Comparing real-life carbamazepine exposure between innovator and generic formulation.

BACKGROUND: Carbamazepine is an anticonvulsant largely used in the treatment of epilepsy. The use of generic antiepileptic drugs (AEDs) is controversial because of the eventual possibility to loss seizures control. The aim of our study was to compare the concentration over dose ratio of two products containing carbamazepine, the innovator (Tégrétol®-NOVARTIS) and the generic (Taver®-MEDOCHEMIE). METHODS: It is a retrospective study (2009-2016) including 32 patients treated with carbamazepine. Patients were treated initially by innovator then switched to generic or vice versa. All patients have at least one level of carbamazepine plasma concentration (C0) with the innovator or the generic formulation. Monitoring of carabamazepine was made using immunoassay method (ARCHITECT-ABOTT®). RESULTS: The mean age of our patients was 28.4 years and ranged from 2 to 55 years. The sex ratio M/F was 1.46. The mean ratio C0/dose for the innovator group was 0.723 (min/max: 0.017/1.73), and the mean ratio C0/dose for the generic group was also 0.607 (min/max: 0.064/1.68). There was no statistically significant difference between both groups (P=0.16). CONCLUSION: Our results confirm the difference between the innovator and the generic formulation of carbamazepine. So, switching from innovator to generic seems to be safe and exposure to carbamazepine remains the same.

Is there a ceiling lamotrigine serum level in epileptic children in remission?

INTRODUCTION: Seizure control, in patients with epilepsy, is proportionally associated with health-related quality of life. Antiepileptic therapy leads to seizure remission in most cases. However, some patients are resistant to treatment despite achieving high doses which can be explained by interindividual variability of antiepileptic drugs' metabolism. A ceiling exposure, in epilepsy, helps to adapt the therapeutic strategy in a faster way and to prevent unnecessary exposure to adverse drug reactions. Due to the increasing use of new generations of antiepileptic drugs, we aimed to explore the distribution of lamotrigine (LMT) trough serum levels in epileptic children, stratified between remission and ongoing seizures, in order to determine whether there is a ceiling effect associated with remission. METHODS: We conducted a retrospective study (2012-2021) including children, with generalized epilepsy (2-18 years), addressed for a therapeutic drug monitoring of LMT trough serum levels. Patients in remission, should have as lasting three times the longest pre-treatment seizure-free interval and more than one year. RESULTS: The population of 114 children with generalized epilepsy was divided in to groups: epileptic children in remission (36) and epileptic children with ongoing seizures (78). There was no significant difference in age and sex in the two groups. Median LMT daily dose and trough serum levels were significantly higher in group 2. The highest LMT serum trough level was 11µg/mL in group 1 and 23.1µg/mL in group 2. Valproate was associated in 29%. There was no significant difference of the distribution of valproate in the two groups (P=0.08). CONCLUSIONS: Children in remission had a LMT trough serum levels under 11µg/mL and a daily dose of 3.36mg/kg/day or less. These results suggest that this LMT serum level and daily dose might be associated with a ceiling effect in epileptic children.

Digoxin therapeutic drug monitoring: age influence and adverse events.

INTRODUCTION: Digoxin is a cardiac glycoside, used to control rapid ventricular rates in atrial fibrillation and to reduce the hospitalizations due to heart failure. Digoxin has a narrow therapeutic range. So, in the treatment of older patients (≥ 65 years), it is important to set the optimal dose of digoxin to prevent toxicity and therapeutic drug monitoring of digoxin trough plasmatic concentration (C0) may be useful. AIM: To assess measured C0, to evaluate age influence on digoxin pharmacokinetic parameters and to report adverse events in patients administered digoxin. METHODS: It consisted in a retrospective study. We included all the patients addressed to the department of clinical pharmacology for digoxin C0 measurement by an automated fluorescence polarization immunoassay. Therapeutic ranges of digoxin C0 were: 1 to 2.5 ng.mL-1 in children, 0.8 to 2 ng.mL-1 in adults and 0.5 to 0.9 ng.mL-1 in older adults (≥ 65 years) in atrial fibrillation and heart failure. RESULTS: We collected 183 samples from 132 patients. Sex ratio M/W was 0.47. Mean age was 60 years and 57% of patients were older adults. Mean dose of digoxin was 0.3 mg.day-1. In older adults, 45% were administered daily doses over 0.125 mg.day-1. Mean digoxin C0 was 1.6 ng.mL-1. There was more supra-therapeutic C0 in older adults than younger ones (p<0.0001).There was no correlation between C0 and daily dose of digoxin. Adverse events, mainly cardiac and digestive, were reported in 47 patients (36%), among this population 47% were older adults. CONCLUSION: TDM is useful to prevent toxicity, mainly in older adults where diagnosis may be difficult to establish.

