FEV, forced expiratory volume; GI, gastrointestinal; IS, isosorbide; ISDN, isosorbidedinitrate; MN, mononitrate. Correspondence: B. Lemmer, Zentrum der ...
Advanced Drug Delivery Reviews, 6 (1991) 83--100
83
Elsevier ADR 00077
Implications of chronopharmacokinetics for drug delivery" antiasthmatics, H2-blockers and cardiovascular active drugs Bj6rn L e m m e r Zentrum der Pharmakologie, J. W. Goethe-Universitiit, Frankfurt am Main, Germany (Received November 8, 1990) (Accepted November 21, 1990)
Key words: Angina pectoris; Asthma; Chronopharmacokinetics; H2-blocker; Hypertension; Nifedipine; Oral nitrate; Peptic ulcer; Propranolol; Terbutaline; Theophylline
Contents Summary .................................................................................................................
83
I. Introduction ...................................................................................................
84
II. Chronopharmacology ....................................................................................... 1. Antiasthmatic drugs ................................................................................... 2. Peptic ulcer disease and H2-blockers .............................................................. 3. Cardiovascular active drugs; 13-blockers, calcium-channel blockers and oral nitrates
87 88 90 95
III. Conclusion .....................................................................................................
98
References ...............................................................................................................
99
Summary Circadian rhythms in the functions of the body are well established. Also the symptoms and onset of diseases are not randomly distributed within 24 h of a day (e.g., coronary infarction, angina pectoris and asthmatic attacks, peptic ulcer perforations). It is, therefore, not surprising that also the effects and/or pharmacokiAbbreviations: AUC, area under the concentration-time curve; ACE, angiotensin-converting enzyme; FEV, forced expiratory volume; GI, gastrointestinal; IS, isosorbide; ISDN, isosorbidedinitrate; MN, mononitrate. Correspondence: B. Lemmer, Zentrum der Pharmakologie, J.W. Goethe-Universit~it, Theodor-SternKai 7, W-6000 Frankfurt am Main 70, Germany. 0169-409X/91/$03.50 © 1991 Elsevier Science Publishers B.V.
B. LEMMER
84
netics of drugs can display significant daily variations. Recent data on mainly the chronopharmacokinetics of antiasthmatics, Hz-blockers, and cardiovascular active drugs (propranolol, organic nitrates, nifedipine) are described as representative examples. These data demonstrate that biological rhythms have to be taken into account when evaluating drug-delivery systems, galenic formulations and pharmacokinetics as a basis for drug treatment. I. Introduction
It is a common paradigm in clinical pharmacology that pharmacokinetic parameters are considered not to be influenced by the time of day at which a given drug is administered. Moreover, concerning drug concentration profiles “the flatter the better” is also a common aim in drug targeting. However, an increasing number of recently published studies convincingly gave evidence that these paradigms cannot be maintained any longer. It is now well established that nearly all functions of the body, including those influencing pharmacokinetic parameters, display significant daily variations (for review see Refs. l-3). Circadian (‘circa diem’ is Latin for: about 24 hours [4]), i.e., endogenously driven rhythms or 24-h or daily rhythms in heart rate, body temperature and blood pressure have already been described at the end of the 18th and in the 19th century [5-91. Though the circadian rhythm in plasma cortisol is the most well-known rhythm, numerous studies in man and in experimental animal have provided convincing evidence for the existence of such rhythms not only in the rhythms already mentioned, but also in blood flow, stroke volume, peripheral resistance, parameters of ECG recordings, in the 4.00
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CHRONOPHARMACOKINETICS AND DRUG DELIVERY
