Rational solvent selection remains a significant challenge in process development. Here we describe a hybrid mechanistic-machine learning approach, geared towards automated process development ...workflow. A library of 459 solvents was used, for which 12 conventional molecular descriptors, two reaction-specific descriptors, and additional descriptors based on screening charge density, were calculated. Gaussian process surrogate models were trained on experimental data from a Rh(CO)
2
(acac)/Josiphos catalysed asymmetric hydrogenation of a chiral α-β unsaturated γ-lactam. With two simultaneous objectives - high conversion and high diastereomeric excess - the multi-objective algorithm, trained on the initial dataset of 25 solvents, has identified solvents leading to better reaction outcomes. In addition to being a powerful design of experiments (DoE) methodology, the resulting Gaussian process surrogate model for conversion is, in statistical terms, predictive, with a cross-validation correlation coefficient of 0.84. After identifying promising solvents, the composition of solvent mixtures and optimal reaction temperature were found using a black-box Bayesian optimisation. We then demonstrated the application of a new genetic programming approach to select an appropriate machine learning model for a specific physical system, which should allow the transition of the overall process development workflow into the future robotic laboratories.
Rational solvent selection remains a significant challenge in process development.
Aims
SAR247799 is a selective G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first‐in‐class ...molecule differentiated from previous S1P1‐desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).
Methods
SAR247799 was administered orally to healthy subjects in a double‐blind, randomized, placebo‐controlled study with single (2.5–37.5 mg) or 2‐week once‐daily (0.5–15 mg) doses. An open‐label single dose pilot food‐interaction arm with 10 mg SAR247799 in cross‐over design was also performed.
Results
SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose‐dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose‐proportional increases in exposure and was eliminated with an apparent terminal half‐life of 31.2–33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7–23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub‐lymphocyte‐reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial‐protective properties, had minimal‐to‐no heart rate reduction and displayed no marked safety findings.
Conclusion
SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.
Breast cancer comprises a group of distinct subtypes that despite having similar histologic appearances, have very different metastatic potentials. Being able to identify the biological driving ...force, even for a subset of patients, is crucially important given the large population of women diagnosed with breast cancer. Here, we show that within a subset of patients characterized by relatively high estrogen receptor expression for their age, the occurrence of metastases is strongly predicted by a homogeneous gene expression pattern almost entirely consisting of cell cycle genes (5-year odds ratio of metastasis, 24.0; 95% confidence interval, 6.0-95.5). Overexpression of this set of genes is clearly associated with an extremely poor outcome, with the 10-year metastasis-free probability being only 24% for the poor group, compared with 85% for the good group. In contrast, this gene expression pattern is much less correlated with the outcome in other patient subpopulations. The methods described here also illustrate the value of combining clinical variables, biological insight, and machine-learning to dissect biological complexity. Our work presented here may contribute a crucial step towards rational design of personalized treatment.
Background
Aprepitant is a neurokinin1 receptor antagonist that, in combination with a corticosteroid and a 5‐hydroxytryptamine3 receptor antagonist, has been shown to be very effective in the ...prevention of chemotherapy‐induced nausea and vomiting. At doses used for the management of chemotherapy‐induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated.
Methods
Study 1 was an open‐label, randomized, incomplete‐block, 3‐period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy‐induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double‐blind, randomized, placebo‐controlled, 2‐period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen.
Results
In study 1, the area under the concentration‐time curve from 0 to 24 hours (AUC0‐24) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2‐fold (P < .010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0‐24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0‐24 of intravenous methylprednisolone 1.3‐fold on day 1 (P < .010) and increased the AUC0‐24 of oral methylprednisolone 2.5‐fold on day 3 (P < .010).
Conclusions
Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.
Clinical Pharmacology & Therapeutics (2003) 74, 17–24; doi: 10.1016/S0009‐9236(03)00066‐3
This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single‐dose study, 8 patients each with mild and moderate hepatic insufficiency ...received 70 mg of caspofungin. In the multiple‐dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration‐time profile over the interval of last quantifiable point to infinity (AUC0‐∞) geometric mean ratio (GMR) (90% confidence interval CI) for mild hepatic insufficiency/historical controls was 1.55 (1.32–1.86) in the single‐dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04–1.39) for day 14 area under the concentration– time profile calculated over the interval 0 to 24 hours (AUC0‐24h) following multidose. The AUC0‐∞ GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51–2.06) following 70 mg; AUC0‐24h GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90–1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70‐mg loading dose is recommended for patients with moderate hepatic insufficiency.
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