Chronopharmacokinetics of oral tegafur and uracil in colorectal cancer patients

Uracil-Ftorafur (UFT) combines the 5-fluorouracil (FU) prodrug tegafur with uracil (at a 1:4 molar ratio), which is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the limiting enzyme of FU catabolism. As a result, sustained FU concentrations are obtained in both plasma and tumor. UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic and adjuvant colorectal cancer treatment. A circadian rhythm for DPD activity has been shown in both human and animal studies, with consequences on FU plasma concentrations in patients receiving FU as a continuous infusion. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine and FU infusions, suggesting that such schedules may improve the fluoropyrimidine therapeutic index. Molecular mechanisms responsible for the circadian dependence of FU pharmacodynamics include circadian rhythms in thymidylate synthase activity and DNA synthesis, as recently reported. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.     

Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery?

Due to advances in chronobiology, chronopharmacology, and global market constraints, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. The last decade has witnessed the emergence of ChrDDS against several diseases. The increasing research interest surrounding ChrDDS may lead to the creation of a new sub-discipline in pharmaceutics known as chronopharmaceutics. This review introduces the concept of chronopharmaceutics, addresses theoretical/formal approaches to this sub-discipline, underscores potential disease-targets, revisits existing technologies and examples of ChrDDS. Future development in chronopharmaceutics may be made at the interface of other emerging disciplines such as system biology and nanomedicine. Such novel and more biological approaches to drug delivery may lead to safer and more efficient disease therapy in the future.     

Current status and approaches to developing press-coated chronodelivery drug systems

The past several decades have seen the development of many controlled-release preparations featuring constant release rates to maintain drug concentrations in the human body, regardless of the patient's physiological condition. However, long-term constant drug concentrations in the blood and tissue can cause problems such as resistance, tolerability, and drug side effects. People vary considerably in their physiological and biochemical conditions during any 24 h period, due to the circadian rhythm, and thus, the constant delivery of a drug into the body seems both unnecessary and undesirable. If the drug release profile mimics a living system's pulsatile hormone secretion, then it may improve drug efficacy, and reduce the toxicity of a specific drug administration schedule. Medication and treatments provided according to the body's circadian rhythms will result in better outcomes. This may be provided by a chronopharmaceutical dosage regimen with pulsatile release that matches the circadian rhythm resulting from a disease state, so optimizing the therapeutic effect while minimizing side effects. The press coating technique is a simple and unique technology used to provide tablets with a programmable lag phase, followed by a fast, or rate-controlled, drug release after administration. The technique offers many advantages, and no special coating solvent or coating equipment is required for manufacturing this type of tablet. The present review article introduces chronopharmaceutical press-coated products from a patient physiological needs perspective. The contents of this article include biological rhythms and pulsatile hormone secretion in humans, the reasons for using pulsatile drug delivery for disease treatment, recent chronopharmaceutical preparations appearing on the market, updated compilation of all research articles and press-coated delivery techniques, factors affecting the performance and drug release characteristics of press-coated delivery systems, and recent challenges for the press coating technique. We also provide a brief overview of press-coating approaches intended for chronotherapy.     

Chronopharmacology

The time of day that drugs are given can have a profound effect upon both their pharmacodynamics, i.e. their effectiveness and toxicity, and their pharmacokinetics, i.e. the way they themselves behave in the body. The chronopharmacokinetics of relatively few drugs have been investigated and are mostly those used for the treatment of cancer. We have shown that the toxicity and chronopharmacokinetics of drugs can be altered by pretreatment with steroids or melatonin.     

The circadian timing system in clinical oncology

Abstract

The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest– activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P = 0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients.     

The cardiovascular system and daily variation in response to antihypertensive and antianginal drugs: recent advances.

This review contains recent data on the pharmacokinetics and the hemodynamic effects on heart rate and blood pressure of three different groups of drugs (beta-blockers: propranolol; oral nitrates: isosorbide-dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN); calcium channel blockers: nifedipine) which were investigated in healthy volunteers or in hypertensive patients after drug application at different times of the day. In the case of IS-5-MN and nifedipine two different galenic formulations were studied. The results clearly demonstrate chronopharmacokinetics for propranolol, ISDN, and the immediate-release formulations of IS-5-MN and nifedipine, whereas no pharmacokinetic daily variations were observed with the sustained-release formulations. However, all drugs exhibited daily variations in their hemodynamic effects. These data greatly support the view that pharmacokinetics and drug effects should be studied simultaneously when chronopharmacologic studies are performed.     