Development and validation method for estimation paclitaxel in plasma.

BACKGROUND: Paclitaxel (PTX) is an anticancer drug used in the treatment of many cancer , alone or in combination with other anti-tumors. It has a narrow therapeutic range, a large inter and intra-individual pharmacokinetic variability and haematological toxicity. The most effective pharmacokinetic parameter seems to be the time during which the plasma concentration is over 0.05 µmol/L. AIM: To develop and validate a new method for PTX quantitation in plasma using HPLC with UV/visible detection. METHODS: A rapid HPLC-UV method was developed for the determination of PTX level in plasma. All solvents used were HPLC grade. RESULTS: After liquid-liquid extraction, chromatographic separation was achieved using an RP 18 (250 mm) column. The mobile phase was composed of acetonitrile and 0.1 M potassium dihyrogenophosphate (49/51) (v/v). Clonazepam was used as internal standard. This technique was linear over the range 50 ng/mL to 1500 ng/mL (r= 0.998). The evaluation of precision showed that our method is repeatable with a within-day coefficient of variation (CV) ranging from 6.94 to 18.78 % and reproducible for three studied concentrations low, medium and high with day-to-day CV of 14.92, 10.46 and 11.8% respectively. Under these conditions, each analysis required no longer than 12.81 min. CONCLUSION: We have developed and validate a new assay for PTX monitoring using HPLC with UV detection which is sensible, specific, reliable and easy to carry out in clinical use for its therapeutic drug monitoring.

Early interaction between tacrolimus and rifampin.

Drug interactions are unavoidable and need to be proactively identified and managed, in particular, the inductive effect of rifampin on tacrolimus whose potency and duration data are limited. We report the case of a renal transplant patient who was prescribed tacrolimus with preserved tough blood levels (C0) of 7.9 +/- 2 ng/mL. He presented ganglionic tuberculosis and started rifampin. One day later, C0 was 2.6 ng/mL with 5 mg/day. The serum creatinin was normal. Nine days later, C0 was 1.6 ng/mL with 7 mg/day. In this case-report, the tacrolimus-rifampin interaction occurred just one day after rifampin introduction necessitating early C0 monitoring.

Therapeutic durg monitoring of cyclosporin using area under the curve in nephrotic syndrome.

The use of cyclosporin in nephrotic syndrome can be considered in cortico-resistance or cortico-dependence. Cyclosporin is an immunosuppressant with a narrow therapeutic range and large pharmacokinetics variability justifying its therapeutic drug monitoring (TDM). The aim of this study was to evaluate the TDM of cyclosporin by the measurement of AUC0-12h in patients with nephrotic syndrome and to study the correlations between the AUC0-12h and the different blood concentrations of cyclosporin. It is a retrospective study from 2009 to 2016. TDM of cyclosporin was carrying out by ARCHITECT®. Determination of the AUC0-12h was made from three samples taken at T0, T60min and T180min obtained by a model of population pharmacokinetics of cyclosporin. A total of 20 patients were evaluated (29 abbreviated kinetics). The median AUC0-12h was 4.76 mg*h/L. Considering the target 5 mg*h/L during the first 6 months, 6 AUC0-12h were sub-therapeutic and 5 supra-therapeutic, no AUC0-12h was in the therapeutic range. Considering the 3 mg*h/L as a target during the following months, 13 AUC0-12h among 18 were supra-therapeutic. A correlation coefficient between the AUC0-12h of cyclosporin and C0 was 0.798. Correlation between AUC0-12h and C2h was 0.909. The median C2h found in our work was 878 ng / mL during the first six months versus 1039 ng / mL in the following months. Our patients are overexposed to cyclosporin and TDM of this drug by determination of AUC0-12h or by C2h would be more interesting than TDM by C0. TDM allows a better individual dose adjustment to avoid especially toxicity of cyclosporin.

