Dosing Time-dependent Changes Research Articles

Time-dependent efficacy of checkpoint inhibitor nivolumab in metastatic lung cancer patients.

9096 Background: Nivolumab (NIV) is a Programmed-cell-Death-1 inhibitor approved as 2nd line treatment for metastatic Non-Small Cell Lung Cancer (NSCLC). NIV mainly targets T(CD8) cells, whose functions and trafficking are regulated by circadian clocks (Nobis et al. PNAS 2019), hence suggesting possible dosing time-dependent changes in NIV efficacy. Methods: Consecutive metastatic NSCLC patients (pts) received single agent NIV (240 mg iv q 2 weeks) at a single institution. NIV timing slots were randomly allocated for each course by the day hospital coordinator on a logistics basis and recorded. The median NIV timing and its intra-pt coefficient of variation (CVar) were computed over the whole treatment span. The study population was split into two NIV timing groups based upon the median value of the median treatment times of all the pts. CTCAE-toxicity rates were compared between groups with c2 or Fisher exact. Progression free survival (PFS) and overall survival (OS) were compared between both NIV timing groups with Log Rank. Results: From 9/2015 to 11/2020, the study accrued 95 stage 4 NSCLC pts (males, 83%; PS 0-1, 96%), aged 41-83 years (median, 67). Primary histological types were adenocarcinoma (55 pts, 58%), squamous cell carcinoma (37 pts, 39%) or unspecified (3 pts, 3%). The pts had a median of 4 metastatic sites, including bone (52% of the pts), pleura (41%), liver (25%), brain (24%) and adrenal gland (20%). A total of 1818 NIV courses were given as 2nd line for 72 pts (76%), or as 3rd or later line for 22 pts (23%). Median PFS and OS (months, mo.) were 3.9 mo. [95% CL, 2.1 – 5.8], and 14.0 mo. [9.5 – 18.4] respectively, for the 95 pts. The majority of NIV administrations occurred between 9:27 and 12:54 for 48 pts (‘morning’ group) and between 12:55 and 17:14 for 47 pts (‘afternoon’ group), with intra-pt NIV timing CVar ranging from 2% to 21% (median, 10%). Main pts characteristics were similar for both groups, except for fewer females (8% vs 26%) and younger age (median, 66 vs 69 years) in the ‘morning’ group compared to the ‘afternoon’ one. Grade 3-4 fatigue, anorexia or myalgias were less in the ‘morning’ group compared with the “afternoon’ one (6% vs 15%; 2% vs 6%; 0% vs 4%, respectively). Strikingly, median PFS [95% CI] were 11.3 mo. [5.5 - 17.1] for the ‘morning’ group as compared to 3.1 mo. [1.5 - 4.6] for the ‘afternoon’ one (p<0.001). Median OS were 34.2 mo. [15.1 - 53.3] for the ‘morning’ group vs 9.6 mo. [4.9 - 14.4] for the ‘afternoon’ group (p<0.001). Multivariate analyses identified NIV ‘morning’ timing and 2nd line administration, as significant independent predictors of longer PFS and OS. Conclusions: NIV was both less toxic and four times as effective following ‘morning’ as compared to ‘afternoon’ dosing in this study in Stage 4 NSCLC pts, possibly as a result of dosing time-dependent pharmacology. Translational and clinical nivolumab timing validation studies are needed, in order to optimize pts benefits from cancer immunotherapy.

RNA editing enzyme ADAR1 governs the circadian expression of P-glycoprotein in human renal cells by regulating alternative splicing of the ABCB1 gene

