Background: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. Methods: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. Results: The combined model accurately predicted observed nadir timing ( r =0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients ( r =0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 μ g m −2 tri-weekly, is G-CSF, 300 μ g, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m −2 , is optimally supported by the slightly less cost-effective G-CSF 300 μ g, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per μ l) under Doc, 100–150 mg m −2 tri-weekly. Conclusions: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.

Background: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A 2 (PLA 2 ). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA 2 (sPLA 2 ) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA 2 and prostaglandin E 2 . These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA 2 inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA 2 inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways. Methods: Rats sensitised with OVA were treated with the sPLA 2 inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mg) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor a (TNFa) by BAL macrophages were determined. Results: Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFa and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge. Conclusions: These findings confirm the pivotal role of sPLA 2 in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA 2 may be a new therapeutic approach to the treatment of asthma.

The decreasing cost-efficiency of drug development threatens to result in a severe shortage of innovative drugs, which may seriously compromise patient healthcare. This risk underlines the urgency to change the paradigm in clinical research. Here, we examine a novel concept of conducting virtual clinical trials for efficiently screening drug candidates, and for evaluating their prospects of being brought to the market successfully. The virtual clinical trials are carried out by using virtual patients (denoted Optimata Virtual Patients — OVPs). The OVP, a set of mathematical algorithms that describe the main pathological and physiological dynamic processes affected by the administered drug, has been shown to accurately predict docetaxel efficacy and safety in individual breast cancer patients. We report a test case in which virtual clinical trials have been conducted by using OVP populations for rescuing a discontinued oncology compound, ISIS-5132 (ISIS Pharmaceuticals Inc.). Our in silico study suggested that ISIS-5132 may be efficacious in combination with another drug, sunitinib malate (Sutent®, Pfizer Inc.), for the treatment of prostate cancer. The recommended combined treatment is predicted to result in a higher five-year Progression-Free Survival than monotherapy with either drug alone.

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