Comparative study of two techniques of mycophenolate mofetyl monitoring.

INTRODUCTION: Mycophenolic acid (MPA) requires routine therapeutic drug monitoring. AIM: To evaluate the suitability of a MPA Immunoassay CEDIA performed on Indiko® analyzer (Thermo fisher) for monitoring of MPA by comparing values obtained by HPLC-UV method. METHODS: This study was carried out on 114 blood samples collected from renal transplant, using high performance liquid chromatography combined with ultraviolet detection (HPLC-UV, reference method) and the new immunoassay on CEDIA. RESULTS: The assay was linear for a mycophenolic acid concentration up to 10 µg/mL. When MPA concentrations in all 114 transplant recipients obtained by the HPLC-UV (x-axis) method were compared with corresponding values obtained by the CEDIA® method (y-axis), the following regression equation was obtained: CEDIA® = 1.558 HPLC + 0.49 (r = 0.86). However more significant positive bias was observed (37 %). CONCLUSION: The data presented suggest that the CEDIA® MPA immunoassay, run on the Indiko® analyzer, over-estimates plasma MPA concentrations. However, CEDIA® immunoassay is less laborious and time consuming than chromatographia techniques.

Therapeutic monitoring of antiepileptic drugs in comatose patients.

OBJECTIVE: In this study, we aimed to analyze the trough plasmatic levels (C0) of the antiepileptic drugs (AED) administered by nasogastric tubes (NGT) in comatose patients and to draw up recommendations for therapeutic drug monitoring (TDM) and for the modalities of AED administration by NGT. METHODS: We conducted a retrospective study on comatose patients addressed over six years and 10 months in Clinical Pharmacology for C0 measurement of AED administered by NGT. RESULTS: In this study, the sex-ratio was 2.38 (44 patients). The patients' median age was 24 years. There was 14.5% of children (≤16 years). Among the 103 samples, C0 measurement concerned valproic acid in 57%, phenobarbital in 28 % and carbamazepine in 15%. Two AED or more were associated in 42% of patients. AED were associated to other drugs in 85% of cases. The AED C0 were subtherapeutic in 71% of cases. C0/Dp lower than recommanded in 65 %. In these samples, 55% presented at least one drug association with the concerned AED. In 45% of the cases, there was no drug association but a non-respect of modalities of AED administration by NGT in patients. CONCLUSION:   The drug monitoring is a useful tool to assess drug-drug interactions and to control modalities of AED administration in comatose patients.

Hypericum Humifusum Leaves Attenuates Hepatic Ischemia-Reperfusion Injury in a Rat Model.

INTRODUCTION: Effective prevention strategies require specific actions during the different phases of ischemia-reperfusion (I-R) injury. The objective of our study is to evaluate the effect of aqueous extract of Hypericum humifusum leaves (HHL) on liver I-R model in Rat. MATERIAL AND METHODS: Animals were subjected to 90 min of hepatic ischemia followed by reperfusion (120 min). HHL extract (25 mg/mL/kg) was injected 15 min before reperfusion. To evaluate the effect of HHL extract on I-R, we have monitored transaminases levels, Malondialdehyde (MDA) concentration, histological lesions (apoptosis and necrosis) and compared the results to a reference oxidant vitamin E. RESULTS: The determination of total phenol extracts of HHL was 59.91 ± 0.35 mg of Gallic Acid/g dry plant material with higher antioxidant activity (91.73% ± 1.67) compared to vitamin E (87.42%). Using aqueous extract of HHL, we noted a significant decrease of AST and ALT [1129 UI (585/1995) and 768 UI (335/1375)] compared to no-treated group [5,585.5 UI (5,035/12,070) and 8,099.5 UI (5,040/12,326)] as a decrease in MDA content [85.7% protection (50.9/91.5)]. HHL extract reduce the damage induced by I-R of 48.7% (27/48.7) and 96.1% (95.7/96.5) for necrosis and apoptosis lesions respectively. CONCLUSION: HHL aqueous extract have potential to protect liver from the damage effect induced by I-R better than vitamin E solution.

