[The revolution of AI in drug development]. / L'intelligence artificielle, une révolution dans le développement des médicaments.

Artificial intelligence and machine learning enable the construction of predictive models, which are currently used to assist in decision-making throughout the process of drug discovery and development. These computational models can be used to represent the heterogeneity of a disease, identify therapeutic targets, design and optimize drug candidates, and evaluate the efficacy of these drugs on virtual patients or digital twins. By combining detailed patient characteristics with the prediction of potential drug-candidate properties, artificial intelligence promotes the emergence of a "computational" precision medicine, allowing for more personalized treatments, better tailored to patient specificities with the aid of such predictive models. Based on such new capabilities, a mixed reality approach to the development of new drugs is being adopted by the pharmaceutical industry, which integrates the outputs of predictive virtual models with real-world empirical studies.

Title: L'intelligence artificielle, une révolution dans le développement des médicaments. Abstract: L'intelligence artificielle (IA) et l'apprentissage automatique produisent des modèles prédictifs qui aident à la prise de décisions dans le processus de découverte de nouveaux médicaments. Cette modélisation par ordinateur permet de représenter l'hétérogénéité d'une maladie, d'identifier des cibles thérapeutiques, de concevoir et optimiser des candidats-médicaments et d'évaluer ces médicaments sur des patients virtuels, ou des jumeaux numériques. En facilitant à la fois une connaissance détaillée des caractéristiques des patients et en prédisant les propriétés de multiples médicaments possibles, l'IA permet l'émergence d'une médecine de précision « computationnelle ¼ offrant des traitements parfaitement adaptés aux spécificités des patients.

Pharmacokinetic advantage of intra-arterial hepatic oxaliplatin administration: comparative results with cisplatin using a rabbit VX2 tumor model.

The aim of this study was to compare intra-arterial hepatic administration (IAH) versus i.v. administration of oxaliplatin and cisplatin in a VX2 tumor model in rabbits. VX2 tumors were implanted in the livers of White New Zealand female rabbits and 2 weeks later they received either cisplatin (4 mg/kg) or oxaliplatin (6 mg/kg) administered by IAH or i.v. Platinum pharmacokinetic parameters were measured by atomic absorption spectrometry at baseline, 2, 5 10, 20, 40 and 60 min, and then at 2, 4, 6 and 24 h after drug administration. Animals were sacrificed 24 h after drug administration to measure platinum concentrations in various tissues. After IAH oxaliplatin administration, we observed a significant decrease for total and filterable platinum in the Cmax compared with i.v. administration (12.4 versus 18.2 microg/l; p=0.02 and 11.2 versus 17.3 microg/l; p=0.02, respectively). Significant differences in various tissue concentrations were reported when comparing IAH and i.v. administration of oxaliplatin with IAH administration offering an advantage over i.v. administration. No differences in pharmacokinetic parameters or platinum tissue accumulation were apparent between the IAH and i.v. administration with cisplatin. We conclude that there is a significant pharmacokinetic advantage to using oxaliplatin for locoregional IAH chemotherapy compared with i.v. administration.

Pharmacokinetics of high-dose melphalan in children and adults

Melphalan pharmacokinetics were studied in 20 children with stage IV neuroblastomas or Ewing's sarcomas and in 10 adults with AML, ALL, or small cell lung carcinomas, after IV administration of high doses (140mg/m2) with furosemide-induced diuresis and 180mg/m2 without induced diuresis) and high fluid intake (3000ml/m2/day). Unchanged melphalan was assayed in plasma and cerebrospinal fluid by means of a high-performance liquid chromatographic procedure. The elimination half-life (1/2<80 min) allows autologous bone marrow transplantation 24 h after the drug administration. In some children we were able to detect melphalan in cerebrospinal fluid samples

Clinical pharmacology of high-dose etoposide associated with cisplatin. Pharmacokinetic and metabolic studies

Twelve patients were treated with high-dose etoposide given alone or in combination with cisplatin during a clinical trail. We had previously observed, in some subjects who received a combination of high-dose etoposide (350 mg/m2/day x 5 days) and cisplatin (40 mg/m2/day x 5 days), delayed hematological recovery after autologous bone marrow transplantation. Therefore we investigated the pharmacokinetics of etoposide and did not find any drug interaction with cisplatin. In four of these patients we also monitored etoposide salivary excretion and found saliva to plasma ratios in the range 0.003-0.25. The secretion of etoposide into saliva may be of concern if we consider that perioxidases in salivary glands are able to oxidize the drug leading to free radicals. In vitro experiments showed that sulfydryl compounds are able to inhibit the formation of the etoposide radical. Futhermore, we were able to detect the presence of a new biotransformation product of etoposide in plasma samples of some patients. Fast atom bombardment liquid chromatography-mass spectrometry allowed us to identified this metabolite as the etoposide aglycone. The presence of this derivative in plasma 48 hs after the last injection prompted us to delay autologous bone marrow transplantation to 72 hc after the end of treatment, since the aglycone is cytotoxic and able to induce DNA stand breaks mediated by topoisomerase II