Background and Aims: We assessed the effect of CYP450 activity assessed by lansoprazole metabolism on 7 year-survival of 89 patients with STEMI treated by PCI together with prasugrel (n = 46) and ticagrelor (n = 49). Methods: Patients were given lansoprazole as a probe drug that is metabolized into 5OH-lansoprazole by CYP2C19 or lansoprazole sulfone by CYP3A4, and concentration of lansoprazole and both metabolites was determined. Results: There was no difference in survival between groups. In ticagrelor group, both lansoprazole sulfone/lansoprazole (HR per doubling = 2.90; 95%CI = 1.32–6.35; p = 8.10-3) and 5OH-lansoprazole/lansoprazole (HR per doubling = 0.34; 95%CI = 0.19–0.61; p = 3.10-4) ratio correlated with survival. The effect remained significant after adjustment for other significant predictors (age, ejection fraction, previous MI and the number of diseased vessels), and gender, smoking, hypertension, diabetes and dyslipidemia. In post-hoc analysis, the effect was only present in patients treated by atorvastatin (n = 30; HR per doubling of lansoprazole sulfone/lansoprazole = 12.68; HR for 5OH-lansoprazole/lansoprazole = 0.25, respectively). No significant effect on survival was found in prasugrel-treated patients. Similarly, the effect of CYP2C19 polymorphisms on lansoprazole metabolite production was only evident in the ticagrelor group. Only 4 deaths occurred during prasugrel/ticagrelor treatment. Conclusions: We hypothesize that CYP450 effect on survival was mediated by factors unrelated to P2Y12-blocking treatment, possibly by atorvastatin, degraded by CYP3A4. The effect was evident in ticagrelor group because prasugrel is a moderate CYP3A4 inhibitor and therefore formation of lansoprazole sulfone in high doses of prasugrel may not reflect the long-term activity of CYP3A4.

Objective: Currently available methods for endogenous cortisol monitoring in patients with hormonal insufficiency rely on measurements of plasma levels only at a single time point; thus, any kind of chronic exposure to cortisol is challenging to evaluate because it requires collecting samples at different time points. Hair cortisol levels acquired longitudinally better reflected chronic exposure (both cortisol synthesis and deposition) and may significantly contribute to better outcomes in glucocorticoid replacement therapies. Design: Twenty-two patients on cortisol substitution therapy were monitored for plasma, urinary, and hair cortisol levels for 18 months to determine whether hair cortisol may serve as a monitoring option for therapy setting and adjustment. Methods: Plasma and urinary cortisol levels were measured using standardized immunoassay methods, and segmented (∼1 cm) hair cortisol levels were monitored by liquid chromatography coupled to mass spectrometry. A log-normal model of the changes over time was proposed, and Bayesian statistics were used to compare plasma, urinary, and hair cortisol levels over 18 months. Results and conclusions: Hair cortisol levels decreased over time in patients undergoing substitutional therapy. The residual variance of hair cortisol in comparison to plasma or urinary cortisol levels was much lower. Thus, longitudinal monitoring of hair cortisol levels could prove beneficial as a noninvasive tool to reduce the risk of overdosing and improve the overall patient health.

We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after a loading dose of 60 mg prasugrel or 180 mg ticagrelor in patients with ST-elevation myocardial infarction (STEMI). Further, we assessed the contribution of CYP2C19 polymorphisms and medication to the CYP enzymatic activity. Patients with STEMI were randomly assigned to the treatment with prasugrel (n = 51) or ticagrelor (n = 46). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the rate of 5-hydroxylation and sulfoxidation of lansoprazole. Further, patients were genotyped for CYP2C19 *2 and *17 alleles. In prasugrel-treated patients, high ADP-induced platelet reactivity 1h after the loading dose positively correlated with 5OH-lansoprazole/lansoprazole ratio (r = 0.44, p = 0.002), a marker of CYP2C19 metabolic activity, and negatively with lansoprazole-sulfone/lansoprazole ratio, which reflects CYP3A4 metabolic activity (r = -0.35, p = 0.018). CYP2C19 poor metabolizers had lower 5OH-lansoprazole/lansoprazole ratio and higher lansoprazole-sulfone/lansoprazole ratio, but without any effect on the ADP-induced platelet reactivity. The treatment with amiodarone, a CYP3A4 inhibitor, influenced neither the metabolic ratios nor the ADP-induced platelet reactivity. The CYP3A4 and CYP2C19 metabolic activity is associated with ADP-induced platelet reactivity in prasugrel-treated, but not ticagrelor-treated patients with STEMI.

STATE OF THE ARTSunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal clear-cell carcinoma and a second line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients and many face adverse effects and/or toxicity. One of the possible causes of the inter-individual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite.AIMSThis review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib.METHODSThe authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed.RESULTSand discussion: There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. In order to avoid toxicity, the total trough levels should not exceed 100 ng/mL. According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinib toxicity.

Aim: We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after the loading dose of 60 mg prasugrel or 180 mg ticagrelor in the patients with ST-elevations myocardial infarction (STEMI) treated by percutaneous coronary intervention. Further, we assessed the contribution of CYP2C19 polymorphisms and amiodarone treatment to the CYP 450 enzymatic activity.