Dear CF Care Provider:
We have received numerous inquiries regarding the procedure for
determination of ibuprofen pharmacokinetics in patients with cystic
fibrosis (CF). The data that we used to address pharmacokinetic
issues were based on the ibuprofen literature, and in particular,
our study documenting the pharmacokinetic changes in ibuprofen
handling in CF1. In addition to these resources, we have also used
pharmacokinetic information from our four year clinical trial2
to formulate a procedure for determining the appropriate pharmacokinetically
derived dose of ibuprofen for clinical use.
In brief, the following describes our recommended approach to
performing pharmacokinetics on CF patients: Patient should fast
for at least two hours before the kinetic study is begun. Insert
a heparin lock into an arm vein. Draw a blood sample into a heparinized
syringe for a zero time point (to be sure that the patient has
not taken anything containing ibuprofen by accident). Administer
ibuprofen, 20-30 mg/kg, in the formulation that will be prescribed
to the patient. Draw blood samples at 60 minutes, 120 minutes,
and 180 minutes after taking ibuprofen. Centrifuge the samples
to obtain plasma. In the trial, patients were permitted to eat
after the 120 minute sample was drawn. If the baseline value is
zero and at least one ibuprofen concentration value is between
50 and 100 µg/ml, and none of the values exceed 100 µg/ml,
then the dose given the patient is the correct dose. If no value
is over 50 µg/ml, the dose should be increased and the test
repeated. If a value is over 100 µg/ml, the dose should be
reduced and the test repeated.
This procedure was developed after careful analysis of all the
available information on ibuprofen pharmacokinetics in CF patients,
and we recommend not deviating from this approach. To assist you
in obtaining pharmacokinetics and appropriately prescribing ibuprofen
to your patients, we have, with the assistance of the Cystic Fibrosis
Foundation (CFF), formed the CF Ibuprofen Laboratory. This commercial
service is available to all CF Centers and CF care providers.
A test kit is provided for each patient, including supplies and
detailed information for performing an Ibuprofen Test. Following
the Test, the care provider ships the plasma samples to the CF
Ibuprofen Laboratory, and a recommendation for dosing ibuprofen
is provided based on the results. Pages here includes a general
information sheet on this service.
Additionally, we assisted the CFF in assembling an information
packet concerning the use of ibuprofen in CF which was distributed
to all CF Center Directors. Please contact your CF Center for
a copy of "Questions and Answers - Ibuprofen for Cystic Fibrosis
Physicians" and "Questions and Answers - Ibuprofen:
Information for Individuals with Cystic Fibrosis."
Thank you for your inquiry.
A paper has been published in the March 30 [1995] The New England
Journal of Medicine that presents data from the four-year
double-blind, placebo-controlled trial of ibuprofen in patients
with cystic fibrosis (CF). Researchers found that ibuprofen, if
taken consistently, will retard progression of CF lung disease
in patients with mild disease at the outset. This is particularly
true if the ibuprofen is begun before age 13, and taken consistently.
The study was conducted at Rainbow Babies and Childrens Hospital
and Case Western Reserve University School of Medicine, in Cleveland,
with assistance from the Children's Hospital Medical Center of
Akron.
The trials was conducted in 85 CF patients age 5-39 years with
FEV1 
60% predicted at the outset. In the intent-to-treat
analysis, patients randomized to ibuprofen had significantly slower
rate of decline
of FEV1 and percent ideal body weight than patients
randomized to placebo. The patients who took the drug consistently
for four years with 70% compliance (by pill counts) had
even better results from ibuprofen, and the effect was most pronounced
for patients less than 13 years of age at the beginning of the
study. For these younger patients, in the intent-to-treat group,
those randomized to ibuprofen lost about 1.5% predicted in FEV1
each year, or about 6% over the trial; however, those randomized
to placebo lost about 4% predicted per year, for a loss of over
16% in four years. The younger patients who completed the trial
on ibuprofen lost only 0.5% predicted per year, or less than 2%
over the course of the trial.
The dose of ibuprofen used in the study was selected to achieve
peak blood levels between 50 and 100µg/ml and was monitored
by pharmacokinetic analysis. This level was selected because the
anti-neutrophil effects of ibuprofen are only achieved at these
high levels.
These findings raise many questions; therefore the authors and
six CFF consultants have put together the following "Q &
A."
What do your patients already know about ibuprofen?
The Upjohn Company developed ibuprofen as a prescription drug
under the name Motrin. It is a non-steroidal anit-inflammatory
drug (NSAID), most often prescribed to treat arthritis, fever,
menstrual symptoms, and pain. After the drug patent expired, ibuprofen
was released for over-the-counter sale. Originally sold in 400
mg or 800 mg tablets, ibuprofen recently became available in 200
mg tablets. Many companies now make it under the trade names:
Advil; Nuprin; Motrin-IB; and several others.