The expression and function of some xenobiotic transporters vary according to the time of the day, causing the dosing time-dependent changes in drug disposition and toxicity. P-glycoprotein (P-gp), encoded by the ABCB1 gene, is highly expressed in the kidneys and functions in the renal elimination of various drugs. The elimination of several P-gp substrates was demonstrated to vary depending on administration time, but the underlying mechanism remains unclear. We found that adenosine deaminase acting on RNA (ADAR1) was involved in the circadian regulation of P-gp expression in human renal proximal tubular epithelial cells (RPTECs). After synchronization of the cellular circadian clock by dexamethasone treatment, the expression of P-gp exhibited a significant 24-h oscillation in RPTECs, but this oscillation was disrupted by the downregulation of ADAR1. Although ADAR1 catalyzes adenosine-to-inosine (A-to-I) RNA editing in double-stranded RNA substrates, no significant ADAR1-regulated editing sites were detected in the human ABCB1 transcripts in RPTECs. On the other hand, downregulation of ADAR1 induced alternative splicing in intron 27 of the human ABCB1 gene, resulting in the production of retained intron transcripts. The aberrant spliced transcript was sensitive to nonsense-mediated mRNA decay, leading to the decreased stability of ABCB1 mRNA and prevention of the 24-h oscillation of P-gp expression. These findings support the notion that ADAR1-mediated regulation of alternative splicing of the ABCB1 gene is a key mechanism of circadian expression of P-gp in RPTECs, and the regulatory mechanism may underlie the dosing time-dependent variations in the renal elimination of P-gp substrates.

Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATP­binding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHP-induced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity.

Circadian oscillation in the intestinal expression of OCTN1/SLC22A4 underlies the dosing time-dependent changes in the absorption of pregabalin and its analgesic effects on diabetic neuropathy

Circadian oscillation in the intestinal expression of OCTN1/SLC22A4 underlies the dosing time-dependent changes in the absorption of pregabalin and its analgesic effects on diabetic neuropathy

Circadian modulation in the intestinal absorption of P-glycoprotein substrates in monkeys.

Recent studies in laboratory rodents have revealed that circadian oscillation in the physiologic functions affecting drug disposition underlies the dosing time-dependent change in pharmacokinetics. However, it is difficult to predict the circadian change in the drug pharmacokinetics in a diurnal human by using the data collected from nocturnal rodents. In this study, we used cynomolgus monkeys, diurnal active animals, to evaluate the relevance of intestinal expression of P-glycoprotein (P-gp) to the dosing time dependency of the pharmacokinetics of its substrates. The rhythmic phases of circadian gene expression in the suprachiasmatic nuclei (the mammalian circadian pacemaker) of cynomolgus monkeys were similar to those reported in nocturnal rodents. On the other hand, the expression of circadian clock genes in the intestinal epithelial cells of monkeys oscillated at opposite phases in rodents. The intestinal expression of P-gp in the small intestine of monkeys was also oscillated in a circadian time-dependent manner. Furthermore, the intestinal absorption of P-gp substrates (quinidine and etoposide) was substantially suppressed by administering the drugs at the times of day when P-gp levels were abundant. By contrast, there was no significant dosing time-dependent difference in the absorption of the non-P-gp substrate (acetaminophen). The oscillation in the intestinal expression of P-gp appears to affect the pharmacokinetics of its substrates. Identification of circadian factors affecting the drug disposition in laboratory monkeys may improve the predictive accuracy of pharmacokinetics in humans.

Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice

Cisplatin, cis-diamminedichloro-platinum (CDDP), is a widely used anticancer agent, the clinical applications of which have been limited by severe nephrotoxicity. Although dosing time-dependent differences in CDDP-induced nephrotoxicity have been reported in both humans and laboratory animals, the underlying mechanism remains unknown. In the present study, we investigated the molecular mechanism for the dosing-time dependency of the nephrotoxic effect of CDDP in mice. CDDP-induced nephrotoxicity was significantly attenuated by injecting CDDP at times of the day when its renal clearance was enhanced. The dosing-time dependency of the nephrotoxic effect was parallel to that of CDDP incorporation into renal DNA. Two types of transporters, organic cation transporter 2 (OCT2, encoded by Slc22a2) and multidrug and toxin extrusion 1 (MATE1, encoded by Slc47a1), are responsible for the renal excretion of CDDP. The expression of OCT2, but not MATE1, exhibited a significant time-dependent oscillation in the kidneys of mice. The circadian expression of OCT2 was closely related to the dosing-time dependency of CDDP incorporation into renal DNA. Molecular components of the circadian clock regulated the renal expression of Slc22a2 mRNA by mediating peroxisome proliferator-activated receptor-α, which resulted in rhythmic oscillations in OCT2 protein levels. These findings indicate a clock-regulated mechanism of dosing time-dependent changes in CDDP-induced nephrotoxicity and also suggest a molecular link between the circadian clock and renal xenobiotic excretion.

