Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review.

BACKGROUND AND OBJECTIVE: Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib. METHODS: Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded. RESULTS: Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations. CONCLUSION: Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.

The effects of ritodrine on experimentally induced intra-uterine growth retardation in the rat.

The effects of oral ritodrine on artificially induced intra-uterine growth retardation in rats were tested in two animal models. In one model, foetal hypotrophy was induced by reduction of the uterine blood supply on ligating of the left uterine artery. In that experiment no significant inhibition of the foetal hypotrophy could be detected in the ritodrine treated animals, but the corresponding reduction of placental weight was inhibited. In the other model, hypotrophy was induced by hypothermia. Oral ritodrine, given twice daily in a dose of 50 mg/kg from day 7 to day 21 of the pregnancy, antagonized the decrease of the foetal weight produced by hypothermia.

Endocrine effects of two new retro-steroids in animal models and in women.

PIP: Endocrine effects of 2 new retrosteroids, DU 164 and DU 41 165, in a nimal models and in women are reported. Both retrosteroids exhibited hi gh progestational activity in the rabbit, their potency being 18 times that of the reference standard, chlormadinone acetate (CMA), when administered orally. Both retrosteroids maintained pregnancy in rabbits and rats with a potency of 6 and 11 times that of CMA for DU 41 164 and DU 41 165, respectively. In the pregnancy maintenance tests in rats the effective dose (ED) 50 of DU 41 164 and DU 41 165 was 2000 mcg/kg/day and 290 mcg/kg/day, respectively, whereas CMA could not maintain pregnancy in doses of 50,000 mcg/kg/day. Both retrosteroids were highly active as antifertility agents in rabbits and rats. Their potencies were 80 and 40 times that of CMA in rabbits and 100 and 300 times that of CMA in rats. In ovulation inhibition tests the ED 50 of oral DU 41 164 and DU 41 165 were .5 and .4 mcg/kg in rabbits, whereas the ED 50 of CMA was 40 mcg/kg. The retrosteroids were also more potent than CMA in ovulation inhibition and antiestrogenic activity. High doses of DU 41 165 induced a decrease in adrenal weight and exhibited some antiinflammatory effects. 23 volunteers treated with 50 or 200 mcg of the compounds/day revealed no consistent inhibition of ovulation and of corpus luteum function. Endometrial biopsy specimens obtained on Cycle Days 12-13 during treatment with 200 mcg of either retrosteroid revealed no signs of progestational effect.^ieng