Is this trial definitive? (There were only 85 patients vs. 968 in the DNase study)
Power analysis for this trial, before it began, indicated that
this number of patients was adequate to detect the effect size
judged "clinically significant." The number of patients
required in this trial was much fewer than in the DNase study
because the ibuprofen trial went on for four years, the DNase
study for six months; and the ibuprofen study was restricted to
patients with FEV1 60% predicted at the outset,
whereas the DNase trial accepted a much broader range of severity
of disease. These two factors allowed statistical significance
for a given effect size to be detected with many fewer patients
in the ibuprofen study. For the ibuprofen trial, there is a 2
in 100 chance that the results observed occured entirely because
of chance, and not because the effect of ibuprofen.
However, the sample size in the ibuprofen study, which is clearly
sufficient to detect the therapeutic effect, is too small to permit
full assessment of possible adverse effects, especially those
that are uncommon.
The study group was CF patients, 5-39 years of age, with FEV1
60% predicted at the outset. The most conservative interpretation
of the data would say that patients who meet these criteria are
candidates for ibuprofen therapy.
However, subgroup analysis showed that patients 5-12 years of
age at the outset had much more striking benefit than older patients.
This group would be the prime target. Subgroup analysis
also showed better effect in those who took the drug consistently.
Thus, habitually non-compliant patients may be exposed to risks
of ibuprofen without gaining the benefits.
What about patients younger than 5?
The trial only included patients able to perform pulmonary functions
tests for at least six months prior to enrollment. Thus, there
are no data on younger patients from this study.
Two adverse effects could clearly be attributed to ibuprofen during
the trial: one patient with exacerbation of conjunctivitis (for
unknown reasons) and one patient with exacerbation of epistaxis
(probably because of the anti-platelet actions of ibuprofen).
What about the GI side effects?
Although patients had GI complaints during this study, they were evenly distributed between the placebo and ibuprofen groups, as was the use of antacids and H2 blockers. Most clincians recognize that abdominal pain is common in CF. During the study, more patients actually reported improvement in abdominal pain than reported worsening. However, because of the relatively small size of the study, we could not be sure of detecting even relatively common side effects of ibuprofen, like gastritis.
It is likely that, as more patients are treated with ibuprofen,
some of them will present with ibuprofen-related gastrointestinal
complaints. One lesson from this study is that many of these
complaints seem to be "part and parcel" of CF as a disease,
and the physician should not attribute all stomach aches to ibuprofen
when the patient is taking the drug. If mild gastritis is suspected to be
due to ibuprofen, and the drug is to be continued, antacids containing
magnesium and aluminum (e.g. Maalox) are the appropriate choice.
Those containing calcium (like Tums) or Pepto-Bismol should be
avoided.
There's been a lot in the papers about renal disease from NSAIDs. What's the story in CF?
No changes in BUN or creatinine were observed in the ibuprofen patients. However, frank renal compromise is rare with ibuprofen, and with this small sample size, we could fail to experience it.
Ibuprofen reduces renal blood flow. It is, therefore, theoretically
possible that ibuprofen could reduce renal clearance of other
drugs. This possibility should be considered in dosing patients
with potentially toxic drugs which are cleared through the kidneys,
such as aminoglycosides.
The trial used very high doses of ibuprofen? Are the adverse effects dose-related?
Other literature suggests that they are. This makes monitoring the
blood levels of ibuprofen important in the management of patients
with CF who are to be treated with ibuprofen.
How do I decide what dose to give?
Most patient in the trial achieved peak plasma concentrations in the target range with dose 20-30mg/kg twice daily (maximum 1600mg/dose). Doses too low might not achieve the beneficial effect, and doses too high increase the risk of side effects. Thus, it is reasonable to perform abbreviated pharmacokinetics for ibuprofen prior to starting the drug.
How should the pharmacokinetics be done?
Patients should fast for at least two hours before the kinetic study is begun. Insert a heparin lock into an arm vein. Draw a blood sample into a heparinized syringe for the zero time point (to be sure that the patient has not taken anything containing ibuprofen by accident). Administer ibuprofen, 20-30mg/kg, in the formulation that will be prescribed for the patient. Draw blood samples at 60 minutes, 120 minutes, and 180 minutes after taking ibuprofen. Centrifuge the samples to obtain plasma and place into appropriately labeled tubes for analysis. In the trial, patients were permitted to eat after the 120 minute sample was drawn.
If body weight increases by 25%, dosage adjustment is probably in order. The levels on the new dose should be checked.
How reproducible are the ibuprofen pharmacokinetics?
In the initial dose-ranging trial, peak concentrations determined a month a part were quite reproducible.
What should a reasonable algorithm for starting and maintaining patients on ibuprofen?
August 22, 1997.
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