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abnormalities such as ST-segment elevation, T-wave pseudonormalization in 13 patients with variant angina [18]; ST-segment depression and painful episodes (n=165) during ambulatory monitoring in patients subsequently undergoing coronary angiography [19]. Myocardial infarction: onset evaluated by the MB-creatinase method in 703 patients [20]. Cerebral infarction: evaluated in 778 male and female patients [21]. Death rate: evaluated in 1251 patients on ischemic heart disease [22]. Figures were redrawn according to the references mentioned (from Ref. 13). (Fig. 1), dynamic c o m p l i a n c e ) , of the liver m e t a b o l i s m , blood flow, first pass effect) and of the kidneys (glomerular filtration, renal plasma flow, p H , urine volu m e , electrolyte excretion) vary with time of day (for review see Refs. 1-3, 12 and 13). A l s o gastric acid secretion exhibits a p r o n o u n c e d circadian variation with peak values in the late a f t e r n o o n in normal subjects as well as in patients suffering from peptic ulcer (Fig. 2 [14]). Finally, also the onset and s y m p t o m s of certain diseases do not occur at r a n d o m within 24 h of a day: already in 1698 John Floyer [15] reported that asthma attacks are m o r e frequent at nightly hours than at other times of day, an observation which has nicely been c o n f i r m e d in m o d e r n e p i d e m i o l o g i c studies in asthmatic patients (Fig. 3; [11,16]). Similarly, the occurrence of coronary
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infarction as well as of angina pectoris attacks and of pathologic ECG-recordings is unevenly distributed over the 24-h span of a day as shown in Fig. 4 [17-22]. In animal experiments significant 24-h rhythms have been demonstrated down to the cellular and subcellular level of, e.g., various neurotransmitter receptors and enzyme activities [23-25]. The rhythmic variations in the 13-adrenergic-mediated signal transmission (i.e., [3-receptor-adenylate cyclase-cAMP-phosphodiesterase system) in the rat brain (Fig. 5) or heart are shown to give an example out of the numerous data published (for review see Refs. 3 and 25). It is interesting to note that the rhythms in basal and in drug-stimulated adenylate cyclase activity in rat cardiac tissue in vitro (!) [24,26] are abolished with increasing age (Fig. 6; [26]), indicating that increased age may be associated with reduced circadian reactivity. II. Chronopharmacology Based on the chronobiologic and chronopathologic findings described above it is
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not surprising that the pharmacokinetics and/or the effects of drugs may also not be constant within 24 h of a day. This has been convincingly demonstrated in experimental animals as well as in clinical studies. In Tables I and II drugs are listed for which daily variations in their pharmacokinetics (Table I) or in the drugs' effects (Table II) have been reported in man. These findings must have also implications for drug targeting including the problems involved in drug delivery. In this review only some representative findings in three different areas of drug treatment will be described to demonstrate that the rhythmic circadian organisation of the body can influence parameters pertinent for the pharmacokinetics as well as the effects and/or side effects of drugs bearing potential importance for drug targeting.
H.1. Antiasthmatic drugs Since nocturnal asthma is a common event in asthmatic disease [10,11,16] it is not surprising that antiasthmatic drugs have also been studied in relation to time of day [11,27]. Theophylline was one of the first drugs for which daily variations in its pharmacokinetics were reported with peak drug concentrations (Cmax) being higher and time-to-peak concentration (tmax) being shorter after morning than after evening application [28]. Up to now more than 49 studies were published [27] covering different theophylline preparations in different galenic formulations. These data in general demonstrated that Cmaxwas lower and/or tmaxwas longer after evening than
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CHRONOPI--IARMACOKINETICS AND DRUG DELIVERY
89
TABLE I Drugs for which daily variations in their pharmacokinetics were reported in clinical studies. From Ref. 12. Chronopharmacokinetics
Chronopharmacokinetics
Cardiovascular active drugs [~-Blockers Propranolol
Antiasthmatic drugs Aminophylline Terbutaline Prednisolone
Calcium-channel blockers Diltiazem Nifedipine Verapamil
NSAIDs, local anesthetics Acetylsalicylicacid Indomethacine Ketoprofen Phenacetin Lidocaine
Organic nitrates Isosorbide-dinitrate Isosorbide-5-mononitrate Digoxin Potassium chloride Dipyridamol Psychotropic drugs Benzodiazepines Diazepam Midazolam Melatonin Hexobarbitone Amitriptyline Lithium Haloperidol Carbamazepine Diphenylhydantoine Valproic acid
Methyldigoxin
Lorazepam Temazepam Nortriptyline
Anticancer drugs Cisplatin Doxorubicine Cyclosporine
Theophylline
Paracetamol Bupivacaine
5-Fluorouracil
Miscellaneous Ethanol Mequitazine Antibiotics AmpiciUin Gentamycin Griseofulvin Sulphasymazine Sulphisomidine GI-tract Cimetidine
after morning application of theophylline, supporting the early data published by Scott et al. [28]. Moreover, recent data indicate th:at theophylline might be dosed higher during the night than during daytime hours - or even a single evening dose might be used - in order to overcome the nocturnal decrease in pulmonary function adequately (Fig. 7 [27,29]). In contrast to the general belief concerning drug concentration curves ("the flatter the better") it seems, therefore, to be advantageous to accept greater fluctuations in drug concentrations throughout 24 hours of a day (Fig. 7) in order to achieve the therapeutic goal better. It is interesting to note that in 1989 for the first time a pharmaceutical company was granted permission from the Food and Drug Administration to market a theophylline tablet product for once-daily evening administration for nocturnal asthma [30]. In the treatment of asthmatic patients 132-sympathomimetic drugs are also of remedies' first choice. Recently, data were published indicating that not only the pharmacokinetics of the 132-sympathomimetic terbutaline but also its effects on
90
B. LEMMER
TABLE II Drugs for which daily variations in their effects were reported in clinical studies From Ref. 12 Chronopharmacodynamics
Chronopharmacodynamics
Cardiovascular active drugs 13-Blockers Acebutolol Atenolol Bevantolol Bopindolol Labetolol Mepindolol
Antiasthmatic drugs Theophylline Aminophylline Orciprenaline Isoprenaline Terbutaline Adrenaline Metacholine Methylprednisolone Dexamethasone Terbutaline + Budesonide
Calcium channel blockers Amlodipine Nifedipine Nisoldipine ACE inhibitors Captopril Diuretics Hydrochlorothiazide Indapamide Xipamide
Metoprolol Nadolol Oxprenolol Pindolol Propranolol Sotalol Nitrendipine Verapamil
Enalapril
Piretanide
Organic nitrates Glyceryl-trinitrate Isosorbide-dinitrate Isosorbide-5-mononitrate Others Clonidine Prazosin Potassium chloride Anticancer drugs Cisplatin THP Combinations Miscellaneous Tuberculine Ethanol Bright light Placebo
Doxorubicin FUDR
Psychotropic drug Diazepam Haloperidol Phenylpropanolamine H~-Antihistamines Clemastine Cyproheptadine Mequitazine NSAIDS, general and local anesthetics and opiods Acetylsalicylicacid Flurbiprofen Ketoprofen Paracetamol Tenoxicam Carticaine Mepivacaine Morphine Halothane
Terfenadine
Indomethacin Metamizole Piroxicam Lidocaine
Endocrinology/gastroenterology Prednisone ACTH Methylprednisolone Insulin Tolbutamide Glucose Bezafibrate Clofibrate H2-Blockers Cimetidine Nizatidine Roxatidine
Famotidine Ranitidine
p e a k e x p i r a t o r y flow w e r e c i r c a d i a n p h a s e - d e p e n d e n t [31-33]. Fig. 8 d e m o n s t r a t e s t h a t a f t e r a s e v e n - d a y s t r e a t m e n t with o r a l t e r b u t a l i n e (7.5 m g at 07.30 h a n d at 19.30 h) Cmax was h i g h e r after m o r n i n g t h a n e v e n i n g d r u g a p p l i c a t i o n with tmax b e i n g 3.5 h a n d 6.2 h, r e s p e c t i v e l y , thus r e s e m b l i n g the daily v a r i a t i o n s o b s e r v e d
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