Pharmacokinetic Characteristics of Minocycline in Debilitated Elderly Patients

Yamamoto, Takatsugu; Takano, Kikuo; Matsuyama, Nobuki; Koike, Yuichi; Minshita, Satoru; Sanaka, Masaki; Kawakami, Yasushi; Yamakana, Masami

doi:10.1097/00045391-199905000-00006

Cited by 10 publications

(7 citation statements)

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“…2 There were two patients where the peak concentrations did not exceed 3 μg/mL, but both patients exceeded 100 kg in body weight and their actual mg/kg dose, given the capped dose at 270 mg, was much less than 3 mg/kg. The half-life of near 24 hours in the stroke population is similar to that previously reported in elderly patients, 17 and will allow once daily dosing in future trials. Another pertinent pharmacokinetic finding in this study was the linearity of the parameters over the doses studied and the high variability in volume of distribution, consistent with the high mean and standard deviation of body weight in these patients.…”

Section: Discussionsupporting

confidence: 78%

Minocycline to Improve Neurologic Outcome in Stroke (MINOS)

Fagan

Waller

Nichols

et al. 2010

Stroke

209

179

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Background Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple pre-clinical stroke models. We conducted an early phase trial of intravenous (IV) minocycline in acute ischemic stroke. Methods Following an open label, dose escalation design, minocycline was administered IV within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. Results Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7), race (83% white) and sex (47% female) were consistent across the doses. The mean baseline NIHSS was 8.5±5.8 and 60% received tPA. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10 mg/kg dose. No severe hemorrhages occurred in tPA treated patients. Pharmacokinetic analysis (n=22) revealed a half life of about 24 hours and linearity of parameters over doses. Conclusions 1.) Minocycline is safe and well tolerated up to doses of 10 mg/kg IV alone and in combination with tPA. 2.) The half life of minocycline is about 24 hours, allowing every 24 hour dosing. 3.) Minocycline may be an ideal agent to use with tPA.

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Section: Discussionsupporting

confidence: 78%

Minocycline to Improve Neurologic Outcome in Stroke (MINOS)

Fagan

Waller

Nichols

et al. 2010

Stroke

209

179

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“…All pharmacokinetic parameters, associated standard deviation (SD), and protein-binding rates were obtained from published pharmacokinetic literature (Table I) [14][15][16][17][18][19][20][21][22]. Minocycline pharmacokinetics were derived from a population analysis of 12 debilitated elderly subjects with bacterial respiratory infections [14].…”

Section: Pharmacodynamics and Pharmacokinetics Indicesmentioning

confidence: 99%

“…Minocycline pharmacokinetics were derived from a population analysis of 12 debilitated elderly subjects with bacterial respiratory infections [14]. The pharmacokinetics of tigecycline were derived from a population pharmacokinetic assessment of 412 patients with community-acquired pneumonia (CAP) or HAP [17].…”

Section: Pharmacodynamics and Pharmacokinetics Indicesmentioning

confidence: 99%

A Monte Carlo pharmacokinetic/pharmacodynamic simulation to evaluate the efficacy of minocycline, tigecycline, moxifloxacin, and levofloxacin in the treatment of hospital-acquired pneumonia caused byStenotrophomonas maltophilia

Wei

Cai

et al. 2015

Infectious Diseases

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“…We performed MCE using ADAPT 5 software, with steps detailed in the past, to identify the once-a-week minocycline and tedizolid dose that would achieve the PK/PD exposures achieved by each of these drugs in the dual therapy regimen ( Gumbo et al, 2004 ; Pasipanodya and Gumbo, 2011 ). For the domain of input, we utilized the minocycline PK parameter estimates from the MINOS study in which patients received a dose of 10 mg/kg daily, and from two other separate studies that also identified similar PK parameters but at lower doses ( Welling et al, 1975 ; Yamamoto et al, 1999 ; Fagan et al, 2010 ). For minocycline, we assumed an oral absorption of 100%, and a lung-to-serum penetration ratio of 3.8 based on prior studies ( Naline et al, 1991 ).…”

Section: Methodsmentioning

confidence: 99%

Minocycline intra-bacterial pharmacokinetic hysteresis as a basis for pharmacologic memory and a backbone for once-a-week pan-tuberculosis therapy

Deshpande

Srivastava²,

Pasipanodya³

et al. 2022

Front. Pharmacol.

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Background: There is need for shorter duration regimens for the treatment of tuberculosis, that can treat patients regardless of multidrug resistance status (pan-tuberculosis).Methods: We combined minocycline with tedizolid, moxifloxacin, and rifampin, in the hollow fiber system model of tuberculosis and mimicked each drugs’ intrapulmonary pharmacokinetics for 28 days. Minocycline-tedizolid was administered either as a once-a-week or a daily regimen. In order to explore a possible explanation for effectiveness of the once-a-week regimen, we measured systemic and intra-bacterial minocycline pharmacokinetics. Standard daily therapy (rifampin, isoniazid, pyrazinamide) was the comparator. We then calculated γf or kill slopes for each regimen and ranked the regimens by time-to-extinction predicted in patients.Results: The steepest γf and shortest time-to-extinction of entire bacterial population was with daily minocycline-rifampin combination. There was no difference in γf between the minocycline-tedizolid once-a-week versus the daily therapy (p = 0.85). Standard therapy was predicted to cure 88% of patients, while minocycline-rifampin would cure 98% of patients. Minocycline concentrations fell below minimum inhibitory concentration after 2 days of once-weekly dosing schedule. The shape of minocycline intra-bacterial concentration-time curve differed from the extracellular pharmacokinetic system and lagged by several days, consistent with system hysteresis. Hysteresis explained the persistent microbial killing after hollow fiber system model of tuberculosis concentrations dropped below the minimum inhibitory concentration.Conclusion: Minocycline could form a backbone of a shorter duration once-a-week pan-tuberculosis regimen. We propose a new concept of post-antibiotic microbial killing, distinct from post-antibiotic effect. We propose system hysteresis as the basis for the novel concept of pharmacologic memory, which allows intermittent dosing.

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Pharmacokinetic Characteristics of Minocycline in Debilitated Elderly Patients

Cited by 10 publications

References 0 publications

Minocycline to Improve Neurologic Outcome in Stroke (MINOS)

Minocycline to Improve Neurologic Outcome in Stroke (MINOS)

A Monte Carlo pharmacokinetic/pharmacodynamic simulation to evaluate the efficacy of minocycline, tigecycline, moxifloxacin, and levofloxacin in the treatment of hospital-acquired pneumonia caused byStenotrophomonas maltophilia

Minocycline intra-bacterial pharmacokinetic hysteresis as a basis for pharmacologic memory and a backbone for once-a-week pan-tuberculosis therapy

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