[Antiepileptic drugs administration by nasogastric tube in comatose patients]. / Modalités d'administration des antiépileptiques par sonde nasogastrique chez des patients comateux : étude des connaissances, attitudes et pratiques.

AIM: To evaluate the modalities of administration of antiepileptic drugs (AED) with nasogastric tube (NGT) by nurses and to draw up recommendations. METHODS: Our study consisted on investigating the modalities of administration of AED's with NGT by nurses during four months. We prepared 10 questions including demographic information. Participation was voluntary and anonymous. The questionnaire was distributed in seven intensive care departments after authorization of each head of the department. Thus, 45 nurses were included. RESULTS: Nurses sex ratio was 1.5 and mean age was 31 years (25 to 37 years). Among the nurses, 60% mentioned that the NGT were silicone made and 4% that they were PVC made. The mean duration before replacing the NGT was thought to be 5±3 days. Among the nurses, 91% affirmed to clear the NGT after each use. All the nurses had agreed that the solid form is the most commonly used pharmaceutical form in the NGT. AED were associated with the enteral feeding solution in 56%. The AED should be crushed before administration for 98% of the nurses even in case of polymedication. Among them, 62% recommended to crush all of the associated drugs together. Before introducing the AED into the NGT, 93% of the nurses reported mixing with tap water. We have noticed that 62% of nurses felt the need to improve their knowledge AED administration with NGT. CONCLUSION: To optimize AED therapy, modalities of administration by NGT in epileptic comatose patients should be enhanced.

Limited sampling strategy for the estimation of mycophenolic acid area under the curve in Tunisian renal transplant patients.

Mycophenolate mofetil is a prodrug widely used in renal transplantation to prevent organ rejection. It is hydrolyzed to its active compound mycophenolic acid (MPA). MPA area under the curve (AUC0-12h) is considered the best pharmacokinetic parameter for the estimation of MPA exposition and for prediction of rejection. MPA-AUC requires several blood samples, making it impractical for clinical practice. Therefore, development of a limited sampling strategy (LSS) to estimate MPA AUC0-12h using three blood samples is very helpful for MPA individual dose adjustment. Results of LSS differ according to the patient background and to the drug formulation. Therefore, the purpose of this study was to develop a LSS for the estimation of MPA AUC0-12h in Tunisian renal transplant patients treated with the generic formulation of mycophenolate mofetil (MMF®, MEDIS). The best correlation was achieved by a profile based on three time points C0.5h, C1.5h, and C4h after drug intake: AUC0-12h = 0.414 + 1.210 × C0.5 + 2.256 × C1.5 + 4.134 × C4 (mei = 1.65% and rmse = 5.81%). The correlation between full AUC0-12h and abbreviated AUC0-12h was 0.917. In conclusion, this model provides a reliable and simple equation to estimate MPA AUC0-12h for the generic formulation of mycophenolate mofetil (MMF®).

[Comparative study of two techniques of ciclosporine monitoring]. / Étude comparative de deux techniques de dosage de la ciclosporine.

Ciclosporine (CsA) is an immunosuppressant drug used in bone marrow transplantation in order to extend allograft survival. Despite its efficiency, CsA can expose to therapeutic failure or to toxicity because of underdosing or overdosage. So, many techniques of monitoring CsA in blood were used, the referance one is the chromatographic technique then, the automated techniques: fluorescence polarization immunoassay (FPIA) and chimiluminescent microparticle immunoassay (CMIA). In this study, we aimed to compare the results of CsA concentrations measured by the two automised techniques. Statistical studies showed that the two techniques were repeatable and reproductible. Results obtained by FPIA were slightly higher than those obtained by CMIA but without a significative difference. In conclusion, FPIA technique could be used to measure CsA blood concentration in replacement of CMIA in case of technical problems.

Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report.

Mitotane provided serious side effects and low doses seemed to be tolerated. Determination of mitotane concentration in plasma is recommended. We report the case of toxic plasma levels with low doses of mitotane in a 47-year-old man with adrenocortical cancer.

