Int J Clin Pharm (2013) 35:344–358
DOI 10.1007/s11096-013-9749-0
REVIEW ARTICLE
Timing is important in medication administration: a timely review
of chronotherapy research
Gagandeep Kaur • Craig Phillips • Keith Wong •
Bandana Saini
Received: 28 August 2012 / Accepted: 2 January 2013 / Published online: 18 January 2013
 Springer Science+Business Media Dordrecht 2013
Abstract Background Chronotherapy involves altering
the timing of medication administration to improve the
overall control of a disease and to minimise treatment side-
effects, and is an emerging concept in the field of thera-
peutics. Aim The aim of this review is to conduct an in-
depth analysis of the recent literature in order to identify
and evaluate the evidence base for drug chronotherapy.
Method A literature search was conducted in three
databases (Medline, Embase, International Pharmaceutical
Abstracts) using the search terms ‘‘Chronotherapy’’,
‘‘Chronopharmacology’’, ‘‘Chronopharmacokinetics’’,
‘‘Chronopharmacodynamics’’, ‘‘Chronoefficacy’’, ‘‘Chro-
noformulation’’, ‘‘Morning and Evening’’, ‘‘Morning and
Bedtime’’ and their combinations. The selection criteria for
the inclusion of articles in the review included currency
(years 2008–Aug 2011), publication in English language,
studies done in Humans and non-review articles that per-
tained to ‘drug’ therapy. Results Our search revealed a total
of 192 journal articles, of which 41 articles were selected
for review. The specific hypothesis for the effectiveness of
chronotherapy that was tested in these 41 studies was
G. Kaur (&)
Room S114, Pharmacy and Bank Building A15, Faculty of
Pharmacy, University of Sydney, Science Road, Camperdown,
NSW 2006, Australia
e-mail: gaga8947@uni.sydney.edu.au
C. Phillips
K. Wong
Woolcock Institute of Medical Research, Missenden Road,
PO Box M77, Camperdown, NSW 2050, Australia
B. Saini
Room S303, Pharmacy and Bank Building A15, Faculty of
Pharmacy, University of Sydney, Science Road, Camperdown,
NSW 2006, Australia
123
chronoeffectiveness (n = 34), followed by chronophar-
macokinetics (n = 5), chronomodulation (n = 3) and
chronopharmacodynamics (n = 2). The findings from two-
thirds (n = 27) of the reviewed studies, support the notion
of chronotherapy. Conclusion The review presents the
scope of chronotherapy in drug utilization. We believe that
the knowledge of chronotherapy is growing and the current
research for chronotherapy is promisingly in the concep-
tualization or early experimental phase. Going forward,
chronotherapy studies should also explore genetic, gender
and age related differences. Preliminary screening of new
drugs for chronotherapeutic potential may be a way of
enhancing quality use of medicines.
Keywords Chronoeffectiveness
Chronomodulation

