Alejandro Pérez-Pitarch

A model-based meta-analysis of sofosbuvir-based treatments in chronic hepatitis C patients

The objective of this study was to compare the efficacy of sofosbuvir-based treatments in patients with chronic hepatitis C virus (HCV) infection using a model-based meta-analysis (MBMA). A bibliographic search was performed to identify clinical trials involving sofosbuvir as a unique direct-acting antiviral (DAA) agent or together with daclatasvir, ledipasvir or simeprevir for the treatment of diagnosed HCV infection. The time course of the virological response (VR) was modelled to estimate the effect of treatment and the influence of population characteristics on the longitudinal efficacy profile. The model was validated and simulations of 10 different treatment schedules were performed. Data from 19 clinical trials were included in the analysis. According to the developed model, therapy with sofosbuvir+ledipasvir is the most effective therapy in all scenarios, but it does not differ greatly in terms of sustained VR with respect to other combinations of DAA treatments. In conclusion, this MBMA generates knowledge regarding hypothetical head-to-head trials that have not been conducted previously. Therapies with sofosbuvir+ledipasvir are probably the most effective sofosbuvir-based treatments.

Impact of nutritional status on the pharmacokinetics of erlotinib in rats

Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats –WN (well‐nourished) and UN (undernourished) – were fed with different diets for 23–26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in the mild‐undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. Copyright

Impact of Undernutrition on the Pharmacokinetics and Pharmacodynamics of Anticancer Drugs: A Literature Review

ABSTRACT The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes interesting trends in the relationship between undernourishment and pharmacokinetics across studies, and indicates that dosing modifications of these drugs may be necessary to optimize chemotherapeutic treatments. Furthermore, this review has compiled evidence regarding undernourishments capacity of enhancing treatment-related myelosuppression, cardiotoxicity, ototoxicity, neurotoxicity, and malignancies.

Dosing of caspofungin based on a pharmacokinetic/pharmacodynamic index for the treatment of invasive fungal infections in critically ill patients on continuous venovenous haemodiafiltration

INTRODUCTION The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.

Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation

Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous‐time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV‐seropositive recipients with CMV‐seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia, but levels >8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, P < .01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases.

Plasma concentrations of caspofungin in a critically ill patient with morbid obesity

The aim of the study was to describe the pharmacokinetic behaviour of caspofungin in a critically ill patient with morbid obesity who received doses of caspofungin higher than labelled doses. A 57-year-old morbidly obese man (BMI = 50 kg/m) was admitted to our ICU after surgical treatment of anastomotic leak in the postoperative period of elective laparoscopic bariatric surgery. The patient was in septic shock, with Candida multicolonization and other risk factors of invasive candidiasis. We decided to start antimicrobial treatment, including meropenem, linezolid and caspofungin. With the intention of maximizing the potential effectiveness of antifungal treatment, caspofungin at a dose of 100 mg/day was chosen. The caspofungin dose was calculated using a population pharmacokinetic model [1]. Target AUC/MIC was set at 860 and therefore AUC values above 107 mg*h/L were necessary assuming MIC = 0.125 mg/L [2]. After administration of the first dose, Cpeak was 4.51 mg/L, Ctrough was 0.94 mg/L and AUC was 115.9 mg*h/L. Three days later, Cpeak was 5.97 mg/L, Ctrough was 1.76 mg/L, AUC was 140.4 mg*h/L and AUC/MIC was 1123. The manufacturer recommends caspofungin dose reduction when AUC values are above 210 mg*h/L and, accordingly, drug exposure was considered safe. The patient became apyretic 10 days after caspofungin treatment initiation; this lasted for 14 days without any adverse effects related to this drug. There are conflicting data on dosing recommendations in obese patients [3]. Payne and Hall [4] found that lower caspofungin AUC was achieved in obese people than in thinner ones, suggesting that dose optimization in heavier patients might improve clinical success rates. If the labelled dose of 70 mg/day had been used in our patient, AUC/MIC would have been 786, below the target AUC/MIC value. Figure 1 shows caspofungin concentrations over time for doses of 100 and 70 mg/day. A dose of 150 mg/day has been recommended in obese patients until simulation studies are completed to provide a bedside dosing formula for caspofungin [4]. There are reports of deterioration of hemodynamic parameters during loading doses in critically ill patients [5]. The monitoring of hemodynamic parameters in these patients is highly recommended. The dose of caspofungin should be adjusted according to both serum caspofungin concentrations and clinical symptoms. However, determination of caspofungin concentrations is performed at only a few laboratories, which makes routine monitoring difficult. This case suggests that caspofungin doses higher than those recommended by the manufacturer may be needed to reach pharmacokinetic/pharmacodynamic targets in ICU morbidly obese patients.

