Joaquín Giráldez

Potential Interaction between Methotrexate and Omeprazole

OBJECTIVE: To report a case of delayed elimination of high-dose methotrexate (MTX) associated with concomitant omeprazole administration. CASE SUMMARY: Delayed MTX elimination was observed in an 11-year-old white boy who concomitantly received high-dose MTX and omeprazole. The patients serum creatinine and liver function tests were normal during treatment and follow-up. The only medication we suspected of inhibiting MTX elimination was omeprazole 20 mg every 12 hours. Twenty-four hours after the first high-dose MTX cycle (15 g), omeprazole was discontinued. Thereafter, the patient received one high-dose MTX cycle without omeprazole every month for five months; MTX elimination was normal throughout MTX cycles 2 to 5. DISCUSSION: MTX is actively secreted in the distal tubules. The renal hydrogen/potassium adenosine triphosphatase (H+/K+-ATPase) pump makes the urine more acidic, by secreting hydrogen ions into the renal tubule and reabsorbing potassium ions. Active tubular secretion of MTX requires the activity of this pump because MTX is excreted with hydrogen ions. Omeprazole can inhibit renal elimination of the hydrogen ion and block the active tubular secretion of MTX. Therefore, the elimination half-life of MTX increases, which may result in potentially toxic concentrations of MTX. At a pH of approximately 5, as found in the renal tubules, pantoprazole is more slowly activated than omeprazole, reducing the incidence of unwanted reactions with sulfhydryl groups and adverse effects occurring outside of the gastric hydrogen pump. CONCLUSIONS: Based on the Naranjo probability scale, a probable drug interaction was observed. Omeprazole may delay MTX elimination; therefore, when prescribing MTX, an alternative to omeprazole should be considered.

Cost-effectiveness of ranibizumab compared with pegaptanib in neovascular age-related macular degeneration.

ObjectiveTo assess the cost-effectiveness of ranibizumab compared with pegaptanib in the treatment of patients with minimally classic/occult neovascular age-related macular degeneration (AMD), from a societal perspective in Spain.MethodsWe constructed a Markov model with five states defined by visual acuity (VA) in the better-seeing eye (Snellen scale): VA >20/40, ≤20/40 to >20/80, ≤20/80 to >20/200, ≤20/200 to >20/400, ≤20/400, and an additional death state. Two cohorts of patients were distributed along the VA states, and treated with either ranibizumab or pegaptanib. Transition probabilities assigned for movement between these states with both drugs were obtained from published randomized clinical trials. Medical costs related to AMD treatment and follow-up, medical costs related to AMD comorbidities, and non-medical-related costs were taken into account. Costs (2008 Euro), health outcomes (Quality-adjusted life years—QALYs), both discounted at a 3.5% annual rate, and incremental cost-effectiveness ratios (ICER: €/QALY), were determined for a lifetime horizon in the base case analysis. Sensitivity analyses were conducted to explore different scenarios and assumptions in the model.ResultsTreating patients with varying degrees of visual impairment with monthly ranibizumab instead of pegaptanib was €71,206 more costly and provided 2.437 additional QALYs (€29,224/QALY). When administered on an as-needed basis, as in the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (PrONTO) trial, the cost per QALY gained with ranibizumab was reduced to €4,623.ConclusionsThe cost per QALY gained with monthly ranibizumab compared with pegaptanib in the minimally classic/occult neovascular AMD population is just below the €30,000 threshold below which new drugs are sometimes regarded as cost-effective strategies in Spain. In this model, the key variables with greater impact on the cost-effectiveness results were the selected time horizon and the chosen extrapolation method, the source for data on pegaptanib efficacy and the number of ranibizumab injections. When administered on an as-needed basis, ranibizumab was a cost-effective strategy compared to pegaptanib in this population.

Pharmacodynamics of High-Dose Methotrexate in Pediatric Patients

OBJECTIVE: To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects. METHODS: This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression. RESULTS: Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h (p < 0.001). CONCLUSIONS: The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 μmol/L was confirmed as an indicator of high risk of toxicity.

Ranibizumab for neovascular age-related macular degeneration

PURPOSE The pharmacology, pharmacokinetics, clinical efficacy, safety, pharmacoeconomics, and place in therapy of ranibizumab are reviewed. SUMMARY Ranibizumab is the humanized fragment of the murine monoclonal antibody that binds all the active forms of the vascular endothelial growth factor, leading to the inhibition of the neovascular process underlying age-related macular degeneration (AMD). In animal studies, intravitreal administration of ranibizumab resulted in penetration of the drug into all layers of the retina and subsequent slow absorption into the systemic circulation. Improvement in visual acuity by 15 or more letters has been observed in 33.8-40.3% of patients treated with ranibizumab in pivotal clinical trials, compared with 5% of patients treated with sham injections and photodynamic therapy (PDT). The addition of PDT to ranibizumab has not been shown to offer any benefit in terms of efficacy and has been found to worsen ocular adverse reactions. The most common adverse ocular reactions reported in patients receiving ranibizumab during clinical trials include conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation. Ranibizumabs efficacy in the treatment of neovascular AMD is well established; however, questions remain regarding the drugs optimal dosing strategy, duration of therapy, and combined therapy with other agents. While ranibizumab has been defined as the best available weapon against AMD, it is also the most expensive. CONCLUSION The efficacy of ranibizumab in the treatment of AMD is well established, but more studies are needed to determine ranibizumabs optimal dosage interval, duration of therapy, and combined use with other agents.