Chronopharmacodynamics
Chronopharmacokinetics

Chronotherapy
Drug therapy
Impact of findings on practice
• There are drugs and disease conditions where previous
research suggests an optimal circadian time of drug
administration. Practitioners need to apply this knowl-
edge to relevant drugs and conditions to maximise
clinical effects.
• When counseling patients about the ‘time’ when
medications should be administered, pharmacy practi-
tioners should pay due attention to the circadian
influence on drugs and disease.
• The chronotherapy literature uses terms and definitions
rather interchangeably. The model that consolidates
relational aspects of the varied terms used in this field
may be a useful reference for practitioners.
Int J Clin Pharm (2013) 35:344–358
Introduction
In the practice of clinical medicine, health care profes-
sionals including pharmacists have a clear understanding of
the concept of homeostasis, where the internal physiolog-
ical environment of the human body is maintained in a
relatively constant state. Therefore, it is considered that the
risk of occurrence of a disease is independent of the time of
the day, month or year. Similarly, the time of day when
diagnostic procedures are conducted is usually not taken
into account and dosing regimens are largely determined
by carefully scrutinising standard pharmacokinetic param-
eters. As a result, the time of the day when medications are
administered is not a key focus for health care profes-
sionals in diagnosis or prescribing [1, 2]. However, during
the last couple of decades, much progress has been made in
the field of sleep and circadian medicine and the concept of
biological rhythms is being viewed as a possible comple-
ment to homeostasis.
Biological rhythms
Biological rhythms have been well documented in plants,
animals and humans [3] and are defined as a regularly
recurring component in a series of measurements of a
biologic variable obtained as a function of time [4]. The
time function associated with these rhythms covers a broad
spectrum of frequencies, varying from very high frequen-
cies (milliseconds and seconds) to low frequencies (sea-
sonal and yearly variation) [1, 5]. The study of biological
rhythms and their underlying mechanisms is known as
chronobiology [6]. The best known and most studied bio-
logical rhythm patterns in humans are the circadian
rhythms with a frequency of about 24 h [2].
Studies have shown that many disease conditions such
as asthma [7], rheumatoid arthritis [8], osteoarthritis [9],
cardiovascular diseases [10], allergic rhinitis [11] and
cancer [12] demonstrate circadian patterns in the occur-
rence or intensity of symptoms. Symptoms of peptic ulcers,
for example, are most prominent at night time [13]. In
addition, circadian rhythms have been observed in the
pharmacokinetics and pharmacodynamics of some classes
of drugs. Theophylline, for example, was one of the first
drugs for which circadian variation in pharmacokinetic
parameters was demonstrated [14]. Thus the effect of the
drug may be affected by the time of its administration [15].
Chronobiological terms
Like many other scientific fields, chronobiology has
developed its own nomenclature. Many of the terms are
frequently used and widely accepted by specialists in the
field. However, there are still many terms which are less
345
frequently used and potentially misunderstood by many
investigators and physicians [4]. A quick scrutiny of the
research literature in this field shows that many terms are
interdependent and interlinked with each other.
Figure 1 below outlines a relational map which has been
developed and conceptualised by tracing the origin of the
terms as they initially appeared in the literature and by
applying common knowledge of key pharmaceutical con-
cepts. An explanation for the figure is outlined through the
definitions below with examples presented in Table 1.
Chronobiology
The branch of biology concerned with biological phe-
nomena that display cyclical patterns. The field of chro-
nobiology may be classified into chronophysiology,
chronopharmacology and chronopathology [16].
Chronophysiology
The branch of chronobiology that explores rhythmic
occurrences in physiological processes and behaviours of
the human body [17]. It aims to understand the mechanisms
and functional significance of biological timing.
Chronopathology
The branch of chronobiology that explores biological
rhythms in the manifestation of disease or symptoms of
disease and mechanisms underlying these rhythmic mani-
festations or occurrence of diseases [18].
Chronopharmacology
The branch of chronobiology that explores the effects of
medication on the timing of biologic events and rhythms, and
the relation of biologic timing to the effects of medications
[19]. It is used as an important tool in drug optimization, i.e.
to maximize the desired effect and/or to minimize the
undesired effect of the drug [20]. Since pharmacology is the
study of the effect of medications on the human body (both
therapeutic and adverse/toxic effects), it is proposed that
chronopharmacology may be further classified into chrono-
toxicology and chronotherapy [21].
Chronotoxicology
The branch of chronopharmacology that explores circadian
rhythms in the manifestation and the severity of side effects
of a drug and/or a patient’s intolerance to chemical,
physical, or other agents (including poisons, pollutants, and
overdoses of drugs) [17]. It has been reported that if a
medication is administered at the inappropriate circadian
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Fig. 1 Relational map—
chronobiological terms
Chr
Table 1 Chronobiological terms with examples
Key concepts in chronobiology
Chronophysiology—circadian rhythms in physiological, biochemical
processes of body
Chronopathology—circadian rhythms in symptoms and diseases
Chronotoxicology—circadian rhythms in toxicity
Chronopharmacokinetics—circadian rhythms in drug
pharmacokinetics
Chronopharmacodynamics—circadian rhythms in the mode of action
of drug
Chronoeffectiveness/chronoefficacy—circadian rhythms in the
beneficial effects
Chronoformulation/chronomodulated medication delivery system— a
system to deliver the drug in higher concentrations during the time of
greatest need
time, the induced toxicity could be more severe than when
administered at other times, thus compromising treatment
outcomes [22].
Chronotherapy
This may be defined as the delivery of drugs in synchrony
with the circadian rhythms inherent in the human body [23].
Chronotherapy is the therapeutic application of chrono-
pharmacology. It integrates chronopathological, chrono-
pharmacological and chronotoxicological information to
enhance both effectiveness and tolerance of a drug by
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Int J Clin Pharm (2013) 35:344–358
- - -
-
Examples
Cortisol is a neurohormone which shows circadian rhythms with peak
levels on awakening and trough levels in the early morning. In
response to these changes those with asthma often experience
symptoms in the early morning when levels of cortisol are low [64]
The morning peak in sympathetic activity is associated with a rise in
blood pressure and heart rate at that time [64]
Nephrotoxicity has been found to be significantly greater when
aminoglycosides were administered between midnight and 7:30 a.m.
than at any other time of day [65]
Theophylline shows circadian rhythms in its pharmacokinetics with
Cmax being higher and Tmax being shorter after morning than after
evening administration [14]
The time of administration of interferon-alpha (IFN-alpha), is
associated with the rhythmicity of IFN-alpha receptor which may
increase the antiviral activity in experimental and clinical situations
[66]
An evening dose of Simvastatin has a better lipid lowering effect than a
morning dose [67]
A chronomodulated drug delivery system for salbutamol sulphate for
the treatment of nocturnal asthma was found to be effective. The
dosage form can be taken at bed time and will release the contents in
the early hours of morning when the asthma symptoms are prevalent
[68]
determining optimal medication administration times from a
circadian perspective [19, 24]. Chronotherapy may be
accomplished by the appropriate timing of administration
using conventionally formulated dosage forms and also
through special drug delivery systems (chronoformulations)
to synchronize medication concentration to circadian
rhythms in disease activity [21, 25]. Since therapeutics is
conventionally studied through concepts such as pharma-
cokinetics, pharmacodynamics, drug delivery/formulation
science and drug efficacy, our relational model uses a
similar notion of positioning chronopharmacokinetics,
chronopharmacodynamics, chronoeffectiveness and
Int J Clin Pharm (2013) 35:344–358
chronoformulations as included within the broader concept
of chronotherapy. We outline these terms below.
Chronopharmacokinetics
The study of circadian rhythms in the absorption, distribu-
tion, metabolism and elimination of drugs [18]. Considering
the circadian rhythmicity in drug pharmacokinetics may
help in determining the optimal time of drug administration
and allow individualisation of medications.
Chronopharmacodynamics
The study of circadian rhythms in the mode of action of
drug [1]. Circadian rhythms at the cellular and sub cellular
level may attribute to significant difference in the phar-
macodynamics of drugs that may not be related to phar-
macokinetics [25].
Chronoeffectiveness/chronoefficacy
The study of circadian rhythms in the desired effects of
drug [26, 27].
Chronoformulation/chronomodulated medication delivery
The technique of manipulating formulation systems so that
the drug release from the delivery system is synchronised