Pharmacokinetik population of methotrexate in tunisian population with acute lymphoblastic leukemia.

BACKGROUND: The use of high dose of MTX in the treatment of the leukemia is actually better controlled by renal preparation, control of plasma concentrations and administration of folinic acid. However, High dose MTX has been proven to cause substantial toxicity and have high intra-and inter-patient variability. Population pharmacokinetic analysis is a useful tool for identification of sources of pharmacokinetic variability during anticancer drug development and can aid the design of alternative dosing regimens to enhance their efficacy and safety. AIM: The aim of our study is to developed and validate a population pharmacokinetics model of our population. We hereby describe the clinical covariates (age, sex and clearance of the creatinine) that influence MTX pharmacokinetic for predicting optimal dose to reduce MTX toxicity. METHOD: It is a prospective study achieved between January 2005 to January 2012 in the Service of Clinical Pharmacology. Including 273 patients treated for acute lymphocytic leukaemia 2582 plasma concentration was achieved. The data have been analyzed with Nonmem© software (non linear regression to mixed effect). RESULTS: The age of our patients varied from 2 to 23 years with an average of 13 years. The patients received high dose MTX therapy (1 to 8 g/m2) in 24 hours infusion every 15 days. Three compartiment models describe the pharmacokinetic of MTX. The most important covariables affecting the model were clearance of the creatinine, age and weight. We obtained a good correlation between the predicted and the observed concentrations. CONCLUSION: The development of population pharmacokinetics model of MTX allows us to propose a therapeutic diagram adapted to every patient according to its morphological and pharmacological features while taking in consideration the therapeutic objective.

[Development and validation of a new HPLC method for determination of Lamotrigine and clinical application]. / Mise au point validation d'une method de dosage de la lamotrigine par chromatographie liquid à haute performance et application clinique.

BACKGROUND: Lamotrigine is an effective anticonvulsant drug used in the treatment of epilepsy. It has a narrow therapeutic range, a large inter and intra-individual pharmacokinetic variability and some concentration-dependent side effects. AIM: The aim of this study was to develop and validate a new method for lamotrigine quantitation in plasma using HPLC with UV/visible detection. METHODS: A rapid HPLC-UV method was developed for the determination of lamotrigine in plasma. All solvents used were HPLC grade. RESULTS: After liquid-liquid extraction, chromatographic separation was achieved using an RP 18 (250 mm) column. The mobile phase was composed of acetonitrile and 0.1 M potassium dihyrogenophosphate (25/75) (v/v). Barbital sodium was used as internal standard. This technique was linear over the 2 µg/mL to 50 µg/mL range (r= 0.99). Detection and quantification limits were 0.07 µg/mL and 0.21 µg/mL, respectively. Within-day coefficient of variation (13.37 to 16 %) and day-to-day coefficients of variation (15.68 to 16.63 %) at three different concentrations. Under these conditions, each analysis required no longer than 10 min. We finally evaluated the plasma concentrations of lamotrigine in Tunisian patients treated with this drug. CONCLUSION: The results found are similar to those previously described and the developed method is repeatable and reproducible. It can be used for clinical applications.

Vancomycin therapeutic drug monitoring in cerebrospinal fluid.

Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year-old man with post traumatic meningitis with vancomycin concentration measured in CSF.

Population pharmacokinetics of bupivacaine in combined lumbar and sciatic nerve block.

OBJECTIVES: The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight and sex on pharmacokinetic parameters. MATERIALS AND METHODS: A total of 31 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. RESULTS: One compartment model with first order absorption, two input compartments and a central elimination was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model (P = 0.156) showed this as a valid model. The selected model predicts a population clearance of 930 ml/min (residual standard error [RSE] = 15.48%, IC 95% = 930 ± 282.24) with inter individual variability of 75.29%. The central volume of distribution was 134 l (RSE = 12.76%, IC = 134 ± 33.51 L) with inter individual variability of 63.40%. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00462/min for the lumbar site and 0.292/min for the sciatic site. Age, body weight and sex have no effect on the bupivacaine pharmacokinetics in this studied population. CONCLUSION: The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.