Pharmacokinetics of Paracetamol before and after Roux-en-Y gastric bypass

The number of bariatric procedures performed in the Netherlands is increasing,
especially the Roux-en-Y gastric bypass (RYGB). Little is known about the
effect of RYGB on the pharmacokinetics of drugs, neither the surgery procedure
itself nor the loss of weight in the long term. It is unclear how to dose drugs
both shortly and long after the surgery.

Paracetamol (PCM) is a widely used analgesic used by patients because of RYGB,
but it can also be used for other reasons. The common dosage is 500-1000 mg,
maximally four times a day.

PCM is a potential hepatotoxic drug when used in too high dosages. In morbidly
obese people, pharmacokinetics of PCM is different compared to healthy
non-obese volunteers. The peak concentration (Cmax) of and total exposure (AUC,
area under the plasma concentration versus time curve) to PCM are lower in
morbidly obese people. The metabolism of PCM was shown to be increased with
higher activity of glucuronidation, sulfatation and CYP2E1-mediated metabolism,
resulting in faster forming and higher concentrations of toxic metabolite
concentrations. The effect on liver toxcity was demonstrated after
administration of a single dose of 2 g PCM. It is unknown whether normalization
of weight may result into normalization of the pharmacokinetics of PCM.




Another pharmacokinetic study showed that at 6 months after bariatric surgery,
the absorption of 500 mg PCM in RYGB patients was faster compared to healthy
subjects. It also showed that Cmax and AUC increased gradually to values that
are comparable to non-obese patients. An important limitation of this study is
that metabolism of PCM was not studied.

In short, morbid obesity, RYGB surgery and the normalization of weight affect
the pharmacokinetics of PCM, including both absorption as elimination, as well
as the formation of toxic metabolites. A higher dosage of PCM could be
considered to overcome the lower Cmax and AUC, but this option may be limited
by the additional forming of toxic metabolites.

This is why all these aspects will be combined in this research to understand
the pharmacokinetics of PCM before and after RYGB surgery.

To assess the effect of a Roux-en-Y gastric bypass on the pharmacokinetics of a
single oral dose of 1000 mg paracetamol before the surgery. within one month
after the surgery and 6 months after the surgery.

This study is an open-label, longitudinal pharmacokinetic study. 20 morbidly
obese patients will be included, who are planned to undergo a Roux-en-Y gastric
bypass surgery. Pharmacokinetics of a single oral dose of 1000 mg paracetamol
(PCM) will be assessed at 3 time points: up to 2 months before RYGB, and at 2
weeks - 1 month after and 5-7 months after surgery.

The moments for pharmacokinetic sampling will be combined with regular visits
of the patients to the hospital to avoid unnecessary burden for the patients.
Furthermore, eight healthy non-obese volunteers will be included to assess the
pharmacokinetics of a single oral dose of 1000 mg PCM.

All participants will be screened and asked for informed consent.

Amendment:
A semi-simultaneous design will be applied to part of the participants. At 5-7
months after surgery, 6 morbidly patients will get an oral dose, followed by an
intravenous dose of 1000 mg PCM 4h later. By comparing the data from the
different dosing regimens, oral bioavaibility (F) can be assessed.

See study design: pharmacokinetics of a single oral dose of 1000 mg paracetamol
(PCM) will be assessed at 3 time points: up to 2 months before RYGB, and at 2
weeks - 1 month after and 5-7 months after surgery.

Amendement:
At the last time points, pharmmacokinetics of a single oral dose of 1000 mg
paracetamol (PCM), followed by an intravenous dose of 1000 mg PCM will be
assessed in 6 RYGB patients

The potential risk for the patients and healthy volunteers is assessed to be
minimal. All subjects will receive a usual dose of paracetamol (PCM). With this
dosage PCM and metabolites can be measured in relevant concentrations. A higher
dosage - even after a single dose - could lead into liver toxicity.

In this study, pharmacokinetics of a single oral dose of 1000 mg PCM will be
assessed at three time points in subjects who are on the waiting list to
undergo RYGB surgery: once before, between 2 weeks - 1 month and between 5-7
months after RYGB. Pharmacokinetics of a single oral dose of 1000 mg PCM will
be assessed once in healthy volunteers.

For this study, patients will be asked to extend their stay in the hospital on
visit days to at least 6 hours. At 9 time points, blood samples will be drawn.
To minimize burden for patients, they will receive a intravenous canula
allowing multiple blood sampling via the same venepuncture for the first 8 time
points. The last sample will Always be drawn via venepuncture. The subject can
decide whether this will take place at their home or in the hospital the next
day. The number of sampling is necessary to assess the absorption and
metabolism of PCM and the metabolites before and after RYGB. The outcomes of
this research outweight the burden, because the understanding of
pharmacokinetic changes will help us to assess whether patients after RYGB are
adequately treated with the standard dose of PCM.

It is necessary to include a control group of 8 healthy subjects to compare the
results of patients before and after RYGB with healthy volunteers without
overweight who do not undergo RYGB. Only then can be assessed if the
pharmacokinetics of morbidly obese patients return to the same profiles as of
healthy subjects without obesity. Based on the results of this comparison, a
new dosage regimen can be suggested.

Moreover, visits of patients will be combined with regular visits of
participants, so that they do not need to come to the hospital for an extra
time. Blood sampling will be done by trained personnel. Thus, risks during
withdrawal of blood are minimized as much as possible.*

Addendum:
6 RYGB patients will get at the last time point a single oral dose of 1000 mg
PCM intravenously via a second intravenous canula in the other arm. 4
additional blood samples will be withdrawn. The length of stay in the hospital
for these RYGB patients remains the same.