From
Journal of Clinical Pharmacology and Therapeutics August 2002 (Volume 27, Number 4)
Pharmacokinetics and Pharmacodynamics of Methylprednisolone After One Bolus
Dose Compared With Two Dose Fractions
Uhl A, Czock D, Boehm B-O, Zellner D, Mertz A, Keller F Journal of Clinical Pharmacology and Therapeutics. 2002;27(4):281-287
Glucocorticoids are usually administered once a day and in some cases every other
day. This administration schedule may result in an insufficient pharmacodynamic
effect because of the short half-life of methylprednisolone. This study compared
the response with a 24-hour single bolus dose of methylprednisolone and two divided
doses (equaling the single dose) given in a 24-hour period. The pharmacokinetics
and pharmacodynamics were evaluated in 8 healthy adult volunteers. In this crossover
study, volunteers were randomized to receive either a single 32-mg methylprednisolone
dose at 7 AM or one 16-mg dose in the morning followed by a second 16-mg dose
at 5 PM. A 1-week washout period was observed between the two treatments. Serial
blood samples were collected after methylprednisolone administration.
Pharmacokinetic parameters were similar between the 2 regimens with the exception
of differences in peak levels. The total 24-hour effect area of CD4+ T-cells was
more suppressed with the divided dose regimen, P = .008.
Editor's Comment
This study was conducted in only a small group of healthy adult males but seems
to suggest that the immunosuppressive effects of intravenous methylprednisolone
are enhanced when the daily dose is divided into two doses rather than given as
a single dose. This observation could have strong implications in the treatment
of many disease states. This pharmacodynamic effect needs to be further clarified
in a larger group of patients, preferably in a population that includes patients
requiring immunosuppressive effects of methylprednisolone.
From Pharmacotherapy September 2002 (Volume 22, Number 9)
Differences in Antimicrobial Drug Exposure in Patients with Various Degrees
of Renal Function Based on Recommendations from Dosing References
Bonapace CR, White RL, Friedrich LV, Bosso JA Pharmacotherapy. 2002;22(9):1097-1104
Adjusting the dose or dosing interval of some medications is necessary in patients
with reduced renal function. Although a dose adjustment may be necessary, the
recommended adjustment can vary, depending on the source of information. In this
study, the investigators assessed the variability among 6 standard references
for patients with normal and various degrees of renal impairment and the resulting
drug exposure that occurred following the recommendations of each resource. The
resources used in the assessment included Bartlett's Pocket Book of Infectious
Disease Therapy, Bennett's Drug Prescribing in Renal Failure, Lexicomp
Infectious Diseases Handbook, Mandell's Principles and Practice of Infectious
Diseases, Physicians' Desk Reference, and The Sanford Guide to Antimicrobial
Therapy. Five levels of renal function were assessed using creatinine clearance
(Clcr) values: 100, 75, 50, 25, and 5 mL/min. A Clcr of
at least 100 mL/min was considered normal.
Based on the dosing recommendations from the 6 references, a wide range of area
under the curve (AUC0-24) was calculated for various renally excreted
medications. Differences were observed both across the range of Clcr
and at the same level of CLcr. With beta-lactams, the AUC0-24
increased with a decrease in Clcr. The AUC0-24 was higher
for the fluoroquinolones when dosed according to the Sanford guidelines compared
with the other references, P </= .0079.
Editor's Comment
Decreased renal function can result in increased exposure of an individual to
a medication. This increased exposure can produce either toxicity or the needless
exposure of a patient to higher drug concentration without any added benefit.
When using a text to adjust does based on renal function, one would assume that
the dosing suggestions are the same across each dosing reference. As is evident
from this study, this is not true. The study did not assess the pharmacodynamic
differences that accompany the different dosing regimens and, therefore, did not
suggest the use of one reference over another. Clinicians need to be aware of
the differences in the texts and use this knowledge to make informed decisions
regarding dosing adjustments for individual patients.
From Clinical Pharmacology and Therapeutics September 2002 (Volume 72, Number 3)
The Pharmacokinetics and Pharmacodynamics of Enoxaparin in Obese Volunteers
Sanderink GJ, Le Liboux A, Jariwala N, et al. Clinical Pharmacology and Therapeutics. 2002;72(3):308-318
Review of data from a recent clinical trial comparing unfractionated heparin to
enoxaparin indicated a statistically nonsignificant trend toward a higher incidence
of venous thromboembolism in patients who were obese. This study was conducted
to evaluate the pharmacokinetics and pharmacodynamics of single-dose and steady-state
enoxaparin in obese volunteers.
The randomized, open-label, 2-way crossover design study included 49 adult volunteers
(24 obese volunteers [body mass index 30 to 40] and 25 nonobese volunteers). Study
participants were given enoxaparin 1.5 mg/kg subcutaneously for 4 days or a single
6-hour infusion of enoxaparin 1.5 mg/kg intravenously. There was a 7-day washout
period between the 2 different regimens. Blood samples were drawn to measure factor
anti-Xa activity, factor anti-IIa activity, and activated partial thromboplastin
time.
After subcutaneous administration, the time to maximum anti-Xa activity was delayed
1 hour but the maximum anti-Xa activity was similar in both groups. After intravenous
administration, Vd and total body clearance were higher in obese volunteers than
in nonobese volunteers but became similar when these values were normalized for
body weight.
Editor's Comment
Trends that are noted in clinical trials can be important questions for future
investigations but should not be accepted as fact until a subsequent study has
confirmed the observations. This study illustrates that point well. Given the
trends observed in other trials, the temptation might be to dose obese patients
at a higher mg/kg dosage than nonobese individuals. According to the findings
of the current study, a higher dosage of enoxaparin is not warranted in obese
individuals.
From British Journal of Clinical Pharmacology August 2002 (Volume 54, Number 2)
Pharmacokinetics of Tibolone in Early and Late Postmenopausal Women
Timmer CJ, Verheul HA, Doorstam DP British Journal of Clinical Pharmacology. 2002;54(2):101-106
This study compares the pharmacokinetics of tibolone in early (45-55 years of
age) and late (65-75 years of age) postmenopausal women. In addition, the study
tested the relative bioequivalence of 2 formulations of tibolone after oral administration.
Sixteen early and 16 late postmenopausal women were recruited for this double-blind,
randomized, 2-way crossover study. Study participants received either tibolone
1.25 mg or tibolone 2.5 mg on study day 1. The other dose was administered on
day 8 after a 7-day washout period. Serum concentrations of tibolone and metabolites
were obtained before dosing and at specified intervals over a 24-hour period.
Maximal concentration, time to maximum concentration, and half-life were independent
of age. Early postmenopausal women had a statistically significant lower value
for the area under the curve of the 3-alpha-hydroxy tibolone metabolite, P
< .05. However, when these values were adjusted for body weight, the differences
disappeared. Bioequivalency was demonstrated for both strengths of tibolone.
Editor's Comment
As the population ages, it is important to consider that even a previously homogenous
group (eg, postmenopausal women) may in fact be significantly diverse. Although
no differences were noted in pharmacokinetics parameters of tibolone in early
and late postmenopausal women, had the results been different, dosing of tibolone
would have required adjustment. More studies that focus on subgroup populations
are important in understanding pharmacodynamic and pharmacokinetic differences.
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