Prediction of tumour response induced by chemotherapy using modelling of CA-125 kinetics in recurrent ovarian cancer patients.

BACKGROUND: The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment. METHODS: The data from the CALYPSO-randomised phase III trial, comparing two platinum-based regimens in recurrent ovarian cancer (ROC) patients, was randomly split into a 'learning data set' to estimate model parameters and a 'validation data set' to validate model performances. A kinetic-pharmacodynamic semi-mechanistic model was built to describe tumour size and CA-125 kinetics during chemotherapy. The ability of the model to predict tumour response induced by chemotherapy, based on CA-125 values, was assessed. RESULTS: Data from 535 ROC patients were used to model CA-125 kinetics and tumour size changes during the first 513 days after treatment initiation. Using the validated model, we could predict with accuracy the tumour size changes induced by chemotherapy based on the baseline imaging assessment and longitudinal CA-125 values (mean prediction error: 0.3%, mean absolute prediction error: 10.6%). CONCLUSIONS: Using a semi-mechanistic model, the dynamic relationships between tumour size changes and CA-125 kinetics induced by chemotherapy were established in ROC patients. A modelling approach allowed CA-125 to be assessed as a biomarker for tumour size dynamics, to predict treatment efficacy for research and clinical purposes.

A critical review of the analytical approaches for circulating tumor biomarker kinetics during treatment.

Changes in serum tumor biomarkers may indicate treatment efficacy. Traditional tumor markers may soon be replaced by novel serum biomarkers, such as circulating tumor cells (CTCs) or circulating tumor nucleic acids. Given their promising predictive values, studies of their kinetics are warranted. Many methodologies meant to assess kinetics of traditional marker kinetics during anticancer treatment have been reported. Here, we review the methodologies, the advantages and the limitations of the analytical approaches reported in the literature. Strategies based on a single time point were first used (baseline value, normalization, nadir, threshold at a time t), followed by approaches based on two or more time points [half-life (HL), percentage decrease, time-to-events…]. Heterogeneities in methodologies and lack of consideration of inter- and intra-individual variability may account for the inconsistencies and the poor utility in routine. More recently, strategies based on a population kinetics approach and mathematical modeling have been reported. The identification of equations describing individual kinetic profiles of biomarkers may be an alternative strategy despite its complexity and higher number of necessary measurements. Validation studies are required. Efforts should be made to standardize biomarker kinetic analysis methodologies to ensure the optimized development of novel serum biomarkers and avoid the pitfalls of traditional markers.

Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements.

BACKGROUND: In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort. METHODS: Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: '(hCG(time))=hCG0*exp(-k*time)+hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance. RESULTS: Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l(-1): receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P<0.0001) and MTX failure-free survival (HR=13.25, P<0.0001) than other reported predictive factors. CONCLUSION: hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.

Oral dosage form administration practice in children under 6 years of age: A survey study of paediatric nurses.

The purpose of this study was to interview paediatric nurses on administration issues using extemporaneous capsules and marketed capsules and tablets in children younger than 6 years old, based on most frequently administered drugs in six participating wards. The 59 responding nurses estimated respectively at 7.7±1.7 and 7.3±1.8years the age from which children would properly swallow extemporaneous capsules and marketed solids, with 33% and 37% of nurses considering that children under 6 would not get their prescribed treatment using these dosage forms. Refusal of the child to take the solid was the first reason to explain administration failure (85% of nurses for extemporaneous capsules, 89% for marketed solids). Although type of formulation and requirement of chewing were factors influencing the age at which children would take solid from nurses' experience, size of conventional tablets was not among these factors. All respondents use to crush tablets in children unable to swallow whole solids; 37% of nurses systematically split the tablets to ease the swallowing in children able to swallow. Only 11 nurses had an information tool at their disposal to guide manipulation of solids, with 7 of them using it in their daily practice. Providing specific-ward questionnaires, this study gives factual information on administration practices, perceptions and issues faced by paediatric nurses.

Oral drug dosage forms administered to hospitalized children: Analysis of 117,665 oral administrations in a French paediatric hospital over a 1-year period.

Selecting the most appropriate dosage form, that ensures safe administration and adherence of medications, is a major issue for children. Marketed drugs, however, have rarely been tested for their use in children. There is a need for more data on drug formulations administered to children to identify unmet needs, and drive future paediatric research. We observed, over a 12-month follow-up, 117,665 oral drug administrations to 1998 hospitalized children. Nine-tenths belonged to five Anatomical Therapeutic Chemical classes: Alimentary tract & metabolism, Nervous system, Cardiovascular system, Anti-infectives for systemic use and Blood & blood forming organs, one third of drug doses administered to school-age children and adolescents were liquids, and extemporaneous capsules were commonly used in younger children. Our study shows that despite the advantages of solid dosage forms and recent evidence from randomized controlled trials showing their acceptability in infants, they are seldom used in paediatric practice.