Chronotherapy in hypertension

Blunted blood pressure (BP) decline during night-time leads to the higher risk of cardiovascular events in hypertensive patients. Therefore, to improve the prognosis of the patients, it is essential for properly controlling BP during night-time sleep as well as day-time activity. In addition, the dosing-time dependent changes are observed in the pharmacokinetics and pharmacodynamics of some antihypertensive drugs. Thus, the efficacy and toxicity of drugs might be affected by their dosing-time. Chronotherapy is the therapeutic application of chronopharmacology and chronotoxicology to enhance the effectiveness and tolerance of drugs by determining optical dosing-time of drugs from a circadian perspective. In this article, chronotherapy of angiotensin-converting enzyme inhibitor, Ca channel blocker, α1 blocker, diuretics and angiotensin II receptor blocker will be discussed.

Dosing-Time Dependence of Lethal Toxicity Induced by Nitroprusside in Young Mice

Sodium nitroprusside (SNP) is a potent vasodilator and is commonly used as an antihypertensive agent in postoperative cardiac surgical patients. In this study, we investigated whether the SNP-induced lethality is influenced by the dosing-time. Mortality was induced by administering SNP in different doses (4.9, 5.4, 6.0, 6.6 mg/kg, i.p.) to Swiss albino mice, 2 to 8 weeks old, synchronized for at least 2 weeks by 12 h light (rest)/12 h dark (activity) span. Each dose was administered to comparable groups of animals (n= 6) at six different circadian times: 1, 5, 9, 13, 17, and 21 hours after light onset (HALO). Both ?2 and cosinor methods were used to analyze the time series data. Statistically significant dosing time-dependent changes were validated in the daily scale with the males more sensitive than females. A ultradian (? = 12 h) rhythm was detected by cosinor (P < 0.002) for each of the three administered doses (4.9, 5.4, 6.0 mg/kg) in 2 week old mice of both genders. Moreover, in addition to the ultradian rhythm, a significant (P < 0.004) circadian (? = 24 h) component had been detected in 6 mg/kg SNP-treated male mice. However, there was only a circadian rhythm detected in 4 and 8 weeks old mice after acute SNP (6.0, 6.6 mg/kg) treatment, with peak time located at ? 21 and ? 17 HALO, respectively. In conclusion, tolerance to nitroprusside varies not only according to the circadian time but also according to the dose, age, and gender of animal.

Glucocorticoid-Dependent Expression ofO6-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

O(6)-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against the alkylating agent-induced cytotoxic lesion O(6)-alkylguanine in DNA. Although a significant circadian variation in MGMT activity has been found in the liver of mice, the exact mechanism of the variation remains poorly understood. In this study, we present evidence that glucocorticoids were required for the 24-h oscillation of MGMT expression in mouse liver. The exposure of mouse hepatic cells (Hepa1-6) to dexamethasone (DEX) significantly increased the mRNA levels of MGMT in a dose-dependent manner. The DEX-induced increase in MGMT expression was reversed by concomitant treatment with RU486 [11beta-[p-(dimethylamino) phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], a glucocorticoid receptor antagonist. The mRNA levels of MGMT and its enzymatic activity in the liver of mice showed significant 24-h oscillations, which were not observed in adrenalectomized mice. A single administration of DEX to adrenalectomized mice significantly increased the mRNA levels of MGMT in the liver. These findings suggest that the 24-h oscillation in the hepatic expression of MGMT is caused by the endogenous rhythm of glucocorticoid secretion. Dacarbazine (DTIC), a potent O(6)-guanine-alkylating agent, causes serious hepatotoxicity accompanied by hepatocellular necrosis and hepatic vein thrombosis. DTIC-induced hepatotoxicity in mice was attenuated by administering the drug at the time of day when MGMT expression was abundant. The present findings suggest that glucocorticoid-regulated oscillation in the hepatic MGMT expression is the underlying cause of dosing time-dependent changes in DTIC-induced hepatotoxicity.

