Investigating the clinical impact of dose-banding for weekly paclitaxel in patients with breast cancer: A retrospective and monocentric study.

AIMS: Dose-banding (DB) consists in approximating the theoretical dose of anticancer drugs calculated according to the body surface area (Dose-BSA) of patients. This concept is supported by pharmacokinetic but not by clinical data. The aim of this study was to assess the clinical outcome of DB defined as dose-fitting up to ±10%. METHODS: This was a retrospective study conducted in patients receiving weekly paclitaxel in neoadjuvant (NAT) and metastatic (M+) settings. Three groups of patients were considered according to type of paclitaxel dosing: Dose-BSA, DB approximated down (DB-Low) and DB approximated up (DB-High). Efficacy was evaluated by the rate of pathological complete response for patients in NAT setting and by the median of progression-free survival plus overall survival for those in M+ setting. Toxicity and efficacy were compared in the 3 groups. RESULTS: A total of 224 and 209 patients were assessable in the M+ and NAT settings, respectively. A toxic event was observed for 31.7 and 27.3% in M+ and NAT, respectively. The rate of pathological complete response was 41.6% in NAT. The median progression-free survival was 5.2 (4.1-5.8) months and overall survival was 16.3 (14.6-18.4) months for patients in M+. Efficacy and toxicity were not different in DB-Low and DB-High groups compared to Dose-BSA group. CONCLUSION: DB with approximated doses up to ±10% does not seem to influence clinical outcome of patients treated with weekly paclitaxel. This is the first study to include clinical observations, which lends support to DB as a safe and effective dosing method.

Formulae recently proposed to estimate renal glomerular filtration rate improve the prediction of carboplatin clearance.

PURPOSE: While doses of carboplatin are mostly individualized according to the Calvert equation based on estimated Glomerular Filtration Rate (eGFR), there is still uncertainty regarding the best formula to predict GFR. Since Janowitz et al. recently proposed a new equation predicting GFR in cancer patients, we aimed to compare this equation to other carboplatin clearance (carboCL) predicting formulae. METHODS: The actual carboCL of 491 patients was compared to predicted carboCL according to the Calvert formula using several equations to predict GFR (Janowitz, Cockcroft-Gault, MDRD, CKD-EPI, CKD-EPI with cystatin C (CKD-EPI-cysC)); and according to two others that directly predict carboCL (Chatelut and Thomas). The formulae were compared on Mean Percentage Error (MPE), Mean Absolute Percentage Error (MAPE) and percentage of patients with a prediction error above 20% (P20). RESULTS: The MPE, MAPE and P20 were, respectively, within the ranges - 5.2 to + 5.9%; 14.0-21.2% and 23-46%. The MAPE and P20 of Calvert-CKD-EPI-cysC were the lowest. The performance of Calvert-CKD-EPI was better than that of other creatinine-based formulae although not significantly different from the Calvert-Janowitz formula. Among formulae based on creatinine only, Calvert-CKD-EPI and Calvert-Janowitz are the least influenced by patient characteristics. CONCLUSION: Whereas CysC improves carboplatin CL prediction, the Calvert-CKD-EPI equation seems the most suitable creatinine-based formula to predict carboCL homogeneously in all subgroups of patients.

Improved Population Pharmacokinetic Model for Predicting Optimized Infliximab Exposure in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Many pediatric patients with inflammatory bowel disease (IBD) lose response to infliximab (IFX) within the first year, and achieving a minimal target IFX trough concentration is associated with higher remission rates and longer durability. Population pharmacokinetic (PK) modeling can predict trough concentrations for individualized dosing. The object of this study was to refine a population PK model that accurately predicts individual IFX exposure during maintenance therapy using longitudinal real-practice data. METHODS: We exported data from the electronic health records of pediatric patients with IBD treated with originator IFX at a single center between January 2011 and March 2017. Subjects were divided into discovery and validation cohorts. A population PK model was built and then validated. RESULTS: We identified 228 pediatric patients with IBD who received IFX and had at least 1 drug concentration measured, including 135 and 93 patients in the discovery and validation cohorts, respectively. Weight, albumin, antibodies to IFX (ATI) detected by a drug-tolerant assay, and erythrocyte sedimentation rate (ESR) were identified as covariates significantly associated with IFX clearance and incorporated into the model. The model exhibited high accuracy for predicting target IFX trough concentrations with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% confidence interval [CI], 0.81-0.91) for population-based predictions without prior drug-level input. Accuracy increased further for individual-based predictions when prior drug levels were known, with an AUROC of 0.93 (95% CI, 0.90-0.97). CONCLUSIONS: A population PK model utilizing weight, albumin, ordinal drug-tolerant ATI, and ESR accurately predicts IFX trough concentrations during maintenance therapy in real-practice pediatric patients with IBD. This model, which incorporates dynamic clinical information, could be used for individualized dosing decisions to increase response durability.

Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen.

Individual dosing of medicines is relevant for paediatrics, geriatrics and personalised medicine. The Solid Dosage Pen (SDP) allows for individual dosing by cutting monolithic, tablet-like drug carriers of pre-defined heights. The aim of the present study was to develop micropellet-loaded rods (MPLRs) with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen. Therefore, micropellets were successfully layered with carbamazepine and coated with polyvinyl acetate (PVAc) and PVAc/polyvinyl alcohol-polyethylene glycol (PVA-PEG). The tensile strength of the sustained release micropellets (300-450 µm) was more than two times higher (12.6-17.1 MPa) than pressures occurring during ram-extrusion of the MPLRs (below 5.8 MPa). Due to relative crystallinities above 93% for PVAc and PVA-PEG a low solubility of the coating films within the PEG-matrix was observed. The sustained release micropellets were successfully incorporated into MPLRs. Drug release properties of the pellets maintained after embedding into the matrix. Hence, the MPLRs provided dose-independent prolonged drug liberation which was not achieved for drug-loaded rods before. The MPLRs permitted the application of the SDP with a precise drug delivery from individually cut single doses. Storage stability was proven for MPLRs containing PVAc/PVA-PEG coated pellets. In conclusion, the MPLRs combined the advantages of multiparticulate dosage forms with the SDP as a device for individual dosing.

Development of sustained and dual drug release co-extrusion formulations for individual dosing.

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification.

Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns.

BACKGROUND: Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities), socioeconomic, and cultural factors. Levofloxacin (LVX) is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic-pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary. METHODS: Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic-pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed. RESULTS: In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic-pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX more efficiently than normal-weight individuals. Compared with the scenario in healthy subjects, standard 2-hour spacing of calcium formulations and oral LVX was insufficient to prevent a chelation interaction in cystic fibrosis patients. Inconsistent conclusions were derived from studies of the influence of sex on the pharmacokinetics of LVX, which might be associated with sample size and administration route. Children younger than 5 years cleared LVX nearly twice as fast as adults. Patients in intensive care receiving LVX therapy showed significant pharmacokinetic differences compared with healthy subjects. Creatinine clearance explained most of the population variance in the plasma clearance of LVX. Switching from intravenous to oral delivery of LVX had economic benefits. Addition of tamsulosin to the LVX regimen was beneficial for patients with bacterial prostatitis because tamsulosin could increase the maximal concentration of LVX in prostatic tissue. Coadministration of multivalent cation-containing drugs and LVX should be avoided. For patients receiving warfarin and LVX concomitantly, caution is needed regarding potential changes in the international normalized ratio; however, it is unnecessary to seek alternatives to LVX for the sake of avoiding drug interaction with warfarin. It is unnecessary to proactively reduce the dose of cyclosporin or tacrolimus when comedicated with LVX. Transporters such as organic anion-transporting polypeptide 1A2, P-glycoprotein, human organic cation transporter 1, and multidrug and toxin extrusion protein 1 are involved in the pharmacokinetics of LVX. CONCLUSION: Personalized LVX therapeutics are necessary for the sake of better safety, clinical success, and avoidance of resistance. New findings regarding individual dosing of LVX in special patient populations and active transport mechanisms in vivo are opening up new horizons in clinical practice.