Comparison of Branded and Generic Imatinib Plasma Concentrations in Patients With Chronic Myelogenous Leukemia: Unicentric Study.

INTRODUCTION: For over a decade, imatinib has been the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Doubts on the bioequivalence and bioavailability of emerging generic compounds have been expressed. Adequate imatinib plasma concentration ([IPC] ≥1000 µmol/L) is associated with a better chance of optimal treatment response in patients with CML. In this study, we compared the achieved IPCs between the branded compound and its 2 generic forms. PATIENTS AND METHODS: IPCs were compared in 24 consecutive patients with CML in the first chronic phase who changed from branded to generic imatinib. The median age was 49 years (range, 22-76 years). Fifteen of them were male. Six patients were switched to Neopax, 13 to Imakrebin, and 5 patients received both generics consecutively. All compounds were used in an equivalent dose of 400 mg orally once daily for at least 1 month before plasma concentrations were measured. High-performance liquid chromatography was used to determine imatinib plasma concentration from a specimen collected 21 to 24 hours after the last dose. RESULTS: The median IPC achieved with branded imatinib was 1454 µmol/L (range, 485-2707 µmol/L) with 18 patients (75%) having IPC ≥ 1000 µmol/L. For Neopax and Imakrebin, median IPCs were 1717 µmol/L (range, 1249-3630 µmol/L) and 1458 µmol/L (range, 707-880 µmol/L), respectively, with 11 of 11 (100%) and 16 of 18 (89%) patients having IPC ≥ 1000 µmol/L. No significant difference in measured IPCs between all 3 compounds was found (P > .257). CONCLUSION: When taken at equivalent doses, imatinib generics are bioequivalent and comparable in clinical efficacy and have the potential for substantial savings in the treatment cost for CML.

Effect of cyclosporine on steady-state pharmacokinetics of MPA in renal transplant recipients is not affected by the MPA formulation: analysis based on therapeutic drug monitoring data.

BACKGROUND: Two oral mycophenolic acid (MPA) formulations, immediate-release mycophenolate mofetil and enteric-coated mycophenolate sodium, have been shown to differ regarding some drug-drug interactions. The aim was to assess whether the effects of cyclosporine (CsA) on steady-state pharmacokinetics (PK) of MPA in renal transplant patients were affected by MPA formulation. METHODS: A prospective, stratified observational study based on therapeutic drug monitoring of MPA (6 total plasma concentrations over a 12-hour dosing interval, τ) in consecutive stable adult renal transplant recipients (n = 68). RESULTS: Patients treated with enteric-coated mycophenolate sodium (n = 45) or mycophenolate mofetil (n = 23) and with either CsA (microemulsion, n = 43) or tacrolimus (Tac) (immediate release, n = 25) were comparable regarding demographics, comorbidity, renal and liver functions, comedication, corticosteroid dose, CsA or Tac dose, and trough concentrations. Based on dose-normalized MPA concentrations and with adjustment for age, sex, body mass index, estimated glomerular filtration rate, and corticosteroid dose, CsA (as compared with Tac) consistently reduced MPA area under the concentration-time curve during the dosing interval at steady state overall [geometric mean ratio (GMR), 0.78; 95% confidence interval, 0.62-0.99] and by MPA formulation (by 22% and 21%, respectively), increased CLT/F,ss overall (1.31; 1.00-1.70) and by formulation (by 25% and 36%, respectively), reduced morning predose MPA concentration overall (0.59; 0.38-0.92) and by formulation (by 34% and 47%, respectively), increased peak-trough fluctuation overall (1.51; 1.06-2.17) and by formulation (by 58% and 45%, respectively), and prolonged tmax,ss overall (adjusted median difference 0.58, 0.04-1.12 hours) and by formulation (by 0.6 and 0.5 hours, respectively). CONCLUSIONS: Qualitatively and quantitatively, the effect of CsA on steady-state PK of MPA is not conditional on MPA formulation.

Association between lamotrigine concentrations and ABCB1 polymorphisms in patients with epilepsy.

BACKGROUND: Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein-encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition. METHODS: We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography-diode array detector (DAD) and immunoassay. RESULTS: A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 µmol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 µmol·L·mg, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C-2677G-3435C carriers had higher lamotrigine concentrations than 1236T-2677G-3435T carriers (P < 0.001), followed by 1236T-2677T-3435C carriers (P < 0.001). CONCLUSIONS: ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.

Ethylene glycol poisoning.

A 40-year-old man was admitted to the emergency department after a suicide attempt. The patient was found at home unconscious, with an open bottle of antifreeze near him. The patient was in a coma on admission, but neurological examination excluded intracranial changes. Results of initial urine and serum toxicological screening tests were negative. Laboratory values indicated metabolic acidosis, leukocytosis, urinalysis revealed hematuria and unrecognized crystals. Osmolality and osmol gap were not determined on patient admission. Treatment with ethanol as an antidote and hemodialysis were started because of metabolic acidosis, anamnestic data and clinical status of the patient, and subsequently led to improvement of his condition. Further toxicological analyses of glycolic and oxalic acids in serum and urine samples were performed by ion-chromatography (IC) method and showed high values in spot urine and serum ultrafiltrate at admission, but during therapy the values progressively decreased. Treatment of poisoned patient for 3 weeks resulted in complete recovery.