Basis for dosing time-dependent change in the anti-allodynic effect of gabapentin in mice

Basis for dosing time-dependent change in the anti-allodynic effect of gabapentin in mice

Basis for dosing time-dependent change in the anti-tumor effect of imatinib in mice

Because a variety of receptor tyrosine kinases are involved in the mechanism of tumor progression, the development of a clinically useful tyrosine kinase inhibitor is expected as a therapeutic agent for the treatment of malignant cancers. Imatinib mesylate, known as Gleevec or STI-571, is a molecule that inhibits the function of various receptors with tyrosine kinase activity, such as Abl, the bcr–abl chimeric product, KIT, and platelet-derived growth factor (PDGF) receptors. In this study, we investigated the influence of dosing time on the ability of imatinib to inhibit tumor growth in mice. Tumor-bearing mice were housed under standardized light/dark cycle conditions (lights on at 07:00 h, off at 19:00 h) with food and water ad libitum. The growth of tumor cells implanted in mice was more severely inhibited by the administration of imatinib (50 mg/kg, i.p.) in the early light phase than when it was administered in the early dark phase. The dosing time-dependency of anti-tumor effects was parallel to that of imatinib-induced anti-angiogenic effect. The inhibitory effect of imatinib on tyrosine kinase activity of PDGF receptors, but not of KIT and Abl, varied according to its administration time. The dosing time-dependency of imatinib-induced inhibition of PDGF receptor activity was closely related to that of its anti-tumor effects. Our results suggest that the anti-tumor efficacy of imatinib is enhanced by administering the drug when PDGF receptor activity was increased. The potent therapeutic efficacy of the drug could be expected by optimizing the dosing schedule.

Diurnal rhythms in quinpirole-induced locomotor behaviors and striatal D2/D3 receptor levels in mice

Dopaminergic drugs, including the D2/D3 agonist quinpirole, produce lasting changes in the brain that lead to altered behavioral responses. The action of these drugs is dosing time-dependent; in fruit flies, behavioral response to quinpirole shows a marked circadian variability. Here we demonstrate diurnal rhythm-dependent variations both in quinpirole-induced locomotor behaviors and in striatal D2 and D3 protein levels in mice. We found opposing diurnal rhythms in striatal D2 and D3 protein levels, resulting in a high D2/D3 ratio during the day and a low D2/D3 ratio at night. Protracted quinpirole treatment differentially altered striatal D2/D3 rhythms depending on the time of injection (i.e., day or night). When quinpirole-induced locomotor activity was analyzed for 90 min, we found hypomotility after the first day or nighttime drug injection. By the seventh injection, daytime quinpirole treatment produced clear hyperactivity while nighttime quinpirole treatment continued to induce a significant initial hypoactivity followed by a hyperactivity period. Our data indicate that quinpirole-induced long-term alterations in the brain include dosing time-dependent changes in dopamine receptor rhythms. Therefore, we propose that diurnal mechanisms, which participate in drug-induced long-term changes in the dopamine system, are important for the development of dopaminergic behaviors.

Chronopharmacology of melatonin in mice to maximize the antitumor effect and minimize the rhythm disturbance effect.

The influence of dosing time on the antitumor effect and the rhythm disturbance effect of melatonin (MLT) was investigated in ICR male mice under a light/dark (12:12) cycle. In tumor-bearing mice, the antitumor effect of MLT (1 mg/kg intraperitoneal) was most effective in the dark phase; and the rhythm disturbance effect of MLT on the locomotor activity was more serious in the light phase than in the dark phase. The antitumor effect and the rhythm disturbance effect of MLT increased when the specific binding of MLT receptor in target tissues, tumor or suprachiasmatic nucleus, increased and they decreased when the level decreased. Furthermore, because luzindole, an MT1 and MT2 blocker, caused the antitumor effect or rhythm disturbance effect of MLT to decrease, it is suggested that the time-dependent change of the pharmacological effects of MLT were influenced by that of MLT receptor(s) function. On the other hand, there was no significant dosing time-dependent change of MLT concentration in tumor or brain after injection. Thus, the pharmacokinetic factor does not seem to contribute to the dosing time-dependent effect of MLT. These results suggest that by choosing the most suitable dosing time for MLT, the efficacy of the drug can be increased, and the toxicity of the drug can be decreased in certain experimental and clinical situations.

