Purpose In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4-5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model for meropenem in critically ill patients and to evaluate different dosage schemes that achieve the optimal PK/PD objectives. Methods This retrospective, observational, single-centre study included 80 critically ill patients (154 samples) treated with meropenem between May 2011 and December 2017. Patient data, concentrations, treatment and bacteriological variables were collected from electronic medical records. Total and free concentrations of meropenem were modelled in Pmetrics. Monte Carlo simulations were performed to assess the probability of achieving the PK/PD target for different dosage regimens. For patients with available data, the number of patients with a free concentration 4 times higher or lower than the observed MIC for the P. aeruginosa and E. coli was investigated. Results A one-compartment model with first-order elimination adequately described serum total and free meropenem concentrations. The only variable that significantly influenced the elimination constant of meropenem was the creatinine clearance (CLcr) calculated using the CKD-EPI formula. The highest probability of achieving the pharmacodynamic objective was with 3-h infusion dosage regimens. Sixty percent and 89% of patients attained a free drug concentration 4 times above the MIC for P. aeruginosa and E. coli respectively. Conclusions This study proposed different dosing regimens depending on renal clearance strata and the MIC of the germ targeted.

Purpose: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. Methods: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. Results: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. Conclusions: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases.

PurposeIrinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment.MethodsWe used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates.ResultsThe final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499.ConclusionCPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.

Irinotecan (CPT-11) is a drug used against a wide variety of tumors, which can cause severe toxicity, possibly leading to the delay or suspension of the cycle, with the consequent impact on the prognosis of survival. The main goal of this work is to predict the toxicities derived from CPT-11 using artificial intelligence methods. The data for this study is conformed of 53 cycles of FOLFIRINOX, corresponding to patients with metastatic colorectal cancer. Supported by several demographic data, blood markers and pharmacokinetic parameters resulting from a non-compartmental pharmacokinetic study of CPT-11 and its metabolites (SN-38 and SN-38-G), we use machine learning techniques to predict high degrees of different toxicities (leukopenia, neutropenia and diarrhea) in new patients. We predict high degree of leukopenia with an accuracy of 76%, neutropenia with 75% and diarrhea with 91%. Among other variables, this study shows that the areas under the curve of CPT-11, SN-38 and SN-38-G play a relevant role in the prediction of the studied toxicities. The presented models allow to predict the degree of toxicity for each cycle of treatment according to the particularities of each patient.

The purpose of this paper was to review the literature regarding the clinical and economic impact of pharmacist interventions (PIs) related to antimicrobials in the hospital setting. A PubMed literature search from January 2003 to March 2016 was conducted using the terms pharmacist* or clinical pharmacist* combined with antimicrobial* or antibiotic* or anti-infective*. Comparative studies that assessed the clinical and/or economic impact of PIs on antimicrobials in the hospital setting were reviewed. Outcomes were classified as: treatment-related outcomes (TROs), clinical outcomes (COs), cost and microbiological outcomes (MOs). Acceptance of pharmacist recommendations by physicians was collected. PIs were grouped into patient-specific recommendations (PSRs), policy, and education. Studies' risk of bias was analyzed using Cochrane's tool. Twenty-three studies were evaluated. All of them had high risk of bias. The design in most cases was uncontrolled before and after. PSRs were included in every study; five also included policy and four education. Significant impact of PI was found in 14 of the 18 studies (77.8%) that evaluated costs, 15 of the 20 studies (75.0%) that assessed TROs, 12 of the 22 studies (54.5%) that analyzed COs, and one of the two studies (50.0%) that evaluated MOs. None of the studies found significant negative impact of PIs. It could not be concluded that adding other strategies to PSRs would improve results. Acceptance of recommendations varied from 70 to 97.5%. Pharmacists improve TROs and COs, and decrease costs. Additional research with a lower risk of bias is unlikely to change this conclusion. Future research should focus on identifying the most efficient interventions.

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.

