Modeling and simulation (M&S) is a diverse discipline that uses tools from mathematics, statistics, and computer science to arrive at quantitative predictions. Its application to biological systems ...has a checkered history with respect to success and failure. The instances of failure may reflect the heterogeneity of M&S approaches. In order to ensure a successful outcome, M&S must be fit for purpose and responsive; connecting with biological concepts is critical; sharing of results has to be done properly; buy‐in is achieved in stages. These concepts are being applied in drug discovery and development and are yielding success. However, bottlenecks remain.
Clinical Pharmacology & Therapeutics (2010) 88 1, 126–129. doi: 10.1038/clpt.2010.87
Systems pharmacology is an emerging approach that sets out to use quantitative concepts rooted in the synergy between modeling and simulation on one hand and large‐scale data collection and analysis ...on the other to investigate biological systems and design therapeutic interventions. Interest in this field has recently increased substantially, but so have perceived challenges and misunderstandings, especially related to implementation. This Commentary explores the opportunities and challenges in the rapidly evolving area of systems pharmacology from a drug discovery and development perspective.
Clinical Pharmacology & Therapeutics (2013); 93 5, 379–381. doi:10.1038/clpt.2013.40
Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or ...lowering the risk of toxicity. Model‐informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large‐scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become “widespread clinical practice,” among those, wider interdisciplinary collaborations and the necessity for further evidence‐based efficacy and cost–benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.
The integrated low-level trigger and data acquisition (TDAQ) system of the NA62 experiment at CERN is described. The requirements of a large and fast data reduction in a high-rate environment for a ...medium-scale, distributed ensemble of many different sub-detectors led to the concept of a fully digital integrated system with good scaling capabilities. The NA62 TDAQ system is rather unique in allowing full flexibility on this scale, allowing in principle any information available from the detector to be used for triggering. The design concept, implementation and performances from the first years of running are illustrated.
High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, ...disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state‐of‐the‐art of large‐scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice.
Amoxicillin is recommended for anthrax prevention in pregnancy. The objective of this study was to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum (PP). Sixteen women ...received amoxicillin during gestation (18–22 weeks (T2) and 30–34 weeks (T3)) as well as 3 months postpartum (PP) to evaluate single‐dose pharmacokinetics. Amoxicillin compartmental pharmacokinetic parameters were used to simulate amoxicillin concentration–time profiles following different dosage strategies. Amoxicillin CLrenal (T2: 24.8±6.7 l/h, P<0.001; T3: 24.0±3.9 l/h, P<0.001; and PP: 15.3±2.6 l/h) and renal CLsecretion (T2: 280±105 ml/min, P<0.002; T3: 259±54 ml/min, P<0.001; and PP: 167±47 ml/min) were higher during pregnancy than postpartum. Simulations suggest that amoxicillin concentrations adequate to prevent anthrax may be difficult to achieve during pregnancy and postpartum. Increases in amoxicillin CLrenal and renal CLsecretion reflect increases in filtration and secretory transport or diminished reabsorption in the kidneys. Amoxicillin may not be an appropriate antibiotic for post‐anthrax exposure prophylaxis.
Clinical Pharmacology & Therapeutics (2007) 81, 547–556. doi:10.1038/sj.clpt.6100126; published online 28 February 2007.
The theme of this month's issue of Clinical Pharmacology & Therapeutics is pharmacometrics. When looking back at the early days of pharmacometrics, current contributions to the drug development ...process look impressive. The questions are whether the original promise is being kept and how the impact can become even greater.
Clinical Pharmacology & Therapeutics (2014); 95 6, 567–571. doi:10.1038/clpt.2014.72
Background and Purpose
The Eph receptor tyrosine kinases and their ephrin ligands are key players in tumorigenesis and many reports have correlated changes in their expression with a poor clinical ...prognosis in many solid tumours. Agents targeting the Eph‐ephrin system might emerge as new tools useful for the inhibition of different components of cancer progression. Even if different classes of small molecules targeting Eph‐ephrin interactions have been reported, their use is hampered by poor chemical stability and low potency. Stable and potent ligands are crucial to achieve robust pharmacological performance.
Experimental Approach
UniPR129 (the L‐homo‐Trp conjugate of lithocholic acid) was designed by means of computational methods, synthetized and tested for its ability to inhibit the interaction between the EphA2 receptor and the ephrin‐A1 ligand in an elisa binding study. The ability of UniPR129 to disrupt EphA2‐ephrin‐A1 interaction was functionally evaluated in a prostate adenocarcinoma cell line and its anti‐angiogenic effect was tested in vitro using cultures of HUVECs.
Key Results
UniPR129 disrupted EphA2‐ephrin‐A1 interaction with Ki = 370 nM in an elisa binding assay and with low micromolar potency in cellular functional assays, including inhibition of EphA2 activation, inhibition of PC3 cell rounding and disruption of in vitro angiogenesis, without cytotoxic effects.
Conclusions and Implications
The discovery of UniPR129 represents not only a major advance in potency compared with the existing Eph‐ephrin antagonists but also an improvement in terms of cytotoxicity, making this molecule a useful pharmacological tool and a promising lead compound.
Erectile dysfunction (ED), the second most common male sexual disorder, has an important impact on man sexuality and quality of life affecting also female partner's sexual life. ED is usually related ...to cardiovascular disease or is an iatrogenic cause of pelvic surgery. Many non-surgical treatments have been developed with results that are controversial, while surgical treatment has reached high levels of satisfaction. The aim is to evaluate outcomes and complications related to prosthesis implant in patients suffering from ED not responding to conventional medical therapy or reporting side effects with such a therapy. One hundred eighty Caucasian male suffering from ED were selected. The patient population were divided into two groups: 84 patients with diabetes and metabolic syndrome (group A) and 96 patients with dysfunction following laparoscopic radical prostatectomy for prostate cancer (group B). All subjects underwent primary inflatable penile prosthesis implant with an infrapubic minimally invasive approach. During 12 months of follow-up, we reported 3 (1.67%) explants for infection, 1 (0.56%) urethral erosion, 1 (0.56%) prosthesis extrusion while no intraoperative complications were reported. Mean International Index of Erectile Function-5 (IIEF-5) was 8.2 ± 4.0 and after the surgery (12 months later) was 20.6 ± 2.7. The improvement after the implant is significant in both groups without a statistically significant difference between the two groups (P-value 0.65). Mean Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score 1 year after the implant is 72.2 ± 20.7, and there was no statistically significant difference between groups A and B (P-value 0.55). Implantation of an inflatable prosthesis, for treatment of ED, is a safe and efficacious approach; and the patient and partner satisfaction is very high. Surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease after surgery common complications (infection and mechanical failure).
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