UNIVERSITY OF SANTO TOMAS

FACULTY OF PHARMACY


Kinsela Franco and Myzhel Inumerable
2C BS Pharmacy

Scholarly Journal Article Critique Paper

Yi, S., Chung, Y., Kim, T., Shin, H., Yoon, S., Cho, J., et. al. 2011. Pharmacokinetics of
extended-release versus conventional tramadol/acetaminophen fixed-dose combination
tablets: an open-label, 2-treatment, multiple-dose, randomized-sequence crossover study
in healthy Korean male volunteers. Clinical Therapeutics, 33(6), 728-737.
Purpose of the Study
It was made clear in the abstract and in the title of the study that it sought to explore the
pharmacokinetic profile of the new ER tramadol/acetaminophen fixed-dose combination and a
conventional immediate-release (IR) formulation after an open-label, 2-treatment, and multiple
dosing, randomized sequence crossover study in healthy Korean male volunteers. Readers can
readily understand the overall purpose and method of the study.
The study stated direct clear questions to be answered. It aimed to explore the following
main research question: Is there a significant difference between the ER formulation of
tramadol/acetaminophen and the conventional IR formulation? The focus of the study was on the
bioavailability of ER formulation and to compare it between the 2 formulations.
Terminology
Tramadol is a centrally acting analgesic. It is a racemic mixture affect the opiate
receptors in the brain and perhaps also those in the spinal cord. The amounts of left- and right-
handed enantiomers of the chiral molecule is equal. Acetaminophen is an analgesic agent that
has demonstrated its efficacy in widespread clinical use of relieving many kinds of minor aches
and pains. A fixed-dose combination of tramadol/acetaminophen provided effective pain
relief in patients with various pain but for only a short duration of action. This combination has
been found to yield synergistic analgesic effects and offer faster and longer lasting pain relief in
patients having dental pain. An extended-release (ER) formulation is recommended for
chronic pain management because it prolongs its analgesic effect and develop patient
convenience by allowing reduction in dosing frequency. Immediate release formulations
disintegrate rapidly and get dissolved to release the medicaments. These preparations have no
special rate-controlling features, such as special coatings and other techniques.
Some concepts may be familiar to average readers, while the others are jargons of the
pharmaceutical field. Not all the terms are completely defined in the study. The study requires
decoding the terminology to fully understand it.
Methodology
The data were obtained in an open-label, 2-treatment, and multiple dosing, randomized
sequence crossover clinical trial. The study appears to be biased because it was designed as
open-label, therefore it could affect the investigator's evaluation of adverse effects. The tests
conducted were limited to healthy Korean male volunteers. The number of subjects recruited was
determined based on the number estimated to provide 80% power at a significance level of 0.05
to demonstrate a 20% difference in AUC. All subjects were randomly assigned to 1 of 2
treatment sequences according to the randomization table, which was prepared in advance
following a block randomization method. The total duration of this study was 14 days,
comprising 4 days of the first treatment followed by a washout period of 5 days and then 4 days
of the second treatment plus an additional day for blood sampling. Treatment duration was
determined based on the known t1/2 of tramadol and acetaminophen.
The researchers made use of various methods to obtain and to compare the
pharmacological profiles of the 2 formulations. Tramadol and acetaminophen concentrations in
plasma were determined simultaneously using LC-MS/MS, and the pharmacokinetic properties
were analyzed by noncompartmental method. To compare the systemic exposure of the 2
formulations, the geometric mean ratios (GMRs) for AUC0-12,ss and the 90% CIs were
calculated. In the assessment of pharmacokinetics, actual blood collection were analysed through
WinNonlin Professional Network. Data for adverse effects were identified through physical
examinations, 12-lead electrcardiography, clinical laboratory assessments and subject interviews
by asking whether the subjects experience, feel or have any discomfort. Statistical analyses of the
pharmacokinetic were performed using SPSS 12.0. Descriptive statistics were performed for the
pharmacokinetic characteristics between treatments.
A research study followed the steps in the process in a logical manner. There was a clear
link between the steps beginning with the purpose of the study and following through the
literature review, the theoretical framework, the research question, the methodology section, the
data analysis, and the findings.
Authors Arguments
The objective of this study is to explore the pharmacokinetic profile of an extended-
release (ER) formulation including an initial sustained release, rather than to investigate the
pharmacologic factors. Although there have been several studies on the metabolites or each
enantiomer of tramadol, further clinical evaluations may be required in the ER formulation
considering these aspects. The research limits their study to healthy male subjects; this should be
considered to avoid generalization of results to a typical patient population including female
patients. The researchers argue that their standard for the investigator to assess adverse effects
was less biased than for other placebo-controlled trials because the control of their study was not
placebo but the different formulas containing the same chemical material with the same dosages.
The arguments were clearly stated. The strengths and limitations were compared and
contrasted with the findings of the study.
Conclusion
ER formulations with less frequent dosing intervals are designed to maintain sustained
effective plasma concentrations of the drug while minimizing fluctuations in peak and trough
concentrations. The fluctuations of the ER formulation were comparable to those of the IR
formulation. These results suggest that the ER formulation may reduce conventional products'
concentration-related side effects, however the safety aspects of the ER formulation should be
evaluated in studies with a large number of patients. In terms of efficacy, the twice-daily
administration of ER formulation did not result in statistically significant difference in systemic
exposure. Further studies are needed to investigate the optimal dosage regimen with ER tablets
by evaluating the duration of analgesia at the therapeutic dose in patients.
Reflection
The data obtained in the study supports the conclusion of the authors. The extended-
release formulation of tramadol/acetaminophen demonstrated a similar drug exposure to that of
the immediate-release formulation. The results were acceptable because it was assumed that
change in formulation has a little influence on the metabolism of tramadol itself. Thus to further
improve this study, future studies must investigate the efficacy and safety of twice-daily dosing
with ER tablets.
In the overall, the study provides us a scientific explanation on understanding
modifications in dosage forms. Clinical trials provides various methods to prove the efficacy of
different drug formulations available in the market. In addition, it pursues to provide information
on how modified-release dosage forms and drug delivery systems could help improve quality of
life in terms of health.