Background: Levetiracetam (LEV) is a second-generation antiepileptic drug extensively used in therapeutics. The aim of this study was to evaluate the influence that sex, age, and weight exert on LEV pharmacokinetics in clinical practice. Methods: We conducted a 6-year retrospective observational study. Patients were classified in subgroups according to sex, weight (normal range, overweight, and obese), and age (young adult: 16-30 years old, middle-aged adult: 31-50 years old, advanced adult: 51-64 years old, and elderly adult: >= 65 years old). We compared LEV apparent oral clearance (LEV CL/F) between the subgroups. Results: A total of 238 LEV basal serum concentrations (LEV C-0) corresponding to 156 patients were identified. Significant differences were observed in LEV CL/F between males and females when LEV CL/F was expressed as L/h [mean (SD): 4.79 (1.84) L/h in males versus 4.13 (1.64) L/h in females; P < 0.001]. These differences were not significant when LEV CL/F was normalized by weight [mean (SD): 60.64 (24.90) mL/h/kg in males versus 64.10 (28.87) mL/h/kg in females; n. s.]. Weight in females was 17% lower compared with males. A progressive reduction in LEV CL/F was observed with increasing age, in a proportion that was similar to the decline in renal function. The elderly patients presented 30% lower LEV CL/F (mL/h/kg) and 43% lower creatinine clearance (CCr) in comparison with adults. No statistically significant differences were observed in LEV CL/F calculated in L/h between weight subgroups. However, when LEV CL/F was expressed in mL/h/kg, a progressive reduction was observed [normal weight: 72.21 (28.97); overweight: 57.84 (25.38); obese: 49.45 (14.50); P < 0.001]. A significant and positive correlation between CCr and LEV CL/F was observed, confirming the important role of the renal function in LEV CL/F. The CCr increased in each sex group when weight increased; however, LEV CL/F (L/h) remained constant. Conclusions: Sex, age, and weight affect LEV pharmacokinetics, having an impact on the individual dosage regimen needed to achieve the therapeutic objective. Sex is a conditioning factor of LEV CL/F, although its influence is principally due to the weight. LEV CL/F decreases with advancing age, proportionally to the decline in renal function. It is confirmed that LEV dosage per body weight is not required, and prescribing higher doses of LEV in obese patients is not justified. These data suggest that routine LEV therapeutic drug monitoring in the elderly patients, patients with renal dysfunction, and obese patients is indicated.

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.

Purpose. To assess the emetogenic potential of different chemotherapy (CT) regimens in daily clinical practice in an outpatient setting. To optimize antiemetic prophylaxis if necessary Methods. Prospective and retrospective review of the emetogenic potential of CT regimens used in adult patients in an outpatient setting Results. We assess the chemotherapy-induced nausea and vomiting (CINV) of 50 different CT regimens used on 157 different patients in an outpatient setting. We found that the CT usually classified as highly emetogenic, including cisplatin and anthracycline-cyclophosphamide combination, had the higher incidence of CINV (37.5 and 54.4% respectively). The antineoplastic drugs usually considered to be moderately emetogenic had, as expected, lower rates of emesis with the exception of irinotecan, which presented a pattern of nausea and/or vomiting (NV) similar to the highly emetogenic CTwith a global incidence of 48.5%. The appearance of emetic symptoms had impact on quality of life in 70% of the patients, with nausea being the main emetic symptom. Conclusion. Antiemetic prophylaxis for highly emetogenic CTcould be improve. Irinotecan CTregimens have a high emetogenic potential more than moderate and require more intensive antiemetic prophylaxis too.

Background: Mosquitoes 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. Results: A 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. Conclusions: This 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.

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.

PURPOSE: To determine the efficacy of cisplatin- or methotrexate-containing acrylic cement for local and systemic antineoplastic drug diffusion. Among the uses of acrylic cement or Polymethylmethacrylate (PMMA), there is the possibility to employ it as vehicle for drug diffusion. This capability is of interest in the treatment of pathological fractures: The curative effects of the cement (cytotoxicity of the monomer and increased temperature) are added to the antineoplastic effect of the drugs. METHODS: In the experimental study, two groups of ten pigs underwent vertebroplasty using cement mixed with 500 mg of powder cisplatin or 1000 mg of powder methotrexate. Vertebroplasty was performed in two non-consecutive lumbar vertebrae with bipedicular cement injection. Transpedicular bone biopsy was performed weekly to measure levels of antineoplastic agent in bone tissue and blood plasma. Cisplatin was studied by atomic absorption spectrometry and methotrexate by fluorescence polarization immunoassay. Renal and hepatic function and blood analysis were performed weekly. RESULTS: Cisplatin and methotrexate levels were found in bone tissue at more than 5 weeks following surgery. The cisplatin peak occurred at week 3 (mean 1269 ¿g/g bone) and the methotrexate peak at week 1 (mean 862.76 ¿g/g bone). Plasma drug levels were found 72 h after surgery, with a peak at 24 h for cisplatin (mean 0.23 ¿mol/L) and at 30 min for methotrexate (mean 0.92 ¿mol/L). None of the animals died during the study. Animals with intracanal cement leaks showed no neurological involvement. Renal, hepatic and hemogram studies remained within normal limits. CONCLUSIONS: There is local diffusion of antineoplastic agents from the cement to bone and plasma. We found methotrexate and cisplatin levels in bone at up to 5 weeks, comparable to previous in vitro reports. At the doses administered, there were no cases of myelosuppression, hepatotoxicity, or nephrotoxicity.

