Azucena Aldaz

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.

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.

Proposal for the creation of a national strategy for precision medicine in cancer: a position statement of SEOM, SEAP, and SEFH

Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical–legal, regulatory, organizational, and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals, and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology, Pathology, and Hospital Pharmacy, we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cancer.

Targeting cattle for malaria elimination: marked reduction of Anopheles arabiensis survival for over six months using a slow-release ivermectin implant formulation

BackgroundMosquitoes that feed on animals can survive and mediate residual transmission of malaria even after most humans have been protected with insecticidal bednets or indoor residual sprays. Ivermectin is a widely-used drug for treating parasites of humans and animals that is also insecticidal, killing mosquitoes that feed on treated subjects. Mass administration of ivermectin to livestock could be particularly useful for tackling residual malaria transmission by zoophagic vectors that evade human-centred approaches. Ivermectin comes from a different chemical class to active ingredients currently used to treat bednets or spray houses, so it also has potential for mitigating against emergence of insecticide resistance. However, the duration of insecticidal activity obtained with ivermectin is critical to its effectiveness and affordability.ResultsA slow-release formulation for ivermectin was implanted into cattle, causing 40 weeks of increased mortality among Anopheles arabiensis that fed on them. For this zoophagic vector of residual malaria transmission across much of Africa, the proportion surviving three days after feeding (typical mean duration of a gonotrophic cycle in field populations) was approximately halved for 25 weeks.ConclusionsThis implantable ivermectin formulation delivers stable and sustained insecticidal activity for approximately 6 months. Residual malaria transmission by zoophagic vectors could be suppressed by targeting livestock with this long-lasting formulation, which would be impractical or unacceptable for mass treatment of human populations.

Influence Of Comedication On Levetiracetam Pharmacokinetics

Background: To evaluate the effect of concomitant antiepileptic therapy on levetiracetam (LEV) pharmacokinetics. Methods: A 6-year retrospective observational study. Patients were grouped according to the antiepileptic drug used as concomitant medication: group A, LEV in monotherapy; group B, LEV + enzyme-inducing antiepileptic drugs (EIAEDs); and group C, LEV + non–enzyme-inducing antiepileptic drugs (NEIAEDs). Apparent oral levetiracetam clearance (LEV CL/F) and basal serum levetiracetam concentrations (LEV C0) were compared among the different groups by analysis of variance. Results: A total of 330 LEV C0 corresponding to 205 patients (56% men) were identified. The mean (±SD) of LEV CL/F in group A (n = 180), B (n = 92), and C (n = 58) was 4.41 ± 2.06 L/h, 7.23 ± 3.72 L/h, and 4.87 ± 1.65 L/h, respectively. EIAEDs increased LEV CL/F (L/h) by 64% compared with the monotherapy group and by 48% compared with the NEIAEDs group. The greatest induction in LEV CL/F, compared with the LEV monotherapy group, was observed with carbamazepine, followed by oxcarbazepine and phenobarbital, and was increased by 81%, 64%, and 44%, respectively. LEV C0 values were significantly lower in the EIAEDs group than in the monotherapy group (17.30 ± 7.77 versus 20.08 ± 9.69 mcg/mL; P = 0.038) or indeed the NEIAEDs group (17.30 ± 7.77 versus 20.49 ± 9.46 mcg/mL; P = 0.027). Conclusions: Comedication with EIAEDs increased LEV CL/F by more than 40%, whereas carbamazepine had the greatest inducing potency with LEV CL/F being 81% higher than that of the monotherapy group. These data suggest that monitoring LEV serum concentration during polytherapy with EIAEDs is indicated.

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.

PHC-020 Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil (5-FU) in Gastrointestinal Cancer Patients

Background Appropriate dosing of chemotherapeutic drugs is critical to reducing mortality and increasing progression-free survival. 5-fluorouracil (5-FU) is a widely used chemotherapeutic drug in gastrointestinal cancer. The standard approach to dosing 5-FU is based on body surface area (BSA). However, BSA does not account for many of the factors that are responsible for 5-FU clearance such as age, gender, genotype, disease state, drug-drug interactions, organ dysfunction and co-morbidities. Clinical evidence indicates a strong correlation between both toxicity and therapeutic efficacy and total 5-FU exposure expressed as area under the curve (AUC) concentration. This evidence make 5-FU a good candidate for pharmacokinetic (PK)-guided dosing. Purpose To evaluate the role of therapeutic drug monitoring (TDM) of 5-FU in daily clinical oncology practise. Materials and Methods Prospective study of adult patients diagnosed with gastrointestinal cancer treated with infusion schedule regimes based on high doses of 5-FU (2.5–3.2 g/m² in 24–46 h infusion) in a university hospital. All patients were included regardless of disease state or general clinical status. Individual pharmacokinetic parameters were calculated based on anthropometrics and history of 5-FU administration using the Bayesian software programme (USC*Pack). In the first cycle the dose was calculated using the BSA, and subsequent doses were adjusted to an optimal target AUC of 30–35 mg·h/L. Results Fifty-four patients were included in the study. Male/female ratio was 31/23, and average age and weight were 60.9 ± 12.8 years and 72.2 ± 16.9 Kg. Mean estimated pharmacokinetic parameters for volume of distribution and 5-FU clearance were 0.49 ± 0.08 L/Kg and 203 ± 68.6 L/h, respectively. To achieve the target AUC of 30–35 mg·h/L, the dose had to be increased in 33 (86.8%) patients and adjusted downward in 5 (13%). No adjustment was needed in 16 patients (29.6%).When the estimate was based on BSA, 30 patients (55.6%) had AUC < 25 mg·h/L. Conclusions BSA-based 5-FU dosing approaches are limited when it comes to achieving optimal plasma levels in most patients. Pharmacokinetically guided dosing represents a better strategy to improve the efficacy and safety of 5-FU. No conflict of interest.