The pharmacokinetics of the ?2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation

Uematsu, Toshihiko; Nakano, Masahiro; Kosuge, Kazuhiro; Kanamaru, Mitsutaka; Nakashima, Mitsuyoshi

doi:10.1007/bf00316473

Cited by 49 publications

(32 citation statements)

References 11 publications

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“…9 When the 2 mg tulobuterol patch was administered to healthy adults, it was found to be well absorbed, with an absorption lag-time of about four hours. Serum tulobuterol concentrations peaked at 9-12 hours and decreased gradually over the 24 hours following application of the patch.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Long-term safety, efficacy, and patient acceptability of the tulobuterol patch

Ichikawa¹,

Sugiura²

2013

RRTD

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Abstract:The tulobuterol patch contains a β 2 -adrenergic agonist, is the first transdermal bronchodilator, and was developed in Japan. It relies on a matrix-type transdermal delivery system that contains both crystallized and molecular forms of tulobuterol. This delivery system enables the drug content to be released steadily over 24 hours. When the tulobuterol patch is applied to the skin at bedtime, the serum concentration of tulobuterol peaks in the early morning, suppressing the morning dip in pulmonary function. This pharmacological property also prevents steep increases in plasma drug levels, which reduces the risk of adverse events. Because the tulobuterol patch is easy to use and requires only once-daily application, treatment adherence in patients using the patch is superior to that of other therapies. The clinical efficacy of the patch in patients with asthma and chronic obstructive pulmonary disease at any age has been established in many clinical studies since launch in 1998, and the product has a good safety profile. Therefore, the tulobuterol patch is currently used for the long-term treatment of patients with asthma and chronic obstructive pulmonary disease. Here we review the characteristics of the tulobuterol patch and the results of clinical trials that have investigated the effects of the patch on pulmonary function, quality of life, and adherence. We also discuss the usefulness of the tulobuterol patch in clinical practice.

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Section: Pharmacokineticsmentioning

confidence: 99%

“…A pharmacokinetic study 9 reported that tulobuterol released from the patch did not accumulate during repeated transdermal application in healthy adults. It was well tolerated, except for an increase in heart rate of 10-20 beats per minute after five consecutive applications of a 4 mg patch.…”

Section: Safetymentioning

confidence: 99%

Long-term safety, efficacy, and patient acceptability of the tulobuterol patch

Ichikawa¹,

Sugiura²

2013

RRTD

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“…The weighted mean of the serum concentration obtained from nine clinical trials of the tulobuterol TTS (Hokunalin ® tape) which have been shown in the prescribing information respectively was used as the comparative. 13,[26][27][28][29][30][31][32][33] Those clinical trials were carried out in 5 to 48 healthy Japanese male volunteers.…”

Section: Calculation Of Clinical Pharmacokinetic Parameters Using Thementioning

confidence: 99%

“…11,12) However, as for several commercially-available TTSs, the blood drug concentration reaches the peak value once and then falls during application. 13,14) The fall of blood concentration is caused by decline of the skin-surface concentration of the drug, that is, depletion of the drug. In this instance, the predicted blood concentration profile obtained from the abovementioned simplified model is quite different from the experimental data because the decline of the blood concentration is not considered.…”

mentioning

confidence: 99%

Evaluation of the Predicted Time–Concentration Profile of Serum Tulobuterol in Human after Transdermal Application

