Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Lew, Kim H.; Ludwig, Elizabeth; Milad, Mark A.; Donovan, Kathleen A.; Middleton, Elliott; Ferry, James J.; Jusko, William J.

doi:10.1038/clpt.1993.167

Cited by 155 publications

(106 citation statements)

References 34 publications

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“…45 Another feature of this model, the dual cosine function, permitted The lymphocyte pharmacodynamic model used in this study also differed from our previous studies. 2,42,43 In this study, a model that is capable of encompassing a substantial rebound component, as demonstrated by the return of T-helper and T-suppressor lymphocytes beyond corresponding baseline cell counts, was needed. This was accomplished by use of a modified precursor-dependent indirect pharmacodynamic response model.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 7 ml blood samples were drawn into heparin-containing collection tubes at 0, 1,2,3,4,6,8,12,14,16,18,20,24,28, and 32 hours. The blood was centrifuged at 2000 rpm for 15 minutes and the plasma harvested and frozen at −20°C until assayed.…”

Section: Methodsmentioning

confidence: 99%

“…Women were found to have a significantly higher clearance of methylprednisolone and thus have a lower drug exposure than do men. 2 However, greater sensitivity to several biomarkers in women was found. Thus, pharmacodynamic differences offset a pharmacokinetic difference.…”

mentioning

confidence: 99%

“…The blood samples were processed as described above. In addition, 3 ml blood was drawn into EDTA-containing tubes at predose and at 1,2,4,6,8,12,18,24, and 32 hours postdose for the determination of T-helper and T-suppressor lymphocyte and neutrophil cell counts. …”

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confidence: 99%

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Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Magee

Blum

Lates

et al. 2001

The Journal of Clinical Pharma

108

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Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T-helper, T-suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight-normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by22%in whites and40%in blacks for oral clearance, p < 0.01; by32%in whites and38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC 50 ) values for T-suppressor cell-trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC 50 or SC 50 values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings.The role of sex as a factor in the pharmacokinetics and the pharmacodynamics (PK/PD) of drugs has become well appreciated. 1 Women often exhibit modestly more rapid clearances of drugs metabolized by the CYP3A4 pathway (e.g., methylprednisolone 2 ). They may also show alterations in the disposition of drugs in relation to the phase of the menstrual cycle (e.g., theophylline 3 ), pregnancy (e.g., caffeine 4 ), or after menopause (e.g., verapamil 5 ). Women receiving oral contraceptives are likely to show more rapid clearances of conjugated NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript drugs (e.g., oxazepam) but have reduced clearances of many oxidized compounds (e.g., prednisolone 6 ). Interpretation of data is sometimes complicated by the need to assess whether pharmacokinetic parameters are properly normalized for body weight differences and if the phase of the menstrual cycle was monitored.The assessment of pharmacodynamic differences between men and women requires control of pharmacokinetic factors and use of appropriate methodology to relate responses to plasma or biophase drug concentrations. There are some notable examples of marked sex differences in drug efficacy. As...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Magee

Blum

Lates

et al. 2001

The Journal of Clinical Pharma

108

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“…where R m is the mean input rate, R b is the amplitude of the input rate, t z is the peak time (baseline acrophase), and 2/24 converts time into radians (Lew et al, 1993). However, more robust mathematical functions have been developed for cortisol secretion, including a form of Fourier analysis and are the subject of comparison (Chakraborty et al, 1999).…”

Section: Mager Et Almentioning

confidence: 99%

Diversity of Mechanism-Based Pharmacodynamic Models

Mager¹,

Wyska²,

Jusko³

2003

Drug Metab Dispos

304

208

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Pharmacodynamics is the study of the time course of pharmacological effects of drugs. The field of pharmacodynamic modeling has made many advances, due in part to the relatively recent development of basic and extended mechanism-based models. The purpose of this article is to describe the classic as well as contemporary approaches, with an emphasis on pertinent equations and salient model features. In addition, current methods of integrating various system complexities into these models are discussed. Future pharmacodynamic models will most likely reflect an assembly of the basic components outlined in this review.

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Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome

Meduri

Headley

Golden

et al. 1998

JAMA

860

207

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Context.-No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. Objective.-To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Design.-Randomized, double-blind, placebo-controlled trial. Setting.-Medical intensive care units of 4 medical centers. Participants.-Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Interventions.-Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Main Outcome Measures.-Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Results.-Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO 2 to fraction of inspired oxygen (FIO 2), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; PϽ.001); improved ratio of PaO 2 to FIO 2 (mean [SEM], 262 [19] vs 148 [35]; PϽ.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; PϽ.001); and successful extubation (7 vs 0; P = .05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P = .002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P = .03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. Conclusions.-In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.

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Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Cited by 155 publications

References 34 publications

Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Diversity of Mechanism-Based Pharmacodynamic Models

Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome

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