Optimizing the dosing schedule of TNP-470 [O-(chloroacetyl-carbamoyl) fumagillol] enhances its antitumor and antiangiogenic efficacies.

Many drugs vary in potency and/or toxicity according to the time of day when they are administered. In this study, we investigated whether antitumor efficacy of angiogenesis inhibitor, TNP-470 [O-(chloroacetyl-carbamoyl) fumagillol], could be improved by optimizing the dosing schedule. Tumor-bearing mice were housed under standardized light/dark cycle conditions (lights on at 7:00 AM, off at 7:00 PM) with food and water ad libitum. The antitumor effect of TNP-470 (30 mg/kg s.c.) was more potent in mice injected with the drug at the early light phase than it was when administered at the early dark phase. The diurnal change in the antitumor effect of TNP-470 was parallel to that in its antiangiogenic activity. The variation in the effects of TNP-470 was closely related to the diurnal variations in its inhibitory action on methionine aminopeptidase activity in tumor masses. There was a significant dosing time-dependent change in the concentration of TNP-470 in plasma. The higher concentration of TNP-470 in plasma was observed when its antitumor and antiangiogenic activities were increased. These results suggest that therapeutic efficacy of TNP-470 can be enhanced by choosing the most appropriate time of day to administer the drug.

Relationship Between 24-Hour Rhythm in Antiviral Effect of Interferon-β and Interferon-α/β Receptor Expression in Mice

The influence of interferon-beta (IFN-beta) dosing time on antiviral activity was investigated in ICR male mice under light-dark cycle conditions (lights on at 07:00, off at 19:00) with food and water available ad libitum. There was a significant dosing time-dependent change in 2',5'-oligoadenylate synthetase (2',5'-OAS) activities, as an index of antiviral activity, in liver at 12 h after IFN-beta (15 MIU/kg, i.v.) injection. IFN-beta-induced 2',5'-OAS activity was more potent after the drug injection during the late dark phase. The higher antiviral effect of IFN-beta was observed when the interferon-alpha/beta receptor (IFNAR) expression in the liver increased, and the lower effect was observed when its expression decreased. IFN-beta-induced fever was more serious after IFN-beta injection from the late dark phase to the early light phase. A significant dosing time-dependent change was demonstrated for plasma IFN-beta concentrations, which showed a higher level during the light phase and a lower level during the dark phase. The dosing time-dependent change of plasma IFN-beta concentrations was not associated with that of the antiviral effect or fever induced by IFN-beta. These results suggest that selecting the most suitable dosing time of IFN-beta, associated with the 24-h rhythm of IFNAR expression in the liver, may be important to increase effectively the antiviral activity of the drug in experimental and clinical situations.

Contribution of diet to the dosing time-dependent change of vitamin D3-induced hypercalcemia in rats