Nakamura

Mori

Tojo

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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We proposed an in vitro/in vivo/in silico method for evaluating the clinical performance of matrix type transdermal therapeutic systems (TTSs). This method is based on the following four approaches: (1) drug release experiment, (2) in vitro penetration experiment using excised hairless mouse skin, (3) clinical pharmacokinetic study, and (4) mathematical model for evaluating the pharmacokinetic profile. The tulobuterol TTS was used as an example of a matrix type TTS in this study. The drug diffusion coefficient in the matrix device was calculated from the result of the release experiment. The drug diffusion coefficient and the partition coefficient in the skin were calculated from the results of in vitro skin penetration experiments where hairless mice and rats were used. Those parameters were used as substitutes of human. Further, these parameters were used for solving the governing partial differential equation on skin penetration. The time profiles of the serum concentration in human after applying the tulobuterol TTS were predicted and compared with the clinical data. The predicted profiles obtained from the data of hairless mice reproduced the influence of drug depletion adequately and well agreed with the clinical data, while those from the data of rats differed clearly in the initial rise. This method is useful for prediction of pharmacokinetic profiles of TTSs.Key words prediction; pharmacokinetic profile; transdermal therapeutic system; drug depletionThe mathematical models to predict pharmacokinetic profiles of transdermal therapeutic systems (TTSs) have been already proposed.1-3) Those models consist of theoretical equations describing drug release from the device, skin penetration and body pharmacokinetics. The general governing formula for skin penetration has been derived from Fick's second law. 4,5) The compartment model and the physiological model are usually used as pharmacokinetic models.The predicted pharmacokinetic profiles after TTS application were calculated by applying some parameters for skin penetration, pharmacokinetics and/or drug release to mathematical models. 6,7) Further, the predicted concentration-time profiles were evaluated by being compared with the experimental data.8-10) Such predicted profiles were usually obtained from the simplified mathematical models where the skin penetration rate is regarded as a constant because the general governing formula for skin penetration is complex and difficult to use and the pharmacokinetic profiles of commercially-available TTSs are often predictable by such simplified models. When the flux is constant during TTS application, the terms for skin penetration rate of the mass-balance equations can be considered as a constant, and the term for drug release is omitted. In this instance, the mass-balance equations of pharmacokinetics after TTS application are given in the form of ordinary differential equations. Incidentally, the drug content of commercially-available TTSs is often several-fold higher than the amount required to maintain the flu...

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“…46) Many reports demonstrate the rationale behind chronotherapy. [47][48][49] However, much of the drug delivery research over the past decades has focused on a constant drug release rate. The reason why the majority of DDS is designed with little emphasis on proven oscillatory phenomena may be found in drug delivery limitations.…”

Section: Influence Of Biological Rhythms On Phar-macodynamics and Phamentioning

confidence: 99%

Chronopharmaceutics: Pharmaceutics Focused on Biological Rhythm

Ohdo

2010

Biological & Pharmaceutical Bulletin

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INTRODUCTIONThe mammalian circadian pacemaker resides in the suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm.1) The circadian clock acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior.2)The individualization of pharmacotherapy has been performed mainly by monitoring drug concentrations. However, a pharmacogenetic approach such as genetic diagnosis has become a very attractive field due to the rapid progress of molecular biology.3) Consequently, dosage adjustment has been based on the interindividual differences in drug pharmacokinetics. However, intraindividual variability as well as interindividual variability should be considered in order to achieve further improvement of rational pharmacotherapy. This is because many drugs vary in potency and/or toxicity associated with the rhythmicity of biochemical, physiological and behavioral processes. [4][5][6][7][8] Theoretically, it has been argued that drug administration at certain times of the day should improve the outcome of pharmacotherapy.Biological rhythms not only impact the function of physiology, but also the pathophysiology of diseases. [4][5][6][7][8] Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy). Chronotherapy is especially relevant in the following cases. [4][5][6][7][8] The risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. From the viewpoint of pharmaceutics, the application of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and special drug delivery systems to synchronize drug concentrations to rhythms in disease activity. 7) Pharmaceutical companies have focused on the investigation of underlying mechanisms as well as the conduct of multicenter clinical studies involving numerous patients with the purpose of devising chronotherapeutic interventions with a variety of medications. New technology for delivering medications precisely in a time-modulated fashion by bedside or ambulatory pumps is being developed to manage human dis...

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The pharmacokinetics of the ?2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation

Cited by 49 publications

References 11 publications

Long-term safety, efficacy, and patient acceptability of the tulobuterol patch

Long-term safety, efficacy, and patient acceptability of the tulobuterol patch

Evaluation of the Predicted Time–Concentration Profile of Serum Tulobuterol in Human after Transdermal Application

Chronopharmaceutics: Pharmaceutics Focused on Biological Rhythm

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