with the circadian rhythms in disease pattern or medication
disposition by the body.
There has been a substantial increase in the attention
paid to chronotherapy in recent years. A MEDLINE and
Embase search performed in December 2011 using the
search term ‘chronotherapy’, for example, shows an
exponential rise in the volume of publications over the last
few years (Fig. 2).
Fig. 2 Number of chronotherapy articles in MEDLINE and Embase
347
Even though there is increased emphasis on chronother-
apy in recent years, there is virtually little literature available
on the application of this knowledge in clinical or pharmacy
practice. A previous article [28] has developed a database
containing optimum timing of drug administration and
reviewed how well such information is applied in clinical
practice. However, it was limited to drugs sold or available in
Germany alone. This review identifies the basis of drug
chronothrapy and proposes a model to enchance the chro-
notherapeutic knowledge among health care professionals.
Aim
The aim of this review is to conduct an in-depth analysis of
the recent literature in order to identify and evaluate the
evidence base for drug chronotherapy.
Method
An extensive search of the literature was conducted to
identify publications focusing on chronotherapeutic aspects
of drug therapy. The search was conducted in August 2011
using the keywords ‘‘Chronotherapy’’, ‘‘Chronopharma-
cology’’, ‘‘Chronopharmacokinetics’’, ‘‘Chronopharmaco-
dynamics’’, ‘‘Chronoefficacy’’, ‘‘Chronoformulation’’,
‘‘Morning and Evening’’, ‘‘Morning and Bedtime’’ and
their combinations. Embase, International Pharmaceutical
Abstracts (IPA) and MEDLINE databases were used for
the search. Articles were limited to English language,
Humans, year (2008–2011) and non-review articles. Fur-
ther, duplicate articles were removed. Abstracts of articles
were then scanned and filtered using set inclusion and
exclusion criteria (Fig. 3). After selection for review,
selected articles were re-read again from the point of view
to classify them based on our operational definitions
(Table 1).
Results
Our search revealed a total of 192 journal articles, of which
41 articles were selected based on the inclusion and
exclusion criteria (Fig. 3).
Of the studies that were included for the purposes of the
review (n = 41), seven tested a combination of drugs, rather
than a single drug, for their chronotherapeutic potential. Of
these 41 selected articles, 7 had been published in 2011, 21 in
2010, 8 in 2009 and 5 were published in 2008. Most of the
selected studies were conducted in Europe (n = 27) fol-
lowed by Asia (n = 9), North America (n = 2), Africa
(n = 2) and South America (n = 1). The most common
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Fig. 3 Search methodology
study design utilized in these studies was the Randomised
Control Trial (RCT) (n = 34). The findings of a third
(n = 14) of the reviewed studies, did not support the notion
of chronotherapy, i.e. the outcome of the clinical trial showed
no difference in effect with respect to the time of the day the
drug was administered. However, the rest demonstrated a
positive outcome i.e. supported the notion of chronotherapy.
The hypothesis for the effectiveness of chronotherapy that
was tested in these 41 studies was chronoeffectiveness
(n = 34), followed by chronopharmacokinetics (n = 5),
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Int J Clin Pharm (2013) 35:344–358
chronomodulation (n = 3) and chronopharmacodynamics
(n = 2).
The compounds which did not demonstrate chrono-
therapeutic potential (n = 14 studies) were prednisone MR
[29], amlodipine/valsartan combination [30], roflumilast
[31], methyl prednisolone [32], dexlansoprazole MR [33],
indacaterol and salmeterol [34], fesoterodine SR [35],
XELOX [36], travoprost/timolol combination [37], val-
sartan [38], vildagliptin [39], tramadol ER [40], ezetimibe/
simvastatin [41] and mometasone furoate [42].
Int J Clin Pharm (2013) 35:344–358
Studies supporting chronotherapy (n = 27) included
randomised (n = 23) as well as non-randomised (n = 4)
studies. Of the randomized studies, bed time administration
(n = 16) was suggested as more effective for drugs such as
aspirin [43, 44], levothyroxine [45], torasemide [46],
ramipril [47], nifedipine gastrointestinal therapeutic system
(GITS) [48] [49], olmesartan [50, 51], amlodipine/valsar-
tan combination [52], amlodipine/olmesartan combination
[53], amlodipine/fosinopril combination [54] and amlodi-
pine/hydrochlorothiazide combination [55]. Evening
administration, which is of course different from bed time
(n = 5) was suggested as therapeutically superior to other
times in the case of bimatoprost/timolol fixed combination
[56], prednisone MR [57], latanoprost/timolol fixed com-
bination [58] and simvastatin [59]. Night time adminis-
tration (n = 2) was suggested for nebicapone [60, 61].
The most studied disease condition was hypertension
(n = 19) followed by ocular hypertension or glaucoma,
hypertension comorbid with type-2 diabetes, respiratory
disease, rheumatoid arthritis (n = 3) and dyslipidemia
(n = 2). Other conditions where only one study was found
included cancer, type-2 diabetes, peptic ulcer, epilepsy,
hypothyroidism, multiple sclerosis, overactive bladder,
pain management and Parkinson’s disease (n = 1). The
study population for these studies included mostly patients
with a given condition (n = 36) but also healthy volunteers
(n = 5).
Discussion
This is one of the first reviews of the research literature
which systematically scopes the evidence supporting the
concept of chronotherapy. This review sought and evalu-
ated current published literature (2008–Aug 2011) which
assessed time of drug administration as an independent
factor possibly affecting drug use outcome. Most impor-
tantly, the presentation of the results was based on a new
model proposed by us for the better understanding of
definitions and terminology in the field of chronotherapy.
To the best of our knowledge this is the first review that has
attempted to dis-entangle the varying terminology and
mechanisms underlying chronotherapy. Importantly, there
is emerging evidence supporting the application of chro-
notherapeutic principles in the case of some drugs. This is
especially the case for some drugs used in conditions where
there is a clear circadian influence on disease pathophysi-
ology such as hypertension. For many years the field of
chronotherapy has been in equipoise, our review suggests
that it may be timely to focus some attention to chrono-
therapeutic principles, at least in the case of key drugs and
conditions.
349
The limited amount of research highlights the novelty of
the field of chronotherapy. It would even appear that terms
and concepts used in chronotherapeutic research or drug
use are nascent. Our analyses indicated that when
researchers report that the drug under test was used at
particular times e.g. morning, awakening, evening, bed-
time, night time, the actual ‘time’ of drug administration is
not clearly understood. For example, terms such as evening
or night time may be used interchangeably. There is scope
to better define these terms with respect to chronotherapy,
so that reporting uses a standard format. Another issue we
noticed in our review was that most of the research ema-
nated from Europe. It is well known that the pharmacoki-
netics of many drugs is prone to inter individual variability,
which is caused by several factors such as gender, age,
weight, impaired renal and hepatic function, and genetics
[31]. In our view it is difficult to generalise the results to
populations in other parts of the world until relevant clin-
ical trials are conducted.
Given the many mechanisms that underlie chronother-
apy, our review suggests research to be skewed towards
chronoeffectiveness trials. This may be due to the greater
ease of conducting such studies. Chronoeffectiveness
studies can easily be ensconced within a regular clinical
trial, as they require only an additional arm where the drug
can be administered at a time opposite in the circadian
clock to the time where the drug is being administered in
the main trial (generally morning and/or evening mea-
surements). However conducting a trial by varying
administration time over only two points in an effective-
ness study reduces the chance of finding optimal drug time
compared to pharmacokinetics and pharmacodynamics
studies. Pharmacokinetics and pharmacodynamics studies
may also be better placed to elicit the mechanism of ‘time’
related effects on drug effectiveness. Understanding the
reason behind effectiveness of one drug may also help
researchers find chronotherapeutic potential for other drugs
in the same class or for same condition (Tables 2, 3, 4, 5).
Another key finding of our review is that most of the
chronotherapeutic studies have been performed with con-
ventional or already marketed drugs. Given the mounting
evidence supporting chronotherapy, it may be tempting to
suggest that all new drugs should be checked for chrono-
therapeutic potential, at least with a preliminary screen to
shortlist a drug prior to expensive and time consuming
testing. The screening may take the form of a checklist of
questions (Table 6), based on the literature concerning
mechanisms that underlie chronotherapeutic effect [24].
We found that most reviewed studies investigated and
reported a main clinical effect but did not report outcomes
such as adherence. The time at which drugs are ingested
constitutes a key element of adherence because adminis-
tration at times that are mis-aligned with the optimal
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Table 2 Results—chronoeffectiveness studies