The influence of dosage time of midazolam on its pharmacokinetics and effects in humans.

The influence of dosage time of midazolam on its pharmacokinetics and effects on the central nervous system were investigated in six healthy volunteers, with pharmacokinetic-pharmacodynamic modeling. Each volunteer received single oral doses of 15 mg midazolam on four separate occasions: 8 AM, 2 PM, 8 PM, and 2 AM. An almost significant circadian variation was found in elimination half-life, shortest at 2 PM (1.26 +/- 0.47 hours, mean +/- SD) and longest at 2 AM (1.57 +/- 0.44 hours) (p = 0.05). Drug effects measured were alpha activity of the electroencepalograph and P100 latency of the visual-evoked response. The maximum drug effect (Emax) model described the concentration-effect relationship, extended with either a threshold drug concentration or a sigmoidicity parameter. A significant circadian variation was found in baseline alpha activity: highest at 8 AM (109% +/- 19% of the 24-hour mean) and lowest at 2 AM (80% +/- 12%). For alpha activity the drug concentration at half-maximum effect of both threshold Emax model and sigmoid Emax model showed lower values at 8 AM and 2 AM and higher values at 2 PM and 8 PM. However, these differences were either not significant (p = 0.10, threshold model) or on the verge of statistical significance (p = 0.05, sigmoid model). No circadian variation was found in the parameters describing the effect on the visual-evoked response. We conclude that the sensitivity of the central nervous system to midazolam, as reflected in alpha activity, possibly shows a circadian variation.     

Chronopharmacokinetics of dexamethasone in young subjects]

Dexamethasone chronopharmacokinetics was studied in six young subjects 20 to 30 years old. The randomized cross-over study consisted of evening (11.00 p.m.) or morning (08.00 a.m.) dose separated by a period of one week. After the evening administration of the drug, only Tmax (1.77 +/- 0.74 à 11.00 p.m. and 0.99 +/- 0.64 à 08.00 a.m.) and Cmax/Tmax were higher than those determined at 08.00 a.m. This difference might be related to a cyclic variation of the absorption phase of dexamethasone. Thus, in our study, the time of administration has only a weak effect on the pharmacokinetics of dexamethasone.     

Circadian variation in number and affinity of beta 2-adrenoceptors in lymphocytes of asthmatic patients

To determine whether circadian variation in adrenoceptor function might underlie the 'morning dip' in peak expiratory flow (PEF) rate and its abolition by salbutamol we measured indices of beta-adrenoceptor function (Bmax. and Kd), the ratio FEV1/FVC, and plasma cortisol at 08.00 and 18.00 hours on and off salbutamol (4 mg given orally every 4 h) in five extrinsic asthmatic patients and five normal volunteers. There was a significant circadian variation in receptor numbers (Bmax.) in both the control and asthmatic groups which was not abolished on treatment with salbutamol. Both groups appeared to compensate for loss of receptor number induced by salbutamol administration by increasing receptor affinity. For comparable combinations of drug/time, there was no significant difference between the control and asthmatic groups. We conclude that the 'morning dip' observed in asthmatic patients cannot simply be explained by changes in cell receptor number or affinity, as our results suggest that both groups have intact beta-adrenoceptor function. Nevertheless, our observations of the normal circadian rhythm has important implications for future studies of beta-adrenoceptors in asthmatic patients.     

CLUSTER AND TRIGEMINAL AUTONOMIC CEPHALALGIAS

The suprachiasmatic nucleus (SCN) of the hypothalamus has been termed the master circadian pacemaker of mammals. Recent discoveries of damped circadian oscillators in other tissues have led to the hypothesis that the SCN synchronizes and sustains daily rhythms in these tissues. We studied the effects of constant lighting (LL) and of SCN lesions on behavioral rhythmicity and Period 1 (Per 1) gene activity in the SCN and olfactory bulb (OB). We found that LL had similar effects on cyclic locomotor and feeding behaviors and Per 1 expression in the SCN but had no effect on rhythmic Per 1 expression in the OB. LL lengthened the period of locomotor and SCN rhythms by approximately 1.6 hr. After 2 weeks in LL, nearly 35% of rats lost behavioral rhythmicity. Of these, 90% showed no rhythm in Per 1-driven expression in their SCN. Returning the animals to constant darkness rapidly restored their daily cycles of running wheel activity and gene expression in the SCN. In contrast, the OB remained rhythmic with no significant change in period, even when cultured from animals that had been behaviorally arrhythmic for 1 month. Similarly, we found that lesions of the SCN abolished circadian rhythms in behavior but not in the OB. Together, these results suggest that LL causes the SCN to lose circadian rhythmicity and its ability to coordinate daily locomotor and feeding rhythms. The SCN, however, is not required to sustain all rhythms because the OB continues to oscillate in vivo when the SCN is arrhythmic or ablated.
Comments: As the central generator for cluster appears to be near the hypothalamic circadian nuclei (May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology. 2000;55:1328-1335), it behooves us to follow the work on understanding the training of circadian and circannual rhythms in order to better understand cluster. Stewart J. Tepper     

