Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

International audienceBACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg(-1). Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody

Personalized Drug Dosage – Closing the Loop

A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed

The stellar halo of the Galaxy

Stellar halos may hold some of the best preserved fossils of the formation history of galaxies. They are a natural product of the merging processes that probably take place during the assembly of a galaxy, and hence may well be the most ubiquitous component of galaxies, independently of their Hubble type. This review focuses on our current understanding of the spatial structure, the kinematics and chemistry of halo stars in the Milky Way. In recent years, we have experienced a change in paradigm thanks to the discovery of large amounts of substructure, especially in the outer halo. I discuss the implications of the currently available observational constraints and fold them into several possible formation scenarios. Unraveling the formation of the Galactic halo will be possible in the near future through a combination of large wide field photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes. Full-resolution version available at http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd

Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis

Receptor mediated endocytosis (RME) plays a major role in the disposition of therapeutic protein drugs in the body. It is suspected to be a major source of nonlinear pharmacokinetic behavior observed in clinical pharmacokinetic data. So far, mostly empirical or semi-mechanistic approaches have been used to represent RME. A thorough understanding of the impact of the properties of the drug and of the receptor system on the resulting nonlinear disposition is still missing, as is how to best represent RME in pharmacokinetic models. In this article, we present a detailed mechanistic model of RME that explicitly takes into account receptor binding and trafficking inside the cell and that is used to derive reduced models of RME which retain a mechanistic interpretation. We find that RME can be described by an extended Michaelis–Menten model that accounts for both the distribution and the elimination aspect of RME. If the amount of drug in the receptor system is negligible a standard Michaelis–Menten model is capable of describing the elimination by RME. Notably, a receptor system can efficiently eliminate drug from the extracellular space even if the total number of receptors is small. We find that drug elimination by RME can result in substantial nonlinear pharmacokinetics. The extent of nonlinearity is higher for drug/receptor systems with higher receptor availability at the membrane, or faster internalization and degradation of extracellular drug. Our approach is exemplified for the epidermal growth factor receptor system

Hepatic profile analyses of tipranavir in Phase II and III clinical trials

<p>Abstract</p> <p>Background</p> <p>The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.</p> <p>Methods</p> <p>Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.</p> <p>Results</p> <p>Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.</p> <p>Conclusion</p> <p>Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline.</p> <p>Trial registration</p> <p>US-NIH Trial registration number: NCT00144170</p

Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity

Экспериментальное изучение влияния глюкозамина гидрохлорида на развитие патоспермии стареющих крыс, вызванной доксорубицином

ГЛЮКОЗАМИНА ГИДРОХЛОРИДДОКСОРУБИЦИНПАТОСПЕРМИЯСТАРЕНИЕФАРМАКОЛОГИЯ КЛИНИЧЕСКАЯЛЕКАРСТВ ФИЗИОЛОГИЧЕСКОЕ ДЕЙСТВИЕРЕПРОДУКЦИЮ КОНТРОЛИРУЮЩИЕ СРЕДСТВАЭКСПЕРИМЕНТЫ НА ЖИВОТНЫХКРЫСЫЦель работы - исследование влияния глюкозамина гидрохлорида на развитие гипофункции семенников крыс, вызванной длительным введением доксорубицина на фоне старения животных