The effect of age on the pharmacokinetics and pharmacodynamics of midazolam

Albrecht, Susanne; Ihmsen, Harald; Hering, W.; Geißlinger, Gerd; Dingemanse, Jasper; Schwilden, H.; Schüttler, J.

doi:10.1016/s0009-9236(99)90084-x

Cited by 131 publications

(71 citation statements)

References 28 publications

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“…The same results were obtained with regards to gender (P>0.05). These data suggest that midazolam pharmacokinetics in Chinese after oral administration are unaffected by either age or gender, and this conclusion is consistent with studies of Caucasian subjects [34][35][36][37] . As an oral hypnotic, midazolam has been in the market for many years in China; however, there have been few pharmacokinetic studies [25][26][27] , and there is significant inter-study variability (Table 5).…”

Section: Midazolam Pharmacokinetics In Chinese After Oral Adminis Trasupporting

confidence: 89%

“…Investigation of the effects on midazolam pharmacokinetics using the PBPK model Previous studies in Caucasians demonstrated that the pharmacokinetics of midazolam were unaffected by age [34][35][36][37] ; however, this topic has never been examined in Chinese. In this study, the verified PBPK model was used to investigate the effects of age on midazolam pharmacokinetics in Chinese from a physiological perspective.…”

Section: Midazolam Pbpk Modelingmentioning

confidence: 99%

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Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

et al. 2015

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Aim: To evaluate the SimCYP simulator ethnicity-specific population model for predicting the pharmacokinetics of midazolam, a typical CYP3A4/5 substrate, in Chinese after oral administration. Methods: The physiologically based pharmacokinetic (PBPK) model for midazolam was developed using a SimCYP population-based simulator incorporating Chinese population demographic, physiological and enzyme data. A clinical trial was conducted in 40 Chinese subjects (the half was females) receiving a single oral dose of 15 mg midazolam. The subjects were separated into 4 groups based on age (20-50, 51-65, 66-75, and above 76 years), and the pharmacokinetics profiles of each age-and gender-group were determined, and the results were used to verify the PBPK model. Results: Following oral administration, the simulated profiles of midazolam plasma concentrations over time in virtual Chinese were in good agreement with the observed profiles, as were AUC and C max . Moreover, for subjects of varying ages (20-80 years), the ratios of predicted to observed clearances were between 0.86 and 1.12. Conclusion: The SimCYP PBPK model accurately predicted the pharmacokinetics of midazolam in Chinese from youth to old age. This study may provide novel insight into the prediction of CYP3A4/5-mediated pharmacokinetics in the Chinese population relative to Caucasians and other ethnic groups, which can support the rational design of bridging clinical trials.

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Section: Midazolam Pharmacokinetics In Chinese After Oral Adminis Trasupporting

confidence: 89%

Section: Midazolam Pbpk Modelingmentioning

confidence: 99%

Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

et al. 2015

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“…The EC 50 for sedation after intravenous midazolam is reduced by 50% in older people (522 Ϯ 236 versus 223 Ϯ 56 ng/ml) despite the absence of significant age-related pharmacokinetic differences (clearance, 399 Ϯ 91 versus 388 Ϯ 97 ml/min) (Albrecht et al, 1999). Similar age-related reductions in EC 50 for sedative and cognitive effects of benzodiazepines, in the absence of major pharmacokinetic changes, have been reported for flunitrazepam (Kanto et al, 1981).…”

Section: The Aging Process and Pharmacodynamic Responsesmentioning

confidence: 99%

Aging Biology and Geriatric Clinical Pharmacology

2004

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“…Elderly individuals are generally more sensitive to pharmacotherapy although bidirectional pharmacodynamic alterations have been observed (Mangoni and Jackson, 2003). The central nervous system is especially vulnerable with aging and centrally acting drugs consistently shown to produce sensitized reactions in the elderly independent of pharmacokinetic changes include benzodiazepines (midazolam), opioids (morphine), and anticholinergic tricyclic antidepressants (imipramine and amitriptyline) (Albrecht et al, 1999;Lotrich and Pollock, 2005;Villesen et al, 2007). Mechanisms by which these pharmacodynamic alterations occur are still relatively unclear but are usually attributed to changes in drug-receptor interactions, altered postreceptor signaling, and impaired homeostatic mechanisms (Shi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats

Goh¹,

Aw²,

Lee³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C max of galantamine and prolonged t 1/2 (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.

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The effect of age on the pharmacokinetics and pharmacodynamics of midazolam

Abstract: These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.

Cited by 131 publications

References 28 publications

Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

Aging Biology and Geriatric Clinical Pharmacology

Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats

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