Objective: Dual PEGylated interferon-¿ (PEG-IFN) and ribavirin therapy has been the main hepatitis C virus (HCV) treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR) to dual PEG-IFN and ribavirin therapy in a representative Spanish population. Methods: Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors. Results: IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) and TNFRSF1B (rs1061622) genotypes, as well as TNFRSF1B/IL-10/TNF¿ (-308) non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3. Conclusions: IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population.

Currently there is no strong evidence to recommend any determined trough plasma levels, and thus we wait for additional observations and clinical trials to clarify the optimal dosage required to avoid unnecessary side effects. Meanwhile, we have found a safe and acceptable response with plasma levels within the lower range of efficacy described.

Study Design: Prospective, experimental study in animals, approved by the local ethics committee for animal research. Aims: To evaluate and compare the histological changes in myeloradicular structures and paravertebral tissue induced by contact with acrylic cement with and without methotrexate in vertebroplasty in pigs. Material and Methods: Ten female pigs of the Large White¿Landrace breed, weighing 30 kg and divided into two groups: control group, containing five pigs that underwent vertebroplasty with acrylic cement, and methotrexate group, with five pigs that underwent vertebroplasty using cement combined with 1 g of methotrexate. A standard fluoroscopy-guide transpedicular vertebroplasty technique was performed with an 11-G trocar. Cement leak to the prevertebral and epidural muscle tissue was induced in two different lumbar vertebrae; 1 cc of cement was injected per vertebra. Animals were sacrificed at 3 weeks. Spines were removed, the section where tissues were in contact with cement was isolated by dissection, the surface in direct contact with cement was marked with India ink, and specimens were processed by fixation and hematoxylin eosin staining for pos-terior microscopic study. Results: Macroscopic results: In both groups, the cement was distributed in layers surrounding the dural sac. Histological results: In the control group, leakage to the prevertebral musculature with atrophy of muscle fibers, inflammatory infiltrate in areas in contact with cement, epithelial dysplasia, and foreign body reaction in relation to cement particles. In addition, epidural leak with dural thickening and inflammatory reaction only in areas of the dura mater in contact with cement. In the methotrexate group, the same changes as in the control group were observed. Clinical results: Neurological lesion due to cement leak was not produced any of the ten pigs. Conclusions:The tube-like laminar distribution of the cement may explain the fact that there was an absence of paraplegia in the study animals. Contact of the muscle and dura with cement seemed to induce an inflammatory reaction, with cell death, and atrophy and thickening of membranes in some cases. Addition of methotrexate to acrylic cement did not seem to increase the local toxicity of cement alone.

An accurate and precise LC method using diode array detection for the determination of voriconazole in human serum/plasma samples has been developed and validated for use in pharmacokinetic studies.A harmonized validation strategy based on the accuracy profiles was used as a suitable tool to guaranty the quality of the results obtained by the use of the analytical validated methodology in a routine setting and to ensure the risk of obtaining the future measurements outside the previously fixed acceptance limits.As pointed recently the FDA, a weighted 1/x2 linear regression model ranging from 0.25 to 10.35 mg/L was selected as the simplest calibration model that maximized the accuracy all over the range. Relative bias was < 7%, assay imprecision was always < 4% and mean extraction recovery from plasma was > 90%. So, accuracy did not exceedthe acceptance limits settled at±15% according to the FDA or Washington conference regulatory requirements for bioanalytical methods.The validated analytical procedure compliants with strongest regulatory standards and their results are rapid and good enough to enable the laboratory to routinely provide useful and accurate pharmacokinetic data in time to adjust patient regimens.