[Oral formulation of choice for children]. / Choisir la forme pharmaceutique orale la plus adaptée à l'enfant.

Selecting the most appropriate oral formulation is very challenging when developing medicines for children and in routine practice. Research in pediatric pharmacology has focused on oral drug formulation, determining whether the active pharmaceutical ingredient can be successfully delivered to children. Pediatric expert committees (EMA, EuFPI) recommend that children's medicines be safe, well tolerated, easy to use (palatable and requiring minimal handling), transportable, easily produced, cost effective, commercially viable, with a minimal impact on children's life-style. Oral liquid drug formulations (OLFs: solutions, syrups, suspensions) are historically considered as the most appropriate oral formulation for children, since they are easy to swallow for younger infants and palatable for children. However, OLFs present numerous disadvantages, such as low stability, potentially toxic excipients for children, and low transportability. In the long-term, dose volume and frequency of administration might lead to non-compliance. Multiple preparation steps and volume calculations are also among risk factors for medicine errors in children. An alternative to OLFs is the conventional solid oral dosage form (OSF), such as tablets and capsules. These offer the advantages of greater stability, easy dose selection, improved transportability, and ease of storage. They also allow the modification of drug pharmacokinetic parameters, minimizing administration frequency. Finally, OSFs are less costly than OLFs, since they are easier to develop, manufacture, transport, store, and deliver. Controlled study results suggest that the use of OSFs in children would be associated with greater acceptability by children, greater preference on the part of caregivers, and higher drug compliance than OLFs. Recent controlled studies, confirming that OSFs with an acceptable size for children (mini-tablets), should shift the current paradigm of OLFs as the reference for children's oral medicine. We lack evidence on OSF acceptability in children and its influence on drug compliance, particularly with appropriate-size OSFs for children. Further investigation on oral formulation should investigate the utilisation of OSFs in young children. Few OSFs are licensed for children under 6 years of age.

A Joint Model for the Kinetics of CTC Count and PSA Concentration During Treatment in Metastatic Castration-Resistant Prostate Cancer.

Assessment of treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) is limited by frequent nonmeasurable bone metastases. The count of circulating tumor cells (CTCs) is a promising surrogate marker that may replace the widely used prostate-specific antigen (PSA). The purpose of this study was to quantify the dynamic relationships between the longitudinal kinetics of these markers during treatment in patients with mCRPC. Data from 223 patients with mCRPC treated by chemotherapy and/or hormonotherapy were analyzed for up to 6 months of treatment. A semimechanistic model was built, combining the following several pharmacometric advanced features: (1) Kinetic-Pharmacodynamic (K-PD) compartments for treatments (chemotherapy and hormonotherapy); (2) a latent variable linking both marker kinetics; (3) modeling of CTC kinetics with a cell lifespan model; and (4) a negative binomial distribution for the CTC random sampling. Linked with survival, this model would potentially be useful for predicting treatment efficacy during drug development or for therapeutic adjustment in treated patients.

A dynamic model of hand-and-foot syndrome in patients receiving capecitabine.

For the purpose of developing a longitudinal model to predict hand-and-foot syndrome (HFS) dynamics in patients receiving capecitabine, data from two large phase III studies were used. Of 595 patients in the capecitabine arms, 400 patients were randomly selected to build the model, and the other 195 were assigned for model validation. A score for risk of developing HFS was modeled using the proportional odds model, a sigmoidal maximum effect model driven by capecitabine accumulation as estimated through a kinetic-pharmacodynamic model and a Markov process. The lower the calculated creatinine clearance value at inclusion, the higher was the risk of HFS. Model validation was performed by visual and statistical predictive checks. The predictive dynamic model of HFS in patients receiving capecitabine allows the prediction of toxicity risk based on cumulative capecitabine dose and previous HFS grade. This dose-toxicity model will be useful in developing Bayesian individual treatment adaptations and may be of use in the clinic.

Tissue distribution of human calcium-binding protein (28 000 g mol-1).

Immunoreactive calcium-binding protein (28 000 g mol-1, L-CaBP) has been quantified using a specific radioimmunoassay to human cerebellar L-CaBP. The level of L-CaBP in post-mortem tissue samples varied from undetectable in muscle to 8 micrograms/mg-1 protein in the cerebellum and 16 micrograms mg-1 protein in the dentate nucleus. L-CaBP was found to be widely distributed throughout the nervous system while the only non-nervous tissue which contained appreciable levels was the renal cortex.