Effectiveness of Nivolumab versus Docetaxel as Second-Line Treatment in Non-Small Cell Lung Cancer Patients in Clinical Practice

Aims: To evaluate the effectiveness of nivolumab as second-line treatment compared to standard therapy with docetaxel in adult patients with non-small cell lung cancer (NSCLC) in clinical practice. Methods: This is an observational, retrospective cohort study of adult patients diagnosed with NSCLC, stage III-IV, treated with docetaxel or nivolumab as second-line treatment. The end points evaluated were overall survival (OS) and progression-free survival (PFS). PFS and OS were described using the Kaplan-Meier method. The Cox proportional hazards model was applied to identify independent prognostic and predictive factors related to disease progression or death. Results: Thirty-three patients were included in this study (i.e., 14 in the nivolumab group and 19 in the docetaxel group). Nonsquamous NSCLC was the most frequent histological subtype. Cohorts were homogeneous. The follow-up time was 116 ± 87.3 days. The median PFS was 84 days (95% CI 39-300) for patients treated with nivolumab and 61 days (95% CI 48-76) for patients treated with docetaxel. The risk of progression was 60% lower for patients treated with nivolumab (HR 0.40; 95% CI 0.16-0.97; p = 0.043) compared to patients receiving docetaxel. Among the patients treated with docetaxel, the median OS was 129 days (95% CI 106-300). More than 50% of the patients treated with nivolumab were alive at the end of the follow-up period; nevertheless, the risk difference was not statistically significant (HR 0.55; 95% CI 0.20-1.51; p = 0.244). Conclusion: NSCLC patients treated with nivolumab as second-line therapy had a longer PFS compared to patients treated with docetaxel in a health care environment.

A Wide Linearity Range Method for the Determination of Lenalidomide in Plasma by High-Performance Liquid Chromatography Application to Pharmacokinetic Studies

A wide linearity range analytical method for the determination of lenalidomide in patients with multiple myeloma for pharmacokinetic studies is required. Plasma samples were ultrasonicated for protein precipitation. A solid-phase extraction was performed. The eluted samples were evaporated to dryness under vacuum, and the solid obtained was diluted and injected into the high-performance liquid chromatography (HPLC) system. Separation of lenalidomide was performed on an Xterra RP C18 (250 mm length × 4.6 mm i.d., 5 µm) using a mobile phase consisting of phosphate buffer/acetonitrile (85:15, v/v, pH 3.2) at a flow rate of 0.5 mL · min−1. The samples were monitored at a wavelength of 311 nm. A linear relationship with good correlation coefficient (r = 0.997, n = 9) was found between the peak area and lenalidomide concentrations in the range of 100 to 950 ng · mL−1. The limits of detection and quantitation were 28 and 100 ng · mL−1, respectively. The intra- and interassay precisions were satisfactory, and the accuracy of the method was proved. In conclusion, the proposed method is suitable for the accurate quantification of lenalidomide in human plasma with a wide linear range, from 100 to 950 ng · mL−1. This is a valuable method for pharmacokinetic studies of lenalidomide in human subjects.

Effectiveness, toxicity, and economic evaluation of vinflunine for the treatment of patients with transitional cell carcinoma in the Spanish outpatient setting.

The aim of this study was to evaluate the effectiveness and toxicity profile of the vinflunine chemotherapy regimen and to examine the cost-effectiveness relation in a real-world sample of patients with transitional cell carcinoma of the bladder. This is a multicenter, observational, retrospective cohort study. To assess the effectiveness and safety of vinflunine treatment, progression-free survival, overall survival, and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios were calculated. A total of 37 patients were included in the study, with a mean age of 67 (SD=9) years. The median progression-free survival was 2.61 months (95% confidence interval 1.79–4.23) and the median overall survival was 5.72 months (95% confidence interval 3.34–10.35). An objective response was achieved in eight (22%) patients. Statistically significant differences were found between patients treated with vinflunine as a second-line therapy and those treated with vinflunine as a third-line therapy (P=0.036). The most commonly reported analytical adverse event was anemia (n=34; 92%), and the most severe was neutropenia (n=19; 51%), with nine patients developing grade 4 neutropenia (9/19; 47%). The total cost of vinflunine treatment was &OV0556;553 873, with a median of &OV0556;8524 (interquartile range, &OV0556;9220) per patient. The median-based cost-effectiveness ratio was &OV0556;44 789 (&OV0556;31 706–58 022) per progression-free year gained and &OV0556;22 750 (&OV0556;14 526–34 085) per life-year gained. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness and might help achieve an optimal quality healthcare system.

Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats

The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well‐ and under‐nourished rats. Absorption studies were performed in male Wistar rats. Concentration–time profiles in proximal and distal intestine were analysed through non‐linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best‐described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright