Rafael Ferriols-Lisart

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.

Intravenous meropenem stability in physiological saline at room temperature

Objectives To evaluate the stability of solutions of 6 mg/mL, 8 mg/mL and 12 mg/mL meropenem in 0.9% NaCl in a polyolefin container (Viaflo), at room temperature, with a view to allowing extended or continuous perfusion in clinical practice. Methods Meropenem was assayed using high-performance liquid chromatography. The technique was validated according to the criteria of the European Medicines Agency. Meropenem stability was evaluated for three different concentrations (6 mg/mL, 8 mg/mL and 12 mg/mL) at room temperature and during 48 h. The pH of the solution and its organoleptic properties were also evaluated. Results The analytical technique abided with the specifications of the European Medicines Agency. The maximum accuracy and precision were 10% and 7.9%, respectively. The limit of detection was 0.000185 mg/mL and the limit of quantification 0.000562 mg/mL. The t90 for the dilution of 6 mg/mL of meropenem was 18 h (95% CI 14 h to 22 h), while the values for the 8 mg/mL and 12 mg/L concentrations were respectively 22 h (95% CI 19 to 32 h) and 17 h (95% CI 13 h to 21 h). The differences were not statistically significant (p<0.05). No variations in pH were seen. Conclusions The results confirm the stability of the solutions of 6 mg/mL, 8 mg/mL and 12 mg/mL meropenem in 0.9% NaCl stored in a polyolefin container at 25°C for at least 12 h, thereby allowing their use as an extended or continuous perfusion.

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.

Stability of tacrolimus ophthalmic solution

Purpose The stability of 0.3‐mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. Methods A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2–8, or −15 to −25 °C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high‐performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3‐mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. Results When stored at 2–8 °C and between −15 and −25 °C, at least 90% of the initial tacrolimus concentration remained throughout the 85‐day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 °C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. Conclusion Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 °C and for at least 85 days when stored at 2–8 °C or between −15 and −25 °C in polypropylene bottles and protected from light.