الفهرس 
ChronotherapyOnly 14 pages are availabe for public view
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Abstract
Understanding the factors that affect the therapeutic effect of drugs is essential to optimize dosing regimens. One source of variation is introduced by the 24 h rhythms in physiology, which are generated by an endogenous clock mechanism that is entrained to light–dark cycle. These rhythms are known to affect the pharmacokinetics, and the pharmacodynamics of drugs. Many physiological processes in the human body are subject to 24 h fluctuations such as gastric emptying time, kidney function, and hepatic en-zyme activity. The complex interplay between these rhythms may result in substantial variation in the pharmacokinetic parameters of a drug over the day and the night. Valsartan is an ARB that has been widely used in treatment of hyper-tension, heart failure, and myocardial infarction. Dose‑dependent antihyper-tensive efficacy has been demonstrated for valsartan at doses up to 320 mg, with 160 mg as the recommended starting dose. Valsartan (160 mg) used as once daily regimen without any specifica-tion of time of administration. Several studies have documented variability in pharmacodynamics of valsartan, according to time of administration, influ-encing its therapeutic and adverse effects. This variability could be explained partly by time dependent variation in PK of valsartan. Circadian time-dependent variation in PK of valsartan has been previously reported in one preclinical trial. Similar clinical trials haven’t been previously performed in human subjects. PK-PD modelling provides a mathematical description of the relation-ships between PK and PD. It allows the estimation of PK-PD parameters and the prediction of clinically relevant parameters. The present study was carried out to investigate how diurnal rhythm could affect pharmacokinetics and pharmacodynamics of valsartan in healthy subjects. And, to construct suitable PK/PD model to correlate valsartan con-centrations with its effect. The study was carried out at Drug Research Center, Cairo, Egypt. Six-teen healthy adult subjects administered valsartan (160 mg/day) either at 7.00 h or at 19.00 h, in an open-label, single dose, two-period, crossover study. Blood samples were collected pre-dose and at specified time points for 48 h after drug administration Plasma concentrations of valsartan were determined using [HPLC MS/MS]. The method was validated in terms of linearity, accuracy, precision, selectivity and determination of LLOQ. A non-compartmental approach was used to determine the pharmacoki-netic parameters of valsartan. For PK assessment the following parameters were calculated: • Peak plasma concentration (Cmax) • The time required for reaching it (tmax) • The area under the plasma concentration from zero to t (AUC 0t) • The area under the plasma concentration from zero to infinity (AUC 0∞) • The elimination half- life (T1/2) • Elimination rate constant. • Mean residence time (MRT) For PD assessment the following parameters were calculated: For the PD assessments, blood pressure (systolic and diastolic) was measured pre-dose and at predetermined time intervals for 24 after drug ad-ministration. The values of change in systolic blood pressure (SBP), diastolic blood pressure (DBP), were calculated by subtracting the blood pressure val-ue at each time point from the base line value for each subject. The current study has shown that: • The absence of dosing time related changes in the plasma concentration after administering of single oral dose 160 mg valsartan by normotensive subjects. • The 90% CI of log-transformed values of primary PK parameters were always between [80% - 125%] indicating that these changes in were in-significant and had no clinical effect. • The time course of change in BP was comparable after daytime or even-ing time administration of single oral dose of 160 mg valsartan by healthy subjects. • Measurement of change in BP appeared not to be informative to con-struct PK-PD model at this dose level in healthy subjects. Another bi-omarker is needed to monitor the circadian phase dependency of valsar-tan’s pharmacodynamics in normotensive subjects.