Pharmacy Division Ramathibodi Hospital


Interesting Articles in 2002 Jul - Sep

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.


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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.

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.


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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