Fetal grasping of the umbilical cord and perinatal outcome.

This study assessed perinatal outcome in pregnancies with accidentally diagnosed fetal grasping of the umbilical cord (FGUC) on ultrasonography (US) in late gestation as a possible cause of fetal hypoxia due to mechanical occlusion of umbilical circulation. In this retrospective clinical study, routine antenatal US examination revealed FGUC from 32 to 41 weeks of gestation in seven normal single pregnancies. Upon FGUC findings, fetal condition was followed up every second day by repeat US findings of FGUC, and then by Doppler parameters of fetoplacental circulation measurement of resistance index in umbilical artery (URI) and middle cerebral artery (CRI), and cardiotocography (CTG), and perinatal outcome (peripartal cardiotocography, 5-min Apgar score, umbilical arterial blood pH, occurrence of meconium amniotic fluid, need of additional treatment at neonatal intensive care unit (NICU), and mode of pregnancy termination (cesarean section, forceps or vacuum extraction-VE for hypoxia). After delivery, neonatal neurosonography and neonatal complications related to pregnancy or birth were evaluated. All URI values were increased, resulting from persistent FGUC and elevated umbilical arterial RI. CRI showed great oscillations in the values for gestational age and decreased CRI. In two cases, cerebral/umbilical ratio was less than 1, indicating initial vasocentralization as a fetal compensatory mechanism for hypoxia. In these cases, a pathological peripartal CTG and pH 7.23, indicative of preacidosis, were verified. All children were discharged from NICU as healthy, free from neurological lesions, with the exception of the latter, who had dystonia syndrome and mild motor deficit as a sign of peripartal hypoxia. Although it probably belongs to normal reflexes, intermittent FGUC should be US controlled. Persistent FGUC should be considered pathological for its possible hypoxic effect and umbilical circulation obstruction. These pregnant women should be hospitalized and closely monitored, as in part confirmed by the present study.

Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population.

AIM: To determine the prevalence of most common mutations of cytochrome P450 (CYP), ie, allelic variants of CYP2C9, CYP2C19, and CYP2D6, and to predict genotype frequency in the Croatian population. METHODS: CYP genotype was determined in 200 non-related Croatian citizens. DNA isolated from blood samples was used for the analysis of the most common allelic variants of CYP2C9, CYP2C19, and CYP2D6 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: For 200 subjects genotyped for CYP2C9, the allele frequencies of CYP2C9*1 (wt), CYP2C9*2, and CYP2C9*3 were 0.74, 0.165, and 0.095, respectively. Among them, 3.5% of subjects were predicted to be poor metabolizers. For CYP2C19, the most frequent alleles were CYP2C19*1 and CYP2C19*2, with frequencies of 0.85 and 0.15, respectively; 3% of subjects were predicted to be poor metabolizers. For CYP2D6, the most frequent alleles were CYP2D6*1 (frequency 0.765), CYP2D62* (0.04), CYP2D6*3 (0.0275), CYP2D6*4 (0.14), CYP2D6*5 ( 0.01), and CYP2D6*6 (0.015). Out of these, 3% were predicted to be poor metabolizers, and 4% were predicted to be ultra-rapid metabolizers. CONCLUSION: The prevalence of allelic variants and predicted genotypes in the Croatian population is in accordance with the other European populations, and it can be interpolated between the values for mid-European and Mediterranean populations.

[Prevalence of ultraextensive drug metabolizers in Croatian population--long-PCR based detection of amplified CYP2D6 gene]. / Prevalencija vrlo brzih metabolizatora lijekova u hrvatskoj populaciji--detekcija amplificiranog gena CYP2D6 metodom long-PCR.

Cytochrome P450 enzyme debrisoquine 4-hydroxylase, responsible for the metabolism of different classes of drugs and other chemical substances, exhibits genetic polymorphism with great interindividual and interethnic differences in metabolic capacity. The activity of enzyme ranges from very expressed, rapid, to total absence of activity. Up to 7% of Caucasians may demonstrate ultrarapid metabolism--UEM of debrisoquine and other drugs, substrates of debrisoquin hydroxylase, due to inheritance of multiplicate functional CYP2D6 gene, causing an increased amount of enzyme to be expressed. Identification of subjects with ultrarapid metabolism is of potential clinical value for optimization of therapy and avoidance of therapeutic failure due to inadequate dosage. In our study we wanted to determine the prevalence of UEM genotype in Croatian population applying long-PCR method. We found a 4% prevalence of ultrarapid metabolizers with multiplicated CYP2D6 gene.