In clinical practice, it is important to consider circadian rhythms in pharmacokinetics and cell responses to therapy in order to design proper protocols for drug administration. Scientists have arrived at this conclusion after several experiments in animals and in humans have clearly demonstrated that all organisms are highly organised according to circadian rhythms. These temporal cycles influence different physiological functions and, consequently, can influence the pharmacokinetic phases of drugs. A drug's pharmacokinetics can be modified according to the time of drug administration. In fact, the circadian changes of > 100 different compounds have been documented. The results obtained have led several scientific societies to provide guidelines concerning the timing of drug dosing for anticancer, cardiovascular, respiratory, anti-ulcer, anti-inflammatory, immunosuppressive and antiepileptic drugs. Absorption may be influenced by circadian rhythms and most lipophilic drugs seem to be absorbed faster when the drug is taken in the morning compared with the evening; for water-soluble compounds, no circadian variation in the absorption of drugs has been found. Concerning drug distribution, the higher the blood flow fraction an organ receives, the higher the rate constant for transferring drugs out of the capillaries. This drug pharmacokinetic phase may be influenced by circadian variations in the protein binding of acidic and basic drugs. Drug metabolism may be influenced by daily modifications of blood flow. For drugs with a high extraction ratio, metabolism depends on hepatic blood flow, while that of drugs with a low extraction ratio depends on liver enzyme activity. Hepatic blood flow has been shown to be greatest at 8 am and metabolism seems to be reduced during the night. Finally, concerning drug elimination, the clearance of ‘flow-limited’ drugs that present a high extraction rate is affected by the blood flow delivered to the organ, independent of the cardiac output fraction supplied. Chronopharmacokinetics can explain individual differences in drug levels revealed by therapeutic drug monitoring and can be used to optimise the management of patients receiving drug therapy.

The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (C_min) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy.

Corticosteroids (CSs) are still the mainstay of induction, rescue, and maintenance in heart transplantation (HTx). However, their use is associated with significant and well-documented side effects usually related to the dose administered and the duration of therapy. Moreover, CSs interfere with the recipient's quality of life and with the active process of graft tolerance. Physicians have been exploring ways to avoid or reduce CSs in association with other immunosuppressive drugs, minimizing side effects and costs. The regimens are classified as steroid-free or steroid withdrawal protocols. The studies analyzed in this review come to similar conclusions as benefits and adverse consequences: steroid-free protocols should be advisable and mandatory in pediatric patients, insulin-dependent diabetes mellitus (IDDM), presence of infection, familial metabolic disorders/obesity, severe osteoporosis, and in the elderly. On the other hand, steroid withdrawal can be successfully achieved in 50-80%, with late better than early withdrawal, no increase in rejection-related mortality, no adverse impact on survival, and probably a better quality of live. Safety and efficacy can certainly be improved by an individualized approach to the transplant recipient.