Circadian phase resetting in older people by ocular bright light exposure.

BACKGROUND: Aging is associated with frequent complaints about earlier bedtimes and waketimes. These changes in sleep timing are associated with an earlier timing of multiple endogenous rhythms, including core body temperature (CBT) and plasma melatonin, driven by the circadian pacemaker. One possible cause of the age-related shift of endogenous circadian rhythms and the timing of sleep relative to clock time is a change in the phase-shifting capacity of the circadian pacemaker in response to the environmental light-dark cycle, the principal synchronizer of the human circadian system. METHODS: We studied the response of the circadian system of 24 older men and women and 23 young men to scheduled exposure to ocular bright light stimuli. Light stimuli were 5 hours in duration, administered for 3 consecutive days at an illuminance of approximately 10,000 lux. Light stimuli were scheduled 1.5 or 3.5 hours after the CBT nadir to induce shifts of endogenous circadian pacemaker to an earlier hour (phase advances) or were scheduled 1.5 hours before the CBT nadir to induce shifts to a later hour (phase delays). The rhythms of CBT and plasma melatonin assessed under constant conditions served as markers of circadian phase. RESULTS: Bright light stimuli elicited robust responses of the circadian timing system in older people; both phase advances and phase delays were induced. The magnitude of the phase delays did not differ significantly between older and younger individuals, but the phase advances were significantly attenuated in older people. CONCLUSIONS: The attenuated response to light stimuli that induce phase advances does not explain the advanced phase of the circadian pacemaker in older people. The maintained responsiveness of the circadian pacemaker to light implies that scheduled bright light exposure can be used to treat circadian phase disturbances in older people.     

A novel approach for constant rate delivery of highly soluble bioactives from a simple monolithic system.

A novel monolithic drug delivery system for highly water-soluble bioactive agents to follow pH-independent zero-order kinetics is described. The system utilizes a hydrophilic gel-based swellable polymeric material (polyethylene oxide), a model drug (metoprolol tartrate, 100% water soluble at 25 degrees C) and different electrolytes, such as sodium carbonate and/or pentasodium tripolyphosphate. Based on the induction of in situ intra-gel chemical reactions between different ionic species, drug and polymer, a heterogeneous structure manifested as 'peripheral boundary stiffening,' is accomplished. The consequence of these interactions essentially include the development of gradient-controlled matrix swelling as elucidated through textural profiling, which may contribute to inhibition of drug solubility and its outward diffusion. Analysis of textural profiles and photomicroscopy distinctly provides information on the disposition of peripheral boundary densification for the electrolyte-containing matrices. Electrolytic conductivity measurements performed with the simultaneous analysis of matrix swelling showed that sodium carbonate forms a highly reactive matrix within the first 3 h of medium penetration. On the other hand, larger molecules such as pentasodium tripolyphosphate maintain a constant conductivity level, which may be related to its lower solubility and diffusion in comparison to sodium carbonate. Based on model fitting and statistical analysis, it is shown that drug release kinetics were adequately described by M(t)/M(infinity)=k(0)t, with zero-order release rate constant k(0) of 0.054 h(-1). This novel approach in formulation development could potentially be used for constant rate delivery of highly soluble bioactive agents over an extended period for specific biopharmaceutical needs.     

In situ electrolyte interactions in a disk-compressed configuration system for up-curving and constant drug delivery.

