dfpk : An R-package for Bayesian dose-finding designs using Pharmacokinetics (PK) for phase I clinical trials

Background and objective Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose-finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations. The objective of this work is to implement these dose-finding methods in an R package, called dfpk. Methods All methods were developed in a sequential Bayesian setting and Bayesian parameter estimation is carried out using the rstan package. All available pharmacokinetics and toxicity data are used to suggest the dose of the next cohort with a constraint regarding the probability of toxicity. Stopping rules are also considered for each method. The ggplot2 package is used to create summary plots of toxicities or concentration curves. Results For all implemented methods, dfpk provides a function (nextDose) to estimate the probability of efficacy and to suggest the dose to give to the next cohort, and a function to run trial simulations to design a trial (nsim). The sim.data function generates at each dose the toxicity value related to a pharmacokinetic measure of exposure, the AUC, with an underlying pharmacokinetic one compartmental model with linear absorption. It is included as an example since similar data-frames can be generated directly by the user and passed to nsim. Conclusion The developed user-friendly R package dfpk, available on the CRAN repository, supports the design of innovative dose-finding studies using PK information

Abrasive wear behaviour of conventional and large-particle tungsten carbide-based cermet coatings as a function of abrasive size and type

Abrasive wear behaviour of materials can be assessed using a wide variety of testing methods, and the relative performance of materials will tend to depend upon the testing procedure employed. In this work, two cermet type coatings have been examined, namely (i) a conventional tungsten carbide-cobalt thermally sprayed coating with a carbide size of between ∼0.3 – 5 μm and (ii) a tungsten carbide-nickel alloy weld overlay with large spherical carbides of the order of ∼50 – 140 μm in diameter (DuraStell). The wear behaviour of these two materials has been examined by the use of two abrasion tests, namely the micro-scale abrasion test using both silica and alumina abrasives (typically 2-10 μm in size), and the dry sand-rubber wheel test (ASTM G65), again with both silica and alumina abrasives (typically 180 – 300 μm in size). It was found that when the abrasive particles were of the same scale or larger than the mean free path between the hard phase particles, then the matrix phase was well protected by the hard phases. Testing (in both test types) with alumina abrasives resulted in wear of both the hard carbide phases and the matrix phases in both the thermally sprayed coating and the weld overlay, with the thermally sprayed coating exhibiting lower wear rates. The wear behaviour of the materials with the more industrially relevant silica abrasive was more complex; the thermally sprayed coating exhibited a lower wear rate than the weld overlay with the fine abrasive in the micro-scale abrasion test due to effective shielding of the matrix from abrasive action due to the fine reinforcement particle size. In contrast, with the coarser silica abrasive in the dry sand-rubber wheel test, the weld overlay with the large carbides was able to provide matrix protection with low rates of wear, whereas the thermally sprayed coating wore by fracture of the more brittle microstructure. These findings demonstrate the importance of selection of appropriate laboratory test procedures and abrasives to simulate behaviour of materials in service environments

Dose Escalation Methods in Phase I Cancer Clinical Trials

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics