Understanding the role of chronopharmacology for drug optimization: what do we know?

INTRODUCTION: Circadian rhythm influences the pharmacokinetics and pharmacodynamics of a number of drugs and affects their therapeutic efficacy and toxicity depending on the time of day they are administered. Chronopharmacology is a method for incorporating knowledge about circadian rhythm into pharmacotherapy. Chronotherapy, which is the clinical application of chronopharmacology, is particularly relevant when the risk and/or severity of symptoms of a disease change in a predictable manner over time. Chronotherapy has potential benefits in the treatment of many diseases. AREAS COVERED: Although a considerable amount of knowledge about chronopharmacology and chronotherapy has been accumulated, its therapeutic application in clinical practice remains limited in terms of therapy optimization. Resolution of these issues will improve our ability to deliver adequate drug treatment. EXPERT OPINION: We propose four approaches for promoting chronotherapy-based drug treatment in clinical practice: targeting drug development and regulatory authorities; education about chronotherapy; drug information for both health professionals and consumers; and a chronotherapy network.

Edoxaban Dosing Time Affects Blood Coagulation Inhibition in Rats.

Coagulation-fibrinolytic system activity shows daily rhythmicity, with hypercoagulability in the morning and hypocoagulability in the evening. Consequently, the efficacy of anticoagulants may be influenced by their dosing time. Edoxaban, a selective inhibitor of the active form of coagulation factor X (FXa), is taken orally once daily, but the optimal dosing time is unknown. This study evaluated the dosing time-dependent effects of edoxaban on coagulation activity and thrombus formation in rats. Edoxaban (10 mg/kg) or vehicle was administered to Wistar rats at zeitgeber time (ZT)-2 (beginning of the light phase) or ZT14 (beginning of the dark phase), followed by blood collection at ZT4, ZT10, ZT16, or ZT22, to measure the activity of coagulation factors and edoxaban concentrations, or followed by inferior vena cava ligations at ZT4 or ZT16, to assess the efficacy of edoxaban against thrombus formation. Coagulation FX activity was high during the light phase, and a single dose of edoxaban administered at ZT2 inhibited FX activity and thrombus formation more potently compared with the same dose administered at ZT14. The inhibitory effects during the light phase could be attributed, at least in part, to the high blood concentration of edoxaban achieved by dosing at ZT2. Morning dosing of edoxaban leads to a high blood concentration of the drug during the morning hours and thus may better counteract the hypercoagulability and hypofibrinolytic activity characteristic of the morning hours. Optimizing the dosing time may contribute to improving the efficacy of edoxaban.

Guidelines for the design and conduct of human clinical trials on ingestion-time differences - chronopharmacology and chronotherapy - of hypertension medications.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.

Chronotherapy of maxacalcitol on skin inflammation induced by topical 12-O-tetradecanoylphorbol-13-acetate in mice.

In general, chronotherapy is desirable for a more effective and/or safe dosage regimen. In this study, a daily rhythm of skin vitamin D receptor (VDR) and chronotherapeutic profiles of maxacalcitol, a vitamin D analogue, were evaluated using mice with skin inflammation induced by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). This study showed that skin nuclear VDR expression in TPA-treated mice has a daily rhythm with the peak at the middle of active period. The effects of maxacalcitol were greater after dosing during early to middle of active period than those after dosing during early to middle of inactive period. These data suggest that chronotherapeutic profiles of maxacalcitol partly depend on the daily rhythm of skin nuclear VDR in TPA-treated mice. Because TPA-treated mice are considered as one of animal models of psoriasis, these animal data might be helpful for establishing chronotherapeutic approach of maxacalcitol in clinical practice.

Influence of a dosing-time on toxicities induced by docetaxel, cisplatin and 5-fluorouracil in patients with oral squamous cell carcinoma; a cross-over pilot study.

Docetaxel, cisplatin plus fluorouracil (DCF) regimen is a useful chemotherapy, but is sometimes withdrawn due to severe adverse effects (AE). In this study, we examined whether the chronotherapy of DCF regimen could reduce the drugs-induced toxicities in clinical practice. Patients with oral squamous cell carcinoma were enrolled. Chemotherapy started at 10:30 (Morning-dosing) or 18:30 (Evening-dosing) for 5 days by a cross-over design. AE were assessed for 14 days after an initiation of each dosing. The grades of nausea, vomiting and neutropenia were smaller during Evening-dosing than during Morning-dosing. These data suggest that the chrono-chemotherapy might provide a merit for reducing the DCF regimen-related severe AE.

Dosing-time-dependent effect of rivaroxaban on coagulation activity in rats.

The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase. A similar chronopharmacological effect was seen in a quantitative model of venous stasis thrombosis. In comparison, the dosing time had minimal influence on the pharmacokinetics of rivaroxaban. These data indicate that the anticoagulant effect of rivaroxaban is influenced by the dosing time. Further studies should confirm this finding in a clinical setting.

Effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.

[Chronotherapy of 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.

Different chronotherapeutic effects of valsartan and olmesartan in non-dipper hypertensive patients during valsartan treatment at morning.

This study was undertaken to evaluate the differences in chronotherapeutic effects of angiotensin-II receptor blockers, valsartan and olmesartan in hypertensive patients with non-dipper blood pressure (BP) pattern during valsartan at morning. Ninety four patients were enrolled, and 40 patients were judged to be non-dippers. In these patients, same dose of valsartan was changed to evening (Val-E, n = 12), or olmesartan (equivalent dose of valsartan) was given at morning (Olm-M, n = 13) or evening (Olm-E, n = 15) for 4 months. BP decreased during sleep and increased during waking hours in Val-E group. In Olm-M and Olm-E groups, BP decreased during sleep and waking hours. Percent reduction in BP at night-time compared to BP at waking hours significantly increased after changing the dose regimen in each group. Serum creatinine decreased and estimated glomerular filtration rate (eGFR) elevated in Olm-M and Olm-E, but not Val-E groups. Positive correlation between systolic BP (SBP) during sleep and serum creatinine, and negative correlation between SBP during sleep and eGFR were detected. These data suggest that dipper BP pattern could be obtained by chronotherapeutic approach using valsartan and olmesartan in non-dipper patients with valsartan at morning. Morning and evening olmesartan, but not evening valsartan improved renal function in these patients.

Dosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosis.

Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P < 0.05). Because an elevated concentration of PAI-1 is known to be associated with the risk of venous thromboembolism, the findings of the present study suggest that the dosing time of raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene.

[Chronotherapy--present and future].

Chronotherapy integrates chronoeffective and chronotoxic data to enhance an effectiveness and tolerance of a drug by choosing optimal dosing-time. Chronotherapy is already performed in several diseases such as hypertension, osteoporosis, dyslipidemia and malignant diseases, and improves the prognosis of these patients. However, it is still a new concept for physicians. Efforts are needed to take chronotherapy into dosage regimen by physicians, who have a major role in providing the benefits of chronotherapy to their patients. In addition, chronotherapy studies are not requested for drug evaluations by the regulatory authorities. However, preliminary screening of new drugs for their chronotherapeutic potential is a way of enhancing the research and development in pharmaceutical industries.

Inhibition of CYP3A4 by 6',7'-dihydroxybergamottin in human CYP3A4 over-expressed hepG2 cells.

OBJECTIVES: We previously established HepG2-GS-3A4, a cell line from hepatoblastoma with overexpression of human CYP3A4 and glutamine synthetase (GS). We further reported that these cells can be applied for screening inhibitors of CYP3A4 in vitro. The purpose of this study was to determine whether our CYP3A4-overexpresed cell could be applied to evaluate mechanisms of CYP3A4 inhibition by 6',7'-dihydroxybergamottin (DHB), which is one of the major furanocoumarins in grapefruit juice, by using these cells. METHODS: Nifedipine oxidation, activity and protein expression of NADPH-cytochrome reductase (POR) of HepG2-GS-3A4 cell were measured. CO-binding spectrumassay in microsomal fraction of the cells was also evaluated. KEY FINDINGS: DHB and ketoconazole, a well-known inhibitor of CYP3A4, inhibited nifedipine oxidation in a concentration-dependent manner. DHB at a concentration of 3.0 µm, sufficient to inhibit the nifedipine oxidation, decreased POR activity; however, ketoconazole at a concentration of 0.9 µm, sufficient to inhibit the oxidation, did not affect the activity. The expression of POR protein in HepG2-GS-3A4 cells was not changed by either DHB or ketoconazole. The expression of CYP3A4 mRNA and protein was not changed by the addition of DHB or ketoconazole. DHB also reduced the absorption rate at 450 nm in a CO-binding spectrum assay without alteration of the wavelength of maximum absorption. The mean absorption value at 450 nm slightly decreased with ketoconazole; however, the difference was not significant. CONCLUSIONS: We concluded that inhibition of CYP3A4 activity by DHB includes the inhibition of POR activity. HepG2-GS-3A4 might be a good tool to evaluate the mechanisms.

[Drug chronotherapy: the coordination of biological rhythms with medical treatment].

Chronotherapy is defined as a coordination of biological rhythms with medical treatment. At present, several medications, including bronchodilating agents and H2 blockers, are administered with consideration for biological rhythms in routine clinical practice. In addition, recent studies have revealed that bedtime administration of antihypertensive medications can ameliorate the disturbed circadian rhythm of blood pressure and improve the prognosis in patients with hypertension. Because chronotherapy is a simple and inexpensive method of optimizing safe and effective pharmacotherapy, merits of this therapy should be evaluated in many medications.

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats.

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects.

AIM: To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS: The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS: Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS: Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.

ACE inhibitors and chronotherapy.

Chronotherapy can improve the effectiveness and reduce the adverse reactions of drugs and actually is used for several conditions including cardiovascular diseases. Although angiotensin converting enzyme (ACE) inhibitors are available for the therapy of patients with hypertension and/or heart failure, these agents have some characteristic adverse effects such as angioedema and dry cough. It has been reported that the dosing of ACE inhibitor at an inactive period has a better protective effect against cardiac hypertrophy in hypertensive rats, and changing dosing time from morning to evening reduces the severity and frequency of the drug-induced dry cough of hypertensive patients treated in the morning. Thus, the dosing of ACE inhibitors in the inactive span is more effective and safe. Dosing in the evening may be an alternative for hypertensives with dry cough with a morning dose of ACE inhibitors, if one ascertains that no circadian hyperamplitude tension is induced by the evening dose of this or any other antihypertensive drug.

Chronotoxicity of nedaplatin in rats.

Chronotoxicologic profiles of nedaplatin, a platinum compound, were evaluated in rats maintained under a 12 light/12 dark cycle with light from 07:00h to 19:00 h. Nedaplatin (5 mg/kg) was injected intravenously, once a week for 5 weeks at 08:00h or 20:00h. The suppression of body weight gain and reduction of creatinine clearance were significantly greater with the 20:00h than 08:00h treatment. Accumulation of nedaplatin in the renal cortex and bone marrow were also greater with 20:00 h treatment. There were significant relationships between the nedaplatin content in the kidney and bone marrow and degree of injury to each. These results suggest that the nedaplatin-induced toxicity depends on its dosing-time, and it is greater with treatment at 20:00 h, during the active phase. The dosing-time dependency in the accumulation of nedaplatin in the tissue of the organs might be involved in this chronotoxicologic phenomenon.