Population pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood pressure measurements

Hempel, Georg; Karlsson, Mats O.; Alwis, Dinesh P. de; Toublanc, Nathalie; McNay, J. L.; Schaefer, Hans

doi:10.1016/s0009-9236(98)90053-4

Cited by 39 publications

(57 citation statements)

References 10 publications

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“…For panels A, B, and C, blood was collected for plasma samples in period 1 at predose (0) and at 1, 2, 6, 12, and 24 h postdose and in remaining periods at predose (0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 18, 24, 30, 48, and 72 h postdose. Semirecumbent diastolic and systolic blood pressure (SBP) measurements were obtained at predose (0), 0.5, 1, 2, 3, 4,6,8,12,24, and up to 48 h postdose; the 18-h SBP was obtained at the discretion of the investigator. Orthostatic blood pressure data were collected much less extensively (at predose (0), 2, and 4 h postdose) and were not further considered in PK/PD model development.…”

Section: Clinical Protocolmentioning

confidence: 99%

“…The set point block forced the feedback system at a characteristic amplitude and period and approximately captured the well-known normal underlying circadian rhythm in BP (15). Introduction of this sinusoidal set point block is a convention which mimics approaches used to describe oscillations in both BP (6,8) and baseline body temperature (16). Other efforts describe nonlinear feedback systems to introduce oscillatory behavior Fig.…”

Section: Physiological Significance and Plausibility Of The Bp Modelmentioning

confidence: 99%

“…A more prolonged BP decrease during sleeping hours would result in BP fluctuations that would not oscillate in time with a fixed period and would consequently not be captured by our simple set point model. Previous studies that report 24-h ambulatory BP measurements have rich data sets for the entire 1-day period; these data sets were amenable to a more thorough analysis of circadian rhythms via cosine and sum of cosine terms (6,8). However, this study was not designed with BP effects as a primary endpoint since BP elevation with compound A was not the intended effect.…”

Section: Physiological Significance and Plausibility Of The Bp Modelmentioning

confidence: 99%

“…To achieve our first aim, we proposed a lumpedparameter PK/PD model that captured both features of the BP response and several facets of the feedback mechanism responsible for BP homeostasis. Several PK/PD models, spanning empirical to physiological, have been proposed to capture the desired or anticipated effect of a drug upon BP (4)(5)(6)(7)(8). Our model development borrowed several features from the physiologically based PK/PD model of Francheteau et al (5), which explicitly models key features of the baroreceptor reflex and the desired effects of intravenous dihydropyridines on lowering BP.…”

Section: Introductionmentioning

confidence: 99%

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Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event

Stroh

Addy

et al. 2009

AAPS J

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Abstract. We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumpedparameter pharmacokinetic-pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlledrelease (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.

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Section: Clinical Protocolmentioning

confidence: 99%

Section: Physiological Significance and Plausibility Of The Bp Modelmentioning

confidence: 99%

Section: Physiological Significance and Plausibility Of The Bp Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event

Stroh

Addy

et al. 2009

AAPS J

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“…So far, models based on trigonometric functions such as the cosine function or Fourier series have been applied for the description of circadian rhythm (Hempel et al, 1998;Chakraborty et al, 1999). However, here we apply a novel feedback model for circadian rhythm, which is described in more detail elsewhere (Sä llström et al, 2005).…”

mentioning

confidence: 99%

Modeling Drug- and System-Related Changes in Body Temperature: Application to Clomethiazole-Induced Hypothermia, Long-Lasting Tolerance Development, and Circadian Rhythm in Rats

Visser

Sällström²,

Forsberg³

et al. 2005

J Pharmacol Exp Ther

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The aim of the present investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of clomethiazole (CMZ)-induced hypothermia and the rapid development of long-lasting tolerance in rats while taking into account circadian rhythm in baseline and the influence of handling. CMZ-induced hypothermia and tolerance was measured using body temperature telemetry in male Sprague-Dawley rats, which were given s.c. bolus injections of 0, 15, 150, 300, and 600 mol kg Ϫ1 and 24-h s.c. continuous infusions of 0, 20, and 40 mol kg Ϫ1 h Ϫ1 using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 mol kg Ϫ1at 3-to 32-day intervals. Plasma exposure to CMZ was obtained in satellite groups of catheterized rats. Fitted population concentration-time profiles served as input for the pharmacodynamic analysis. The asymmetric circadian rhythm in baseline body temperature was successfully described by a novel negative feedback model incorporating external light-dark conditions. An empirical function characterized the transient increase in temperature upon handling of the animal. A feedback model for temperature regulation and tolerance development allowed estimation of CMZ potency at 30 Ϯ 1 M. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 Ϯ 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 Ϯ 3 days. This multicomponent turnover model was able to quantify the CMZ-induced hypothermia, circadian rhythm in baseline, and rapid onset of a long-lasting tolerance to CMZ in rats.Clomethiazole (CMZ) has sedative, hypnotic, anticonvulsive, and neuroprotective properties and has been used clinically in elderly patients as a useful sedative/hypnotic for 40 years (Green, 1998). In a recent investigation, we showed that CMZ is able to induce hypothermia in rats and that even a single injection of CMZ rapidly induces complete tolerance lasting for more than 10 days, with a 50% return of effect after a month . This observation of tolerance partly explained why conflicting reports exist regarding the ability of CMZ to induce hypothermia and the relationship between hypothermia and neuroprotective properties in vivo (Cross et al., 1991;Green, 1998;Chaulk et al., 2003). For CMZ, it was observed that the tolerance is induced directly by the drug, rather than via a decrease in body temperature, because hypothermic tolerance to CMZ did not affect hypothermic responses to other drugs and could not be attenuated . Moreover, the tolerance appeared to last for more than 15 days, which suggests that CMZ downregulated a necessary but so far unknown mediator, which by itself has a slow turnover. In the present investigation the objective was to quantify the CMZ-induced hypothermia and the rapid onset of long-lasting tolerance by developing a pharmacokinetic-pharmacodynamic (PK/PD) model. Article, publication date, and citation information can be found at

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Redefining Blood Pressure Assessment — The Role of the Ambulatory Blood Pressure Monitoring Study for Drug Safety

Garnett

Johannesen

McDowell

2019

Clin Pharma and Therapeutics

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According to models developed from large epidemiological studies, mean increases in systolic blood pressure of 2–3 mmHg can increase the risk of cardiovascular (CV) adverse events, especially in patients with a high risk for CV disease. There are new regulatory recommendations for the use of a safety ambulatory blood pressure monitoring (ABPM) study to assess the blood pressure (BP) effects of drugs used chronically. The ABPM study collects BP measurements over 24 hours at baseline and during treatment in patients with underlying CV risk. Our evaluation of ABPM studies submitted to the US Food and Drug Administration (FDA) shows these studies can provide precise estimates of BP changes and lack a pronounced placebo response. With the assessment of BP effects in development programs, opportunities exist for developing quantitative safety models to predict CV risk, support dose selection, identify patients with increased BP response, and provide insight into underlying mechanisms.

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Population pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood pressure measurements

Abstract: The pharmacokinetic-pharmacodynamic model for 24-hour ABPM can be used to estimate the concentration-effect relationship of antihypertensive drugs.

Cited by 39 publications

References 10 publications

Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event

Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event

Modeling Drug- and System-Related Changes in Body Temperature: Application to Clomethiazole-Induced Hypothermia, Long-Lasting Tolerance Development, and Circadian Rhythm in Rats

Redefining Blood Pressure Assessment — The Role of the Ambulatory Blood Pressure Monitoring Study for Drug Safety

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