@article{PilariPreusseHuisinga2011,
  author    = {Pilari, Sabine and Preusse, Cornelia and Huisinga, Wilhelm},
  title     = {Gestational influences on the pharmacokinetics of gestagenic drugs a combined in silico, in vitro and in vivo analysis},
  series = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS},
  volume    = {42},
  journal   = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS},
  number    = {4},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0928-0987},
  doi       = {10.1016/j.ejps.2010.12.003},
  pages     = {318 -- 331},
  year      = {2011},
  abstract  = {During preclinical development of a gestagenic drug, a significant increase of the total plasma concentration was observed after multiple dosing in pregnant rabbits, but not in (non-pregnant) rats or monkeys. We used a PBPK modeling approach in combination with in vitro and in vivo data to address the question to what extent the pharmacologically active free drug concentration is affected by pregnancy induced processes. In human, a significant increase in sex hormone binding globulin (SHBG), and an induction of hepatic CYP3A4 as well as plasma esterases is observed during pregnancy. We find that the observed increase in total plasma trough levels in rabbits can be explained as a combined result of (i) drug accumulation due to multiple dosing, (ii) increase of the binding protein SHBG, and (iii) clearance induction. For human, we predict that free drug concentrations in plasma would not increase during pregnancy above the steady state trough level for non-pregnant women.},
  language  = {en}
}
@article{vonKleistMenzStockeretal.2011,
  author    = {von Kleist, Max and Menz, Stephan and Stocker, Hartmut and Arasteh, Keikawus and Schuette, Christof and Huisinga, Wilhelm},
  title     = {HIV quasispecies dynamics during pro-active treatment switching impact on multi-drug resistance and resistance archiving in latent reservoirs},
  series = {PLoS one},
  volume    = {6},
  journal   = {PLoS one},
  number    = {3},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0018204},
  pages     = {12},
  year      = {2011},
  abstract  = {The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at \& 80 days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after a single pro-active treatment switch. The clinical validity of this finding, however, remains to be shown by a corresponding trial.},
  language  = {en}
}
@article{WeissHuisinga2011,
  author    = {Weiss, Andrea Y. and Huisinga, Wilhelm},
  title     = {Error-controlled global sensitivity analysis of ordinary differential equations},
  series = {Journal of computational physics},
  volume    = {230},
  journal   = {Journal of computational physics},
  number    = {17},
  publisher = {Elsevier},
  address   = {San Diego},
  issn      = {0021-9991},
  doi       = {10.1016/j.jcp.2011.05.011},
  pages     = {6824 -- 6842},
  year      = {2011},
  abstract  = {We propose a novel strategy for global sensitivity analysis of ordinary differential equations. It is based on an error-controlled solution of the partial differential equation (PDE) that describes the evolution of the probability density function associated with the input uncertainty/variability. The density yields a more accurate estimate of the output uncertainty/variability, where not only some observables (such as mean and variance) but also structural properties (e.g., skewness, heavy tails, bi-modality) can be resolved up to a selected accuracy. For the adaptive solution of the PDE Cauchy problem we use the Rothe method with multiplicative error correction, which was originally developed for the solution of parabolic PDEs. We show that, unlike in parabolic problems, conservation properties necessitate a coupling of temporal and spatial accuracy to avoid accumulation of spatial approximation errors over time. We provide convergence conditions for the numerical scheme and suggest an implementation using approximate approximations for spatial discretization to efficiently resolve the coupling of temporal and spatial accuracy. The performance of the method is studied by means of low-dimensional case studies. The favorable properties of the spatial discretization technique suggest that this may be the starting point for an error-controlled sensitivity analysis in higher dimensions.},
  language  = {en}
}