References Participants Drug and dose Study design Suggested Author’s observation
Country Participants Drug (dose) Design (study duration) administration
(sample size, age) time

Asmar et al. Essential hypertensive Amlodipine (A)/valsartan Multicenter, PROBE Mo/Ev Both treatments had
[30] patients with BP (V) combination [5 mg comparing Mo versus similar effects on BP
France and uncontrolled by 5 mg (A) and 160 mg Ev admn in 2 parallel control
Tunisia amlodipine (n = 463), (V) increase to 10 mg groups (12 weeks)
age—56 ± 10 years (A) and 160 mg
(V) after 4 weeks
(optionally)]
Ayala et al. Untreated Grade 1 Aspirin (100 mg/day) PROBE and parallel study Bdt Ambulatory BP reduced
[43] (mild) hypertensive comparing Aw versus significantly after
Spaina patients (n = 316), Bdt admn (3 months) bedtime treatment,
age—44.1 ± 13.2 yrs irrespective of gender.
Ambulatory and
nocturnal BP was
significantly less in
women compared to
men
Balan et al. Mild to moderate Perindopril (P), verapamil RCT comparing Mo Ev Evening administration of
[69] hypertensive patients hydrochloride/2 mg versus, Ev admn (6 and drugs lead to significant
Romaniaa (n = 60), age— trandolapril (V) and half months) reduction in anatomical
57 ± 12 yrs Amlodipine besilat and functional
(A) ((P)—cp 10 mg, parameters of the left
(V) cp 180 mg, (A) cp ventricle. All drug
10 mg) regimens had similar
clinical outcome
Bolk et al. Primary hypothyroidism Levothyroxine (100 lg/ Randomised double blind Bdt Bedtime administration
[45] patients (n = 90), day) crossover comparing significantly improved
Netherland age—18? yrs Mo versus Bdt admn thyroid hormone levels.
(6 months) Plasma lipid levels
showed no significant
changes with bedtime
versus morning intake
Glass- Multiple sclerosis (MS) Intravenous Pre post study—Dyt None Matrix metalloproteinases
Marmor relapse patients methylprednisolone (10:00 a.m.–14:00 p.m.) (MMP-9) which was a
et al. [32] (n = 35), age— [1 g/day (days 1–3) and versus Ntt admn disease marker, had
Israela 18–55 yrs then 0.5 g/day (days (22:00PM–02:00 a.m.) reduced serum levels
4–6)] (7 days) after night-time
administration
He et al. Type 2-diabetic patients Vildagliptin (100 mg) Randomised double blind, Mo/EV Evening dose
[39] USA (n = 39), age— two period cross over significantly reduced
53.3 ± 8.9 yrs comparing pre-Brkfst fasting plasma glucose.
versus pre Din (77 days) 24 h glycaemic control
did not differ among
morning or evening
dose
Hermida Prehypertensive patients Aspirin (100 mg/day) Single centre, PROBE, Bdt Clinical BP reduced
et al. [44] (n = 244), age— parallel group slightly but significantly
Spain 43 ± 13.0 yrs comparing Aw versus with bedtime
Bdt admn (3 months) administration
Hermida Grades 1–2 Torasemide (5.0 mg/day) PROBE, parallel group Bdt Efficacy of bedtime BP
et al. [46] uncomplicated comparing Aw versus treatment was
Spain essential hypertensive Bdt admn (6 weeks) significantly better than
patients (n = 113), morning treatment
age—51.7 ± 10.6 Yrs
Hermida Untreated Grades 1–2 Ramipril (5.0 mg/day) Multicenter, PROBE, Bdt Nocturnal BP reduction
et al. [47] uncomplicated parallel group was greater with
Spaina essential hypertensive comparing Aw versus bedtime administration
patients (n = 115), Bdt admn (6 weeks) of Ramipril
age—46.7 ± 11.2 yrs

