature, 4 degrees C, -20 degrees C and -80 degrees C was assessed over short and long time intervals using HPLC-UV methodology. The area ratio of AcMPAG/IS on spiked plasma at pH 2.5 with method A was 63% of the respective ratio in water, in contrast to 102% with method B, suggesting partial deconjugation and/or incomplete release of AcMPAG from proteins with method A. At room temperature, AcMPAG concentrations in both whole blood and non-acidified plasma decreased significantly after 2-5 h. MPA, MPAG and AcMPAG concentrations remained stable in acidified plasma stored at -20 degrees C and -80 degrees C, but not longer than 5 months after collection. It is concluded that adequate sample collection, storage measures and deproteinization methods should be applied in order to avoid deconjugation and hence underestimation of MPA, MPAG and AcMPAG concentrations.