Pharmacokinetic Interaction Between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized, Open-label, Two-period, Crossover, Multiple-dose Study

Son, Mijeong; Kim, Yukyung; Lee, Donghwan; Roh, Hyerang; Son, Hankil; Guk, Jinju; Jang, Si‐Hyong; Nam, Su Youn; Park, Kyungsoo

doi:10.1016/j.clinthera.2014.06.007

Cited by 23 publications

(49 citation statements)

References 22 publications

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“…Rosuvastatin is commonly used in combination with telmisartan, an angiotensin II type-I receptor antagonist (ARB). Recently, Son et al [12] reported increased pharmacokinetic (PK) exposure of rosuvastatin when coadministered with telmisartan. The absorption of rosuvastatin was accelerated (C max was doubled, with T max change from 5 h to 0.75 h), whereas its AUC increased by only 1.18-fold when coadministered with telmisartan, although the cause of this phenomenon was not identified by the authors.…”

Section: Introductionmentioning

confidence: 99%

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

Park

Jang

Han

2016

Transl Clin Pharmacol

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The C max and AUC of rosuvastatin increase when it is coadministered with telmisartan. The aim of this study was to explore which of the pharmacokinetic (PK) parameters of rosuvastatin are changed by telmisartan to cause such an interaction. We used data from drug-drug interaction (DDI) studies of 74 healthy volunteers performed in three different institutions. Rosuvastatin population PK models with or without telmisartan were developed using NONMEM (version 7.3). The plasma concentration-time profile of rosuvastatin was best described by a two-compartment, first-order elimination model with simultaneous Erlang and zero-order absorption when given rosuvastatin alone. When telmisartan was coadministered, the zero-order absorption fraction of rosuvastatin had to be omitted from the model because the absorption was dramatically accelerated. Notwithstanding the accelerated absorption, the relative bioavailability (BA) parameter estimate in the model demonstrated that the telmisartan-induced increase in BA was only about 20% and the clearance was not influenced by telmisartan at all in the final PK model. Thus, our model implies that telmisartan may influence the absorption process of rosuvastatin rather than its metabolic elimination. This may be used as a clue for further physiologically based PK (PBPK) approaches to investigate the mechanism of rosuvastatin-telmisartan DDI.

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Section: Introductionmentioning

confidence: 99%

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

Park

Jang

Han

2016

Transl Clin Pharmacol

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“…Of these BP measurements, data collected only up to 24 hours were used for the analysis, with those obtained from the combination therapy with metformin being excluded. [12][13][14] …”

Section: Tcpmentioning

confidence: 99%

“…Detailed descriptions of each clinical trial were reported elsewhere. [12][13][14] Subjects received rosuvastatin, angiotensin II receptor blocker (ARB) and metformin monotherapies and the combined therapy of rosuvastatin and ARB or rosuvastatin and metformin, with ARB specifically indicating olmesartan and telmisartan. Then, vital signs of SBP and DBP were measured at predose during the multiple dose periods in an outpatient clinic.…”

Section: Tcpmentioning

confidence: 99%

Blood pressure lowering effect of statin drugs with an application to rosuvastatin

Heo

Son

Park

2016

Transl Clin Pharmacol

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Hyperlipidemia and hypertension are among the major risk factors for cardiovascular disease (CVD) and they often co-exist within a single patient. Recently, many studies published results regarding the potential role of statins in decreasing blood pressure (BP) however there is still a controversy over the efficacy of statin therapy on BP. This study aimed to investigate the potential role of rosuvastatin in BP lowering properties in Korean population. Data were taken from three randomized, multiple-dose cross over studies for rosuvastatin, angiotensin II receptor blocker (ARB) and metformin monotherapies and the combined therapy of rosuvastatin and ARB, in total of 91 healthy male normotensive subjects. Measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) at the baseline before treatment begins and for 24 hours after the last dose were used in the analysis. The analysis variables used were (i) the mean change in steady-state BP from the baseline, symbolized as ΔBP, and (ii) the difference in ΔBP between the ARB monotherapy and the combined therapy, symbolized as ΔBP,d. The △BP and ΔBP,d for SBP from each study varied in -0.1 ~ -1.3 mmHg and 1.2 ~ 1.6 mmHg, respectively, and were not significantly different from zero. The △BP and ΔBP,d for DBP from each study varied in -2.8 ~ -1.4 mmHg and -2.9 ~ -1.8, respectively, which were statistically significant for △BP (p < 0.05) but was not for ΔBP,d (p > 0.05). These results indicated that the rosuvastatin monotherapy may produce small blood pressure lowing effect in DBP.