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Table 2 continued
References Participants Drug and dose Study design Suggested Author’s observation
Country Participants Drug (dose) Design (study duration) administration
(sample size, age) time

Hermida Untreated hypertensive Nifedipine PROBE, parallel group Bdt Bedtime treatment
et al. [48] patients (n = 180), gastrointestinal comparing Aw versus resulted in greater
Spain age—52.5 ± 10.7 yrs Therapeutic System Bdt admn (8 weeks) efficacy in regulating
(GITS) (30 mg/day) ambulatory BP when
asleep, with reduced
incidence of oedema
Hermida Untreated Grades 1–2, Olmesartan (20 mg/day) PROBE, parallel group Bdt 24 h BP reduction was
et al. [50] uncomplicated study comparing Aw similar for both the
Spain hypertensive patients versus Bdt admn treatment arm. However
(n = 123), age— (3 months) bedtime administration
46 ± 12.3 yrs reduced the nocturnal
BP to a greater extent
than morning
administration
Hermida Untreated Grades 1–2, Spirapril (6 mg/day) Open Label, parallel Bdt Nocturnal BP regulation
et al. [70] uncomplicated group, blinded endpoint was significantly better
Spaina hypertensive patients comparing Aw versus with Bedtime
(n = 165), age— Bdt admn (12 weeks) administration
42.5 ± 13.9 yrs
Hermida Untreated Valsartan (V) and PROBE and parallel Bdt Bedtime treatment with
et al. [52] uncomplicated amlodipine (A) (160 mg group study. V ? A A ? V lowered the BP
Spaina essential hypertensive (V) and 5 mg (A)/day) (Mo) versus V ? A more than other three
patients (n = 203), (Bdt) versus V timings
age—56.7 ± 12.5 yrs (Mo) ? A (Bdt) versus
A (Mo) ? V (Bdt).
(12 weeks)
Hermida Untreated Grades 1 or 2 Nefidipine GITS (30 mg/ PROBE and parallel Bdt Bedtime administration
et al. [49] uncomplicated day) design comparing Aw reduces the entire 24 h
Spaina essential hypertensive versus Bdt admn BP. Bedtime treatment
patients (n = 238), (8 weeks) significantly reduces
age—53.3 ± 11.4 yrs nocturnal BP as well as
the morning BP surge
Hermida Hypertensive patients One or more anti- PROBE design comparing Bdt C1 hypertension
et al. [71] with type-2 diabetic. hypertensive Aw versus Bdt admn medication improved
Spaina (n = 448), age— medications (Based on [5.4 yrs (median)] ambulatory BP control
62.5 ± 10.8 yrs patients condition) when administered at
bedtime and reduces
cardiovascular risk
Hermida Resistant hypertensive 3 antihypertensive drugs PROBE and parallel Bdt Treatment with 1 anti-
et al. [72] patients taking (Prescribed by study. Changing 1 drug hypertensive drug at
Spain antihypertensive drugs physicians) (new) and keeping 2 (all bedtime was more
at awakening at Aw) versus 1 new effective in reducing
(n = 250), age— drug (Bdt) and keeping both ambulatory BP and
60.1 ± 11.7 yrs 2 (Aw) (12 weeks) nocturnal BP than 3
antihypertensive drugs
administered in the
morning
Hermida Resistant hypertensive C1 antihypertensive Cross sectional Bdt Treatment with C1
et al. [73] patients taking all drug(s) (Prescribed by comparative study hypertensive drugs
Spaina antihypertensive physicians) comparing Aw versus when given at bedtime
medication on Bdt admn (2 days) provides significant
awakening reduction in both
(n = 1,306), age— ambulatory BP as well
61.6 ± 11.3yrs as nocturnal BP
compared to morning
intake

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Table 2 continued
References Participants Drug and dose Study design Suggested Author’s observation
Country Participants Drug (dose) Design (study duration) administration
(sample size, age) time