We have recently reported that the degree of hypercalcemia as an adverse effect induced by a single large-dose of active vitamin D3 varied with its dosing time without alteration in therapeutic effect for secondary hyperparathyroidism in patients with chronic renal failure. The present study was conducted to elucidate an effect of intestinal calcium (Ca) absorption on the chronopharmacological profiles of vitamin D3. 1, 25-dihydroxy-cholecalciferol (D3, 2 μg/kg) or vehicle alone was orally administered at two different times (2 and 14 hours after lights on; HALO) to male Wistar rats (n=10) kept in rooms with a 12 h light-dark cycle. Blood samples for serum Ca concentration were taken before and 3, 6, 9, and 12 hours after the administration. Urine was collected for 6 hours after dosing. An identical protocol was repeated using the same animals after 16 hours fasting by a cross-over fashion. Under free-fed condition, basal concentration of serum Ca was higher at a resting period (lights on) than during an active period (lights off). Serum Ca reached its peak at 6 hours after dosing in both timings, while the value was significantly higher in the 2 HALO trial than in the 14 HALO trial. Area under the serum Ca concentration-time curve from 0 to 12 hours (AUC0-12h) and urinary excretion of Ca for 6 hours were also significantly higher in the 2 HALO trial than in the 14 HALO trial. When fasted, basal Ca concentration was reduced compared with the free-fed condition, while the daily variation was maintained. Serum Ca concentration profiles from 3 to 12 hours after dosing were not significantly different between the 2 HALO and 14 HALO trials. The AUC0-12h of serum Ca or its urinary excretion was not different between both trials. Serum concentrations of parathyroid hormone and total protein, measured before and 6 hours after the dosing were not affected by the dosing schedule. We have concluded that intestinal Ca absorption is a major factor for the chronopharmacological phenomenon of D3-induced hypercalcemia in intact rats, while intestinal and renal involvement may be relatively small in the mechanism of the intrinsic diurnal variation of serum Ca.

Basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol.

The objective of the present study was to determine the basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol in pigmented rabbits. The gamma scintigraphic technique was used to monitor the changes in precorneal solution retention following instillation. Changes in timolol concentration in the plasma over 120 min and in various anterior segment eye tissues at 30 min following the topical instillation of 25 microliters of 0.65% timolol maleate solutions at various dosing times were monitored using reversed phase HPLC. Corneal and conjunctival permeability at various dosing times was evaluated in the modified Ussing chamber. The results indicated that precorneal solution drainage was slowest at noon. Suppressing tear production by anesthesia led to an increase in ocular timolol absorption at 6 a.m. but not at other dosing times, in spite of the lowest corneal permeability then. There was no statistically significant dosing time influence on systemic timolol absorption following nasal or conjunctival dosing. In conclusion, possible diurnal changes in precorneal solution clearance may be the main factor underlying the diurnal changes in ocular as well as systemic timolol absorption in rabbits. In addition, diurnal changes in corneal permeability may also contribute to diurnal changes in ocular timolol absorption.

Concepts in chronopharmacology.

Circadian and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical and chemical agents including medications and foods are rather common phenomena. Time-related differences in drug effects depend upon endogenous circadian rhythms, which include metabolic pathways. In addition, chronopharmacology investigates drug effects on parameters (e.g. circadian period, peak time, amplitude, and adjusted mean) used to characterize biological rhythms. A better understanding of periodic and thus predictable changes in drug effects can be attained by consideration of complementary concepts: (a) The chronokinetics for a drug, i.e. dosing time-dependent and predictable (rhythmic) changes in parameters used to characterize the pharmacokinetics (or the bioavailability) of a drug, e.g. Cmax, tmax, AUC, and t1/2; (b) the chronesthesy, i.e. rhythmic changes in susceptibility of the target biosystem to this drug, including CR in pharmacodynamic processes; and (c) the chronergy, i.e. the drug-integrated overall effect. One of the aims of chronopharmacology refers to the use of a chronopharmacological approach to clinical treatment so as to enhance both effectiveness and tolerance of a drug by determining the best biological time for its administration.

Concepts of Circadian Chronopharmacology

Circadian and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical as well as chemical agents including medications and foods are rather common phenomena. Modern chronopharmacology investigates drug effects (a) as a function of biological timing and (b) upon parameters characterizing the endogenous bioperiodicities. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of complementary concepts: (1) the chronokinetics of a drug--dosing time-dependent and predictable (rhythmic) changes in parameters used to characterize the pharmacokinetics (or the bioavailability) of a drug, e.g., maximum concentration (Cmax), span of time to reach Cmax (tmax), area under the concentration-time curve (AUC), half-life (t1/2), etc.; (2) the chronesthesy (rhythmic changes in susceptibility of a target biosystem to this drug); and (3) the chronergy (the drug-integrated overall effects). One of the aims of chronopharmacology is solving problems of drug optimization. Chronotherapy refers to the use of a chronopharmacologic approach to clinical treatment so as to enhance both effectiveness and tolerance of a drug by determining the best biological time for its dosing.