Evaluation of the Interaction of Intravenous and Oral Voriconazole with Oral Cyclosporine in Iranian HSCT Patients.

OBJECTIVE: Voriconazole as a triazole antifungal agent is widely used for prophylaxis or treatment of fungal infections in allogeneic hematopoietic stem cell transplantation (HSCT). It can increase blood concentrations of other medications including cyclosporine A (CsA) which are substrates for cytochrome P450 3A4. The aim of this study was to evaluate comparatively the interaction between oral/intravenous (IV) voriconazole and oral CsA. METHODS: Twenty-nine recipients of allogeneic HSCT who had been already on a steady dose of CsA and were started on oral or IV voriconazole were evaluated in a prospective cohort study. Blood concentration of CsA was determined before and 5-8 days after voriconazole initiation. Plasma concentration of voriconazole was measured in steady state. The changes in blood concentration of CsA after administration of voriconazole were evaluated. FINDINGS: The concentration/dose (C/D) ratio of CsA increased significantly (P < 0.001) after voriconazole initiation in both routes of administration (8.40%-174.10% increase in C/D ratio). The C/D ratio alteration of CsA did not differ significantly between oral and IV voriconazole group (P = 0.405). There was a significant correlation in all patients between plasma concentration of voriconazole and percentage of CsA C/D ratio increment (P = 0.046). CONCLUSION: There was a significant intrapatient variability in the magnitude of CsA blood concentration increment after voriconazole initiation. We also demonstrated that magnitude of drug interaction did not differ in IV and oral voriconazole administration. Furthermore, we found that the magnitude of drug interaction was correlated with plasma concentration of voriconazole.

Impact of CYP2C19 Polymorphisms on Serum Concentration of Voriconazole in Iranian Hematological Patients.

OBJECTIVE: This study aimed to determine the portion of Iranian patients who attain therapeutic serum concentrations of voriconazole (VRCZ) following administration of fixed doses. In addition, the effect of CYP2C19 polymorphism on serum levels of VRCZ was also investigated. METHODS: Forty-eight adult patients of Iranian origin with hematologic malignancies, who received VRCZ for treatment of invasive aspergillosis, were recruited into the study. Blood samples were drawn at day 4 of treatment to measure trough drug concentrations and determine genotyping of CYP2C19 polymorphisms of each patient. High-performance liquid chromatography method was used for measuring VRCZ serum level and CYP2C19 polymorphisms were conducted by Sanger sequencing. Demographic and clinical characteristics of patients alongside with CYP2C19 polymorphisms were assessed to determine the effective factor/s on VRCZ serum concentration. FINDINGS: Seventy-three percent of patients achieved therapeutic serum concentrations of VRCZ with administration of usual fixed doses in clinical practice. There was no correlation between weight-adjusted dose and serum concentrations of VRCZ. Mean serum levels were significantly different neither in genders nor in routes of administrations. Extensive and ultrarapid metabolizers (URMs) comprised 48.7% and 21.6% study population, respectively. CYP2C19 polymorphism dramatically influenced the trough levels of VRCZ, so that all patients with subtherapeutic levels expressed URM phenotype. CONCLUSION: With respect to high incidence of URM phenotype in Iranian population, and observed association of this phenotype with sub-therapeutic levels in our study, performing therapeutic drug monitoring is strongly recommended for all patients.

Pharmacokinetic Behavior of Phenytoin in Head Trauma and Cerebrovascular Accident Patients in an Iranian Population.

OBJECTIVE: Acute brain injury is one of the leading causes of morbidity and mortality worldwide. Phenytoin has been commonly used as an anticonvulsant agent for the treatment or prophylaxis of seizures following acute brain injury. After a severe head injury, several pharmacokinetic changes occur. The aim of this study is the comparative evaluation of phenytoin serum concentration in patients with traumatic and nontraumatic brain injury (TBI). METHODS: This prospective observational study was performed on twenty adult brain injury patients who were admitted to an Intensive Care Unit and required phenytoin for the treatment or prophylaxis of postinjury seizures. For all the patients, phenytoin serum concentration was determined in three scheduled time points. Phenytoin serum concentration and pharmacokinetic parameters were compared between patients with TBI and cerebrovascular accident (CVA). FINDINGS: The Vmaxand Kmwere significantly higher in head trauma (HT) patients than the CVA group. The phenytoin concentration (Cp) and the Cp/dose ratio were significantly higher in the CVA group patients during the first sampling (P < 0.05). The Acute Physiology and Chronic Health Evaluation П (APACHE П) score was significantly lower than the baseline at the end of the study in each group of patients (P < 0.05). In addition, no significant correlation was observed between Vmax, Km, Cp, Cp/dose ratio, and APACHE II scores at the time of sampling. CONCLUSION: Due to significant differences in phenytoin plasma concentration and pharmacokinetic parameters between HT and CVA patients, close attention must be paid to the pharmacokinetic behavior of phenytoin in the efforts to improve the patient's outcome after a severe HT.