Hermida Untreated hypertensive ARBs, ACEIs, CCBs, b- Randomised study Bdt Bedtime administration
et al. [74] patients (n = 2,156), blocker and diuretics comparing Aw versus with C1 drug exerts
Spain age—55.6 ± 13.6 yrs (monotherapy/ Bdt admn [5.6 yrs better ambulatory BP
multitherapy (if (median)] and nocturnal BP
required) prescribed by control as compared to
physicians) morning administration.
A significantly lower
incidence of CVD was
found in the bedtime
treatment group
Hoshino Essential hypertensive Amlodipine (A) and Open label, randomised Bdt Bedtime treatment
et al. [53] patients (n = 31), olmesartan cross over study significantly reduced
Japana age—69 ± 11 yrs (O) combination comparing Mo versus morning blood pressure
[2.5–10 mg (A) and Bdt admn (40 weeks) surge and nocturnal BP
20–40 mg (O)] in non-dippers
Konstas Caucasian exfoliative Bimatoprost/timolol fixed Randomised, prospective, Ev BTFC therapy
et al. [57] glaucoma patients combination (BTFC) observer masked, cross administered in the
Greece (n = 60), age— and Bimatoprost (B) over comparison study evening reduces both
68.2 ± 8.4 yrs comparing Mo versus the morning and early
Ev admn (7.5 months) afternoon IOP when the
reduction maybe most
required
Magnussen Moderate to severe Indacaterol (I) and Multicenter, randomised, Mo/Ev Improvement in
et al. [34] chronic obstructive salmeterol (S) [300 lg double blind, double symptoms regardless of
Germany, pulmonary disease dry powder (I) and dummy, placebo- (I) dosing time
Spain and (COPD)patients 50 lg twice daily (S)] controlled, incomplete
France (n = 83), age— block crossover study
64.1 ± 8.7 yrs comparing (I)Ev versus
(I)Mo versus (S) twice
daily versus placebo
(70 days)
Meng et al. Grades 1 or 2 essential Amlodipine (A) and Prospective, randomised, Bdt Nocturnal BP reduction
[54] China hypertensive patients fosinopril (F) (A-5 mg and open label study was greater with
undergoing treatment and F-10 mg) comparing Mo (A) and bedtime administration
with (A) or Bdt (F) versus Mo only of (F)
(F) monotherapy (A ? F) (4 weeks)
(n = 40), age—
52 ± 9.17 yrs
Okeahialam Grades 1 and 2 essential ARBs, ACEIs, CCBs, b- Randomised Controlled Ntt Cardiovascular outputs
et al. [60] hypertensive patients blocker and diuretics trial—comparing Mo showed significant
Nigeria (n = 165), age— (based on patients versus Ntt (12 weeks) change for night time
49.0 ± 13.8 (G1) condition) administration
50.4 ± 14.5 (G2) yrs
Pizzuto et al. Primary hypertensive Atenolol (A) and Parallel controlled Mo (A) and (P) provides
[75] Malta patients (n = 43), perindopril (P) design— comparing Mo better BP control during
age—not older than versus Ev admn (24 h) early morning hours
75 years following a morning
dose
Povedano Hypertensive patients Olmesartan [40 mg, Randomised crossover Bdt Significant reduction in
et al. [51] with type-2 diabetic. reduced to 20 mg (when design comparing Aw nocturnal BP with
Spaina (n = 38), age— required)] (07:00–09:00) versus bedtime administration
53.7 ± 12.4 yrs Bdt (22:00–0:00) admn compared to
(16 weeks) administration at
awakening. No
significant difference in
24 h BP control in the
two schedules

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Table 2 continued
References Participants Drug and dose Study design Suggested Author’s observation
Country Participants Drug (dose) Design (study duration) administration
(sample size, age) time

Suic et al. Open angle glaucoma or Travoprost (Tr) and Multicentre, prospective, Mo/Ev No statistically significant
[37] ocular hypertensive Timolo (Ti) open label, clinical difference in IOP
Croatiaa patients currently [0.004 %(Tr) and 0.5 % observation study between morning and
treated with pressure (Ti)] comparing Mo versus evening dosing
lowering monotherapy Ev admn of the schedules was observed
(n = 40), age— combination (6 months)
18? yrs
Suzuki et al. Hypertensive patients Valsartan (80 mg twice Three period crossover, Mo/Ev No significant differences
[38] Japan with mild-to-moderate daily versus 160 mg Mo randomised study found in morning home
diabetic nephropathy. versus 160 mg Ev) comparing Mo versus BP/office BP between
(n = 34), age— Ev admn for the 160 mg morning and evening
57.8 ± 1.8 yrs dose as well as a 80 mg dosing schedules
dose (36 weeks)
Takmaz Primary open angle Latanoprost/timolol Prospective, randomized, Ev The evening dose
et al. [58] glaucoma patients maleate fixed investigator blind study, administration
Turkeya taking latanoprost in combination (LTFC) single centre comparing demonstrated better
evening (20:00) (0.005 % latonoprost- Mo (08:00) versus Ev effect in controlling
(n = 30), age— 0.5 % timolol maleate (20:00) admn (4 weeks) morning IOP
66.4 ± 10.2(G1) fixed combination)
62.3 ± 8.1 (G2) yrs
Tharavanij Dyslipidaemia subjects Simvastatin (10 mg) Randomized double blind Ev Evening administration
et al. [59] (n = 52), age—18–70 controlled study significantly reduces
Thailand yrs comparing Mo hsCRP and LDL after
(06:00–10:00) versus Ev 4 weeks of therapy.
admn (19:00–22:00) However, there was no
(12 weeks) change in LDL over
12 weeks
To et al. Rheumatoid arthritis Methotrexate (MTX) Prospective single arm Bdt Bedtime schedule to be
[76] Japan patients receiving (6 mg (4–8)/week) study—Day 1—after found better in
MTX three times a brkfst, supper and Day controlling the
week (n = 17), age— 2—after brkfst versus symptoms of RA
61 (41–78) yrs once daily Bdt dose (3
times a week)
(3 months)
Yoon et al. Primary Ezetimibe/simvastatin Multicenter, open label, Mo/Ev Morning administration
[41] hypercholesterolemia (10 mg/20 mg) randomised, 2-sequence, was not inferior to
Koreaa patients (n = 145), 2 period cross over evening administration
age—18? yrs study— comparing Mo with respect to low
or Ev admn (16 weeks) density lipoprotein
lowering ability
Zeng et al. Essential hypertensive Amlodipine (A) and Multi centre, open label Bdt Both the ambulatory and
[55] China (n = 80), age— hydrochlorothiazide randomized trial nocturnal BP was
67.8 ± 9.8 yrs (H) fixed combination comparing Mo (08:00) significantly lower in
[5 mg (A) and 25 mg versus Bdt (22:00) admn the bedtime
(H)] (14 weeks) administration group
Zetterstrom Mild to moderate Mometasone Furoate Multicentre, open label, Mo/EV No significant differences
et al. [42] asthmatic patients (400 lg dry powder randomized, parallel in symptom control in
Sweden, (n = 1,022), age— inhaler) group comparing Mo the treatment arms
Norway, 18? yrs versus Ev admn
Finland (12 weeks)
Mo morning, Ev evening, Aw awakening, Bdt bedtime, Dyt daytime Ntt night time, Admn administration, Brkfst breakfast, Din dinner, yrs years,
PROBE prospective randomised open lable blinded endpoint, RCT randomised controlled trail, BP blood pressure, IOP intraocular pressure,
CVD cardio vascular disease, hsCRP high sensitive C-reactive protein, LDL low density lipoprotein, ARBs angiotensin receptor blockers, CCBs
calcium channel blockers, ACEIs angiotensin converting enzyme inhibitors
a
First author’s country

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Table 3 Results—chronopharmacokinetic studies

References Participants Drug and Study design Suggested Author’s observation
dose administration
Country Participants Drug (dose) Design (study duration) time
(sample
size, age)

Bethke Healthy Roflumilast Randomised, open label, two- Mo/Ev Tmax and Cmax slightly higher after
et al. [31] subjects (500 lg period, cross over comparing after morning versus evening administration,
Germanya (n = 16), single dose) Brkfst versus after Din admn but differences were not clinically
age— (18 days) significant
22–44 yrs
Malhotra Healthy Fesoterodine Randomised, open label, two- Dyt/Ntt No significant difference was found
et al. [35] subjects sustained period, two treatment cross over between morning or night time
USAa (n = 14), release study comparing after Brkfst or treatment on the AUC. A 21 %
age— (SR) after Din admn (17 days) reduction in Cmax for night-time
18–55 yrs (8 mg) treatment was thought to be clinically
non significant. No safety issues were
apparent
Warnke Healthy Tramadol Randomised open study comparing Mo/Ev The bioavailability was not affected by
et al. [40] subjects extended before Brkfst or before Din admn time of administration
Brazil (n = 18), release of the drug (48 h)
age— (ER)
22–47 yrs (200 mg/
day)
Mo morning, Ev evening, Brkfst breakfast, Din dinner, Dyt daytime, Ntt night time, Admn administration, Yrs years, AUC area under curve, Cmax
maximum concentration that drug achieves after dosing, Tmax time after drug administration reaches maximum plasma concentration
a
First author’s country

Table 4 Results—chronomodulation studies

References Participants Drug and dose Study design Suggested Author’s
Country Participants Drug (dose) Design (study duration) administration observation
(sample size, age) time

Alten et al. Rheumatoid arthritis Prednisone modified release (MR) Randomised, multicentre, double None Switching IR to
[29] patients (n = 28), age— and prednisone immediate release blind, active controlled phase III— MR did not
Germanya 56.1 ± 9.6 yrs (IR) (3–10 mg/day IR or MR) trial comparing MR prednisone at influence the
Bdt/IR versus prednisone admn in response
the Mo (12 months)
Buttgereit Rheumatoid arthritis Prednisone modified release (MR) Multi center, randomized double MR Ev Prednisone MR
et al. [57] patients (double blind arm and immediate release (IR) blind (DB) study followed by open administered in
Germany n = 251, open label arm (1–5 mg/day) label (OL) extension. The double the evening
and n = 219), age—20–79 yrs blind arm compared IR (Mo) reduced morning
Poland versus MR (Ev) admn and the open stiffness
label extension had all patients significantly
administered the MR form in the
evening (DB-3 months (MR vs IR),
OL–MR for another 9 months)
Qvortrup Metastatic unresectable Short time infusion of oxaliplatin Non-blinded randomised study— None XELOX30chrono
et al. [36] adenocarcinoma of the (XELOX30) AND XELOX30 ? (C) with 50 % of the does not reduce
Denmarka colon or rectum patients chronomodulated (XELOX30chrono) drug administered in the Mo and toxicity or
(n = 139), age—G1 [30 min oxaliplatin 130 mg/m2 in 50 % in Ev. versus improve efficacy
63(42–75) G2 65(36–80) 250 ml of dextros 5 % oral XELOX30chrono ? (C) with 20 %
yrs capecitabine 2,000 mg/m2 (C)] at afternoon and 80 % at Ev.
(14 days treatment for 8 cycles
repeated every 3 weeks)

Mo morning, Ev evening, Admn administration, Yrs years

a
First author’s country

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Table 5 Results—combined chronopharmacodynamic and chronopharmacokinetic studies

References Participants Drug and dose Study design Suggested Author’s observation
Country Participants Drug (dose) Design (study duration) administration
(sample size, time
age)

Almeida Young Nebicapone Single centre, double blind, Ntt Nebicapone and nebicapone-
et al. Caucasian [100 mg (G1), randomised, placebo-controlled, glucuronide concentration were
[61] healthy 200 mg (G2), parallel group with the drug lower before 8PM dose in
Portugal subjects placebo (G3)] administered every 4 h (7 days) comparison to 8AM dose. Higher
(n = 18), does may be necessary at the end of
age—18–45 the day compared to morning dose.
yrs Cricadian changes were observed
for Nebicapone (G1 and G2) in
S-COMT
Lee et al. Healthy Dexlansoprazole Randomised, open label, 4 way None AUC and Cmax were significantly
[33] subjects MR (60 mg) crossover, single centre, higher after morning dose. Intra-
USA (n = 46), multidose admn—30 min before gastric pH control was better after
age—18–55 Brkfst, Lun, Din or Ev snack evening dose
yrs (43 days)
Mo morning, Brkfst breakfast, Lun lunch, Din dinner, Ev evening, Admn administration, Yrs years, Cmax maximum concentration that drug
achieves after dosing, AUC area under curve, S-COMT soluble catechol-O-methyltransferase

Table 6 Checklist to screen for chronotherapeutic potential of a drug
[24]
1. Do the diseases and/or its symptoms show significant circadian
variation?
2. Does the pharmacokinetics of the drug or its active metabolite
differ significantly with respect to the dosing time?
3. Does the target tissue show significant time-dependent
susceptibility to the drug?
4. Is the severity of the toxicity or side effects of the drug
dependent on the dosage time?
5. Does the efficacy of the drug depend on its delivery in a time
modulated fashion?
6. Does the dosage form get affected by food, posture or other
exogenous effects?
circadian time may compromise therapeutic effect and
sometimes even patient safety [62]. A better perceived
clinical effect or a less discomfort from an adverse effect
may be major adherence prompts for patients. Conversely,
chronotherapy may impose the necessity of high degrees of
patient adherence, as patients will be required to take the
drug at a particular time of day/night. Patients with mul-
tiple co-morbidities are typically dependent on several
classes of medications. In such cases, the particular dosing-
time requirements of chronotherapeutic preparations may
be impossible to meet [63]. Therefore, it may be useful for
chronotherapeutic experts or researchers to consider mea-
surements of adherence or the effect of chronotherapeutic
administration on adherence in future studies.
Chronotherapy is now accepted by biologists and
researchers; however, it still is a novel concept for the
clinical community such that there is a lag in translating
pharmacological research to clinical practice. A key
example is that of hypertension, where there is a robust
body of evidence to support optimising drug administration
time to match the times of day at which blood pressure is
higher. Efforts are required to bring chronotherapy within
mainstream clinical practice including clinical practitioners
such as pharmacists, nurses and physicians, who have a
major role in bringing the benefits of chronotherapy to their
patients. Pharmacists, particularly as medication use
experts are in an excellent position to facilitate patient
education regarding differences between conventional and
chronotherapy drug administration, the rationale for their
use and advantages of using drugs at prescribed times. A
current understanding of chronotherapy should be embed-
ded in curricula. A robust understanding of chronobiology
and chronotherapy will, in our opinion, leads to quality use
of medicines and improved quality of life for patients.
Limitation
Our review has some limitations worth mentioning, we
only considered studies published since 2008 and also
excluded studies which targeted pregnant women and
children, the latter were but a few. We excluded studies
which were dealing purely with the effect of time on the
stability of a drug, since we were investigating actual drug
administration. We have also excluded studies comparing
efficacy of two different drugs at the same time of the day;
such studies of course appear when we used our defined
search terms. Most studies were short term, and therefore
we could not examine the effect of Chronotherapy in

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reducing long term adverse outcomes. Our review has
provided a broad overview, and whilst we report the results
from all reviewed studies, we do not make any systematic
evaluation of the effects of chronotherapy on disease
endpoints. This cannot be so easily done on such a heter-
ogeneous group of studies, covering different diseases, and
different drugs.
Conclusion
This review has highlighted various concepts and defini-
tions in the field of chronotherapy for the first time in
recent literature. Using these definitions, our review pre-
sents the scope of chronotherapy in drug utilisation. There
is considerable evidence for the effect of time on drug
effect in key conditions such as hypertension and diabetes.
In such conditions, it may be prudent for professional
practice guidelines to make due reference to chronothera-
peutic principles. We believe that the knowledge of chro-
notherapy is growing and current research is promisingly in
the conceptualization or early experimental phase. Future
studies should also explore genetic, gender and age related
differences. While chronotherapy studies are currently not
mandated by the regulatory bodies across the world, pre-
liminary screening of new drugs for their chronothera-
peutic potential may be a way of enhancing quality use of
medicines. Clinical curricula should include some exposure
to chronotherapeutic concepts. Healthcare professionals
may also benefit with dedicated findings summarized sys-
tematically in an applicable format, for example product
information should include reference to optimal dosing
time if these are known.
Acknowledgments We would like to acknowledge the Faculty of
Pharmacy, University of Sydney and the Woolcock Institute of
Medical Research for providing infrastructure support.
Funding None.
Conflicts of interest Authors have no conflicts of interest to
declare.
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