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“…© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) Basic & Clinical Pharmacology & Toxicology, 2018, 122, 139-148 Doi: 10.1111 dose, 2 9 2 crossover design conducted in healthy male volunteers in 2012 at Severance Hospital, Seoul, Korea [10].…”

Section: Methodsmentioning

confidence: 99%

“…The data were acquired from a PK interaction study between rosuvastatin and telmisartan using a randomized, open-label, multipleAuthor for correspondence: Kyungsoo Park, Department of Pharmacology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea (e-mail kspark@yuhs.ac). dose, 2 9 2 crossover design conducted in healthy male volunteers in 2012 at Severance Hospital, Seoul, Korea [10].…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Model for Blood Pressure and Heart Rate Changes Produced by Telmisartan in Human Beings

Chae

Son

Kim

et al. 2017

Basic Clin Pharma Tox

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Telmisartan, an angiotensin receptor blocker (ARB), is indicated for the treatment of essential hypertension. This study aimed to develop a mechanistic model of telmisartan drug effect in human beings using non-invasive markers. Data were acquired from a previous study where telmisartan 80 mg was given once daily for 6 days. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were measured before dosing for days 1-5 and serially after the last dose. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated from SBP and DBP. Relationships between MAP, PP, HR and total peripheral resistance (TPR) were developed. Circadian variation was incorporated into PP and HR, and TPR was assumed to adjust itself in response to changes in PP and HR based on baroreflex mechanism. Drug effects were then described as lowering the set point of MAP through TPR with a physiological feedback effect stimulating HR and PP. Drug concentrations were described by a two-compartment disposition model with first-order absorption and lag time, and first-order elimination. Circadian variation was described by cosine functions, having periods of 12 and 24 hr. A log-linear model was used to describe drug effect, with estimated drug effect parameter of 0.051/hr. Estimated fractional turnover rate of PP, HR and TPR was 11.2 hr. The model successfully described the time courses of these cardiovascular variables. This work demonstrated the feasibility of using non-invasive cardiovascular measurements to derive a mechanistic model for telmisartan in human beings. The model may be suitable for other ARBs.Telmisartan is an antagonist of the angiotensin II type 1 (AT1) receptor that is used for the treatment of hypertension. It selectively inhibits stimulation of the AT1 receptor by angiotensin II. It has a high volume of distribution and is eliminated mainly by the kidneys which results in a long terminal elimination half-life. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions [1,2].The action of telmisartan is known to lead to inhibition of aldosterone secretion and reduced vasoconstriction. The time course of its effect involves both rapid and slow responses. The rapid response is mainly due to antagonizing angiotensin II vasoconstriction. The slow response is due to antagonizing angiotensin-mediated aldosterone secretion which leads to a natriuretic effect, followed by decreased plasma volume and consequent decrease in cardiac stroke volume. Both the rapid and slow effects contribute to lowering of blood pressure [1].A population pharmacokinetic (PK) model for telmisartan was first published in 2003 [3] and reported that a two-compartment disposition model with first-order absorption and elimination described the data. A PKPD model of telmisartan has been published [4] in spontaneously hypertensive rats. To the authors' knowledge, no PKPD model of telmisartan has been published in human beings. Previous PKPD models used either an empirical modelli...

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Pharmacokinetic Interaction Between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized, Open-label, Two-period, Crossover, Multiple-dose Study

Cited by 23 publications

References 22 publications

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

Blood pressure lowering effect of statin drugs with an application to rosuvastatin

Mechanistic Model for Blood Pressure and Heart Rate Changes Produced by Telmisartan in Human Beings

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