Determination of 5-fluorouracil and its prodrug tegafur in plasma and tissue by high-performance liquid chromatography in a single injection: Validation for application in clinical pharmacokinetic studies

Tegafur, a prodrug of 5-fluorouracil (5-FU), is an oral fluorouracil antitumor drug used for the management of adenocarcinomas. It has an efficacy similar to that of intravenous 5-FU, with potential advantages in terms of convenience and quality of life for the patient and cost-effectiveness as compared with intravenous chemotherapy. The authors developed a high-performance liquid chromatography (HPLC) assay for the determination of tissue or plasma tegafur and 5-FU concentration in a single step extraction and a single HPLC injection. The retention times of 5-FU and tegafur were 5 and 16.5 minutes, respectively, and the internal standard retention times were 11.5 and 17.5 minutes for 5-bromouracil (5-BU) and &bgr;-hydroxyethyltheophylline, respectively. The limit of quantification was 0.0125 &mgr;g/mL for 5-FU and 0.05 &mgr;g/mL for tegafur. The assay had good recovery (96.5% ± 9.45% and 97.5% ± 7.89% for 5-FU in plasma and tissue, respectively, and 88.5% ± 12.17% and 104.9% ± 8.77% for tegafur in plasma and tissue, respectively). Precision was good: the within-day and between-day standard deviation of the mean (RSD) for 5-FU (0.0125–5 &mgr;g/mL) and tegafur (0.5–150 &mgr;g/mL) was always <8%. The authors conclude that the method described here is ideally suited for the therapeutic monitoring of 5-FU and tegafur.

Effects of hepatic function on vancomycin pharmacokinetics in patients with cancer.

Vancomycin is widely used in the prophylaxis and treatment of infections in neutropenic patients with cancer. The objective of this study was to analyze liver damage effects on vancomycin pharmacokinetics and determine the necessity for liver function evaluation when selecting vancomycin dosing schedules in these patients. A population pharmacokinetic analysis was performed using the global two-stage method. To this purpose serum vancomycin concentrations from 154 cancer patients were measured and individual vancomycin pharmacokinetic parameters were estimated by the Sawchuk and Zaske method. Mean and standard deviation of the vancomycin pharmacokinetic parameters were estimated for various subgroups of patients classified according to the degree of liver damage. Then a multiple linear regression analysis was performed to select the best predictive models for vancomycin clearance (Clvan) and steady state distribution volume (V). Results revealed that Clvan is not influenced by liver failure. Differences in V between patients with and without hepatic failure were initially observed, but these disappeared when patients with ascites were excluded. In conclusion, vancomycin dosing schedule does not need to be modified for patients with liver failure, with the exception of patients with ascites.

LC method for therapeutic drug monitoring of levetiracetam: Evaluation of the assay performance and validation of its application in the routine area

OBJECTIVES An accurate and precise high-performance liquid chromatographic method using diode array detection for the determination of levetiracetam in human plasma has been developed and validated for use in pharmacokinetic studies. METHODS A harmonized validation strategy based on the accuracy profiles was used to select the most appropriate regression model and to determine the limits of quantitation as well as the concentration range of the developed analytical procedure. On the other hand, the present paper also shows this validation approach as a suitable tool to guaranty the quality of the results obtained by the use of the analytical validated methodology for plasma levetiracetam determination in a routine setting and to ensure the risk of obtaining the future measurements outside the previously fixed acceptance limits. RESULTS As pointed recently, the FDA, a weighted 1/x(2) quadratic regression model ranging from 0.53 to 107.00 mg/L was selected as the simplest calibration model that maximized the accuracy all over the range. Relative bias was <5%, assay imprecision was always <6% and mean extraction recovery from plasma was >90%. So, accuracy did not exceed the acceptance limits settled at + or - 20% according to the FDA or Washington conference regulatory requirements for bioanalytical methods. Internal quality control has been assessed over a 2 year time period. All controls were essentially found to provide levetiracetam concentrations within the target range according to the FDA. CONCLUSIONS The validated analytical procedure complies with strongest regulatory standards. The validated method has a sufficiently rapid turnaround time and their results are good enough to enable the laboratory to routinely provide useful and accurate pharmacokinetic data in time to adjust patient regimens.

Population pharmacokinetic parameters of gentamicin in patients with solid tumors : Estimation by one- and two-stage methods

Gentamicin monitoring has been improved with the introduction of Bayesian methods but the usefulness depends on the quality of the population parameters (PP) used. The objective of this study was to determine PP of gentamicin in patients with solid tumors. A total of 198 adult patients with cancer were included in the analysis. Population parameters were estimated by both a two-stage and a one-stage method (NPEM, Non Parametric Expectation Maximization). Individual parameters (IP) were estimated by the Sawchuk-Zaske method and by nonlinear regression. The estimated distribution volume and clearance of gentamicin (mean +/- SD) were 18.37 +/- 5.021 (0.30-0.32 l/kg of dosing weight) and 3.34 +/- 1.6 l/h, respectively. No significant differences between IP or PP obtained by the different methods were found. The results indicated a wide variability of gentamicin pharmacokinetics making monitoring necessary and that patients with solid tumors may have larger gentamicin volume and slower clearance than normal patients. These observations imply that different population pharmacokinetic parameters should be used for this group of patients.