A new approach in drug delivery system design for meeting the needs that are associated with certain circadian variations is presented. The system is comprised of a pure compressed drug disk, which is encased by a polymeric coat using hydroxypropylmethylcellulose or polyethylene oxide. Within the polymeric coat, a physiologically acceptable binary electrolyte combination such as sodium deoxycholate and adipic acid is disposed. Through this process and upon exposure to dissolution media, ionic interactions occur and a texturally variable matrix is manifested in the form of peripheral stiffening' with self-correcting boundaries as demonstrated by texture analysis studies. The peripheral boundaries erode and progressively shift toward the disk-core, thus constantly reducing the diffusional pathlength with the resultant up-curving kinetics. Utilizing these mechanisms, a lag time is induced and drug is delivered over a 24-h period in one of two ways namely, in an up-curving or constant manner for drug models theophylline and diltiazem hydrochloride with water solubilities of 0.85% and > 50% at 25 degrees C, respectively. It appears that for both sparingly and highly soluble drugs, sum of the dissolution/diffusion rates, dynamics of diffusional pathlength and system erosion rate control the release process. The heterogeneous nature of changes in coat thickness, stiffening dynamics and erosion rate in relation to disk geometry is discussed. The developed technology has potential to provide release patterns, compatible with specific chronophysiological conditions, and overcome the absorption-limited capacity of the distal gastrointestinal tract     

Discrepancy between circadian rhythms of inulin and creatinine clearance.

To elucidate the disparity between circadian rhythmicity of inulin and creatinine clearance, we simultaneously measured inulin and creatinine clearances every 3 hours during 1 day in 14 normal subjects and in 8 patients with nephrotic syndrome. All patients and normal subjects had a circadian rhythm for inulin clearance with a maximum during daytime and a relative amplitude of 21% +/- 2%. For creatinine clearance a rhythm was either absent or reduced in relative amplitude (p less than 0.01). In all subjects the rate of tubular creatinine secretion was higher at minimum of inulin clearance (night) than at maximum (day). The fractional clearance (relative to inulin) of creatinine was also higher during the night: normal subjects, 1.28 +/- 0.02 versus 1.10 +/- 0.02; patients, 1.78 +/- 0.08 versus 1.45 +/- 0.05 (p less than 0.005). This demonstrates the inaccuracy of creatinine clearance as a measure of glomerular filtration rate (GFR). By subsequent blocking of the tubular secretion of creatinine with cimetidine in four normal subjects, creatinine clearance became similar to inulin clearance during day and night. This confirms that high tubular secretion of creatinine during the night counteracts the normal rhythmicity of glomerular filtration of creatinine. As a result, plasma creatinine concentration is nearly constant during a 24-hour period. In conclusion, tubular creatinine secretion has a circadian rhythm with a phase opposite to the rhythm of GFR, thus blunting or causing absence of a circadian rhythm for creatinine clearance.     

Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice

The toxicities and tissue uptake of cisplatin (CDDP) and carboplatin (CBDCA) vary largely according to the time of injection of a single dose. Repeated dosages may alter the mechanisms involved with such circadian-dependent toxicity. Weekly i.v. injections of CDDP (5 mg/kg) or CBDCA (50 mg/kg) were given over 2 months to 288 male B6D2F1 mice standardized by an alternation of 12 hr of light and 12 hr of darkness at any one of three circadian dosing times (0, 8 or 16 hr after light onset--HALO). Survival; body weight; complete blood cell counts; histologic lesions in kidney, liver, spleen, bone marrow and intestinal tract; platinum concentration in kidney, spleen and colon were determined every 2 weeks throughout treatment. Thrombocytopenia was 10-fold larger following CBDCA as compared with CDDP. Severe bone marrow necrosis was cumulative following CDDP, but reversible following CBDCA. Leukopenia and bone marrow lesions were, respectively, half as severe following the dosing of either drug at 16 HALO compared with 0 or 8 HALO. Cortical tubular necrosis was observed in CDDP-treated mice. It was cumulative and half as extensive after drug dosing at 16 HALO, as compared with 0 or 8 HALO (P less than or equal to .05). Total Pt accumulation in all three tissues was 3- to 4-fold higher following repeated dosages of CDDP as compared with CBDCA. Tissue Pt uptake was halved after CDDP or CBDCA dosing at 16 HALO as compared with 8 HALO (P less than or equal to .01). Dosing either Pt complex at the appropriate time is even more critical if administrations are to be repeated. Mechanisms appear to involve the circadian rhythm-dependent ability of target tissues to take up the drug.     

