Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different delivery systems in healthy volunteers and in psoriasis patients

Publisher Copyright: © 2019 Novartis. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological SocietyAims: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. Methods: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1-mL prefilled syringe or 1 × 2-mL prefilled syringe. Results: Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1-year phase 3 study in patients confirmed PK results observed in the phase 1 study. Conclusion: Collective evidence from both studies demonstrated that 2-mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.Peer reviewe

How to link biomarkers using physiologically based pharmacokinetic models.

Summary and comments ("Research Highlights" in News and Views of the journal "Biomarkers in Medicine") on : Combining the “bottom-up” and “top-down” approaches in pharmacokinetic modelling: Fitting PBPK models to observed clinical data. Nikolaos Tsamandouras, Amin Rostami-Hodjegan, Leon Aarons BJCP, Sep 2013, on line doi: 10.1111/bcp.12234 “How to link biomarkers: by using PBPK models” Translational Medicine approaches impose to use many biomarkers from in vitro ones to clinical endpoints. The integration and articulation of those biomarkers are typically organized by “modelling and simulation” techniques. In this article, the authors delineate the process by which they can combine different approaches of modelling, using the specific example of pharmacokinetics. The article summarizes well the 3 levels of complexity of modelling techniques. The first level is the empirical approach i.e. data are described by a mathematical model chosen on the “best fit”. The second level is best described by being between level 1 and level 3 i.e. it is a so-called “semi-mechanistic” model using in some parts an empirical approach and in other parts a mechanistic approach. The level 3 is the mechanistic model and in pharmacokinetics, it is the complex physiologically based pharmacokinetic (PBPK) model. In this case, all key pathways through which a test drug is expected to go in a living organism, is computed. Recent tendency in drug development is to use more the level 3. This was made possible by improvements in computers and softwares, by increased use of in silico methods and by development of in vitro in vivo extrapolation methods. Numerical sensitivity of a model is often assessed by sensitivity analysis. This type of analysis tries to evaluate the origin of the variability of the model output by assessing different sources of variation included in the model. Ultimately, there is the good advice that all PBPK models should be assessed on the plausibility of the physiological parameters and their assigned range of values. Correlation between parameters must be carefully examined. If there is a high correlation, one of the parameters should be quantified, using a physiologically plausible value. For parameter estimation, 2 aspects are underlined. The authors are suggesting that most of the parameters should be fixed from physiological values and only a few should be estimated by model optimization techniques. Additionally, the reliability of the estimate should be described and this is often a challenging task for non physiologically parameterized values. A very interesting clarification is made between the 2 terms, uncertainty and variability. “Variability refers to differences attributable to environmental or genetic factors” when “Uncertainty is variation that derives from errors in the experimental procedure, measurement, modelling and assumptions of the studied system”. A possibility to incorporate Bayesian statistics approaches into PBPK is discussed. One key advantage is to bring a distribution of probability perspective i.e. sort of variability description. However, a disadvantage is the need for high power, high speed computers and highly (or at least specifically) skilled scientists. Ultimately, good PBPK models are sometimes considered overparameterized because they include many different parameters. The whole body system, sometimes described, encompasses too many dimensions in comparison to the available data. Then, it is reasonable to use techniques such as lumping procedures and semi-mechanistic models instead. The conclusion is driven by common sense and proposes “to develop mechanistically sound models with clinical relevance”. In drug development, mechanistic approaches are often key to resolve difficult hurdles because they permit to identify the key parameter(s) driving the failure of a particular molecule

Secukinumab treatment does not alter the pharmacokinetics of the CYP3A4 substrate midazolam in patients with moderate to severe psoriasis – results from an open label disease-drug-drug interaction study

This open-label disease drug–drug interaction study assessed whether blockade of the interleukin (IL)-17A pathway by secukinumab and subsequent down regulation of inflammatory cytokines like IL-6 or high sensitivity c-reactive protein (hsCRP) affects the pharmacokinetics of a senstive probe substrate of the cytochrome P450 3A4 isoform (CYP3A4). The pharmacokinetics of midazolam, metabolized by CYP3A4, was evaluated before and after 7 and 35 days of treatment initiation of subcutaneous secukinumab at a dose of 300 mg weekly in 24 patients with moderate-to-severe psoriasis. While demonstarting the expected decrease in downstream inflammatory cytokines, secukinumab had no clinically relevant effects on the pharmacokinetics of midazolam, provided substantial clinical benefit, and was generally well tolerated. In summary, blockade of IL-17A signaling in moderate to severe psoriasis patients does not significantly affect CYP3A4 enzyme activities and therefore the use of secukinumab is unlikely to influence the pharmacokinetics of CYP3A4 substrates

Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different 2 mL delivery systems in healthy volunteers and in psoriasis patients

Aims The aim of the study was to compare the pharmacokinetics, safety and tolerability of secukinumab with different devices for subcutaneous administration of 2 mL (i.e. 300 mg) secukinumab. Methods A phase 1 study in healthy subjects with six devices to administer 2 mL injection volumes was conducted to evaluate the serum pharmacokinetics (PK), safety and tolerability of secukinumab following s.c. injection of 300 mg in the abdomen or in the thigh at either the left or right side of the body. Primary PK endpoints were maximum observed concentration (Cmax), and areas under the curve (AUCinf and AUClast). The impact of site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 x 1 mL prefilled syringe or 1 x 2 mL prefilled syringe. Results Mean serum concentration-time profiles for administrations as 2 x 1mL injections or as 1 x 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 x 1 mL injections. A non-clinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a one year phase 3 study in patients confirmed PK results observed in the phase 1 study. Conclusions Collective evidence from a phase 1 study and phase 3 study demonstrated that 2 mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characerisitics and were all well tolerated without noticable pain experiences

Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different delivery systems in healthy volunteers and in psoriasis patients

Publisher Copyright: © 2019 Novartis. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological SocietyAims: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. Methods: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1-mL prefilled syringe or 1 × 2-mL prefilled syringe. Results: Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1-year phase 3 study in patients confirmed PK results observed in the phase 1 study. Conclusion: Collective evidence from both studies demonstrated that 2-mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.Peer reviewe