An inhibitor of casein kinase I epsilon induces phase delays in circadian rhythms under free-running and entrained conditions

Casein kinase Iepsilon (CKIepsilon) is an essential component of the biological clock, phosphorylating PER proteins, and in doing so regulating their turnover and nuclear entry in oscillator cells of the suprachiasmatic nucleus (SCN). Although hereditary decreases in PER phosphorylation have been well characterized, little is known about the consequences of acute enzyme inhibition by pharmacological means. A novel reagent, 4-[3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamine (PF-670462), proved to be both a potent (IC(50) = 7.7 +/- 2.2 nM) and selective (>30-fold with respect to 42 additional kinases) inhibitor of CKIepsilon in isolated enzyme preparations; in transfected whole cell assays, it caused a concentration-related redistribution of nuclear versus cytosolic PER. When tested in free-running animals, 50 mg/kg s.c. PF-670462 produced robust phase delays when dosed at circadian time (CT)9 (-1.97 +/- 0.17 h). Entrained rats dosed in normal light-dark (LD) and then released to constant darkness also experienced phase delays that were dose- and time of dosing-dependent. PF-670462 yielded only phase delays across the circadian cycle with the most sensitive time at CT12 when PER levels are near their peak in the SCN. Most importantly, these drug-induced phase delays persisted in animals entrained and maintained in LD throughout the entire experiment; re-entrainment to the prevailing LD required days in contrast to the rapid elimination of the drug (t(1/2) = 0.46 +/- 0.04 h). Together, these results suggest that inhibition of CKIepsilon yields a perturbation of oscillator function that forestalls light as a zeitgeber, and they demonstrate that pharmacological tools such as PF-670462 may yield valuable insight into clock function.     

Neuropeptide Y and its receptors as potential therapeutic drug targets

Neuropeptide Y (NPY) is a 36-amino-acid peptide that exhibits a large number of physiological activities in the central and peripheral nervous systems. NPY mediates its effects through the activation of six G-protein-coupled receptor subtypes named Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). Evidence suggests that NPY is involved in the pathophysiology of several disorders, such as the control of food intake, metabolic disorders, anxiety, seizures, memory, circadian rhythm, drug addiction, pain, cardiovascular diseases, rhinitis, and endothelial cell dysfunctions. The synthesis of agonists and antagonists for these receptors could be useful to treat several of these diseases.     

The importance of circadian rhythms on drug response in hypertension and coronary heart disease--from mice and man

The cardiovascular system is highly organised in time; blood pressure (BP), heart rate (HR), peripheral resistance, pressure and the release/activity of vasodilating hormones all display pronounced circadian variations. Pathophysiological events within the cardiovascular system are also not random, as shown for instance by sudden cardiac death (SCD), stroke, ventricular arrhythmias (VA), arterial embolism, and symptoms of coronary heart disease (CHD) such as myocardial infarction (MI) and ischemia, angina attacks (AA) in stable angina (stA) or variant angina (varA) or silent ischemia. In hypertensive patients various anti-hypertensive drugs were investigated in crossover studies (morning vs. evening dosing); however consistent data were only obtained for angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Whereas in dippers ACE inhibitors had a super-dipping effect when dosed at night, no consistent difference in BP lowering effect on the 24-hr BP profile was found with calcium channel blockers after morning and evening dosing. In non-dippers the calcium channel blockers isradipine and amlodipine consistently transformed non-dippers into dippers, after evening dosing. Diuretics are also able to normalize a non-dipping behaviour. Moreover, a circadian phase-dependency in pharmacokinetics has been demonstrated for various cardiovascular active drugs such as beta-blockers, calcium channel blockers, oral nitrates and ACE inhibitors, modified by the pharmaceutical formulation. There is evidence that in hypertensive dippers anti-hypertensive drugs should be given in the early morning, whereas in non-dippers it may be necessary to add an evening dose or even to use a single evening dose in order to not only reduce high BP but also to normalize a disturbed non-dipping 24 hr BP profile. In CHD, calcium channel blockers-mainly short acting and non-retarded preparations-seem to be less effective than beta-adrenoceptor antagonists in reducing ischemic events during the night and early morning. However, the role of formulation and/or subclasses of the calcium channel blockers remains to be elucidated. In order to get more insight into the circadian regulation of the cardiovascular system animal models of primary and secondary hypertension have been studied in various strains of normotensive and hypertensive rats and mice. At least in rodents there is ample evidence that the 24-hr rhythms in BP and HR are under the control of biological clock(s) as they persist under constant darkness (i.e. in free-run conditions) with a period deviating from 24 hr; these rhythms are abolished by lesioning of the "master clock" located in the suprachiasmatic nuclei (SCN). In conclusion, chronobiological and chronopharmacological studies are important experimental and clinical approaches to get a better insight into the physiological and pathophysiological regulation of the cardiovascular system including their rhythmic organisation. Circadian time-dependent clinical studies also have implications for drug therapy in hypertension and CHD.