The difference in pharmacodynamic and pharmacokinetic profiles between Tentin and magistral dexamphetamine in adults with attention deficit hyperactivity disorder, a double blinded randomised crossover-controlled trial.

For a long time, dexamphetamine 2.5 mg (magistral) was only available as an
unregistered drug prepared by local pharmacies in the Netherlands. This
situation changed in 2016 when the brand-name Amfexa 5 mg was brought to the
market. In 2020, the manufacturer changed the name Amfexa to Tentin, while the
composition remained the same. The brand-name drug Tentin (Amfexa) should have
the same effect as the unregistered drug prepared by a pharmacy, since the
active compound, dexamphetamine, is identical in both tablets.

The Dutch Pharmacovigilance Centre Lareb identifies side effects associated
with the use of medicines in daily practice and it is the Knowledge Centre for
adverse drugs reactions (ADRs). Following the conversion of magistral
dexamphetamine (GD) to Tentin (Amfexa), Lareb has received a substantial number
of reports for Tentin (dexamphetamine). The same increase in adverse reaction
reports is also reported at EudraVigilance. The reported side effects
associated with Tentin (Amfexa) use have been assessed by the Medicines
Evaluation Board (College ter Beoordeling van Geneesmiddelen) and Lareb, which
has not led to warnings regarding the safety of the drug or the quality (tablet
contents; excipients) of Tentin. The Medicines Evaluation Board (CBG) and Lareb
regard the number of reports as a consequence of nocebo effects, and thus
psychological rather than pharmacological effects, where patients expect a
negative effect, in this case side effects, by switching to another
brand(name), despite the fact that the active compound and dosing has remained
the same.

Another possible cause for the reported complaints can be sought in a
difference in absorption and dissolution rate between Tentin and magistral
dexamfetamine. Patients reported side effects that can be explained by delayed
absorption of Tentin, such as ineffective/decreased/incomplete therapeutic
effects, insomnia, restlessness, disturbance in attention and experiencing
negative emotions. A delayed absorption can be caused by a lower dissolution
rate, which might be caused by the excipients or the preparation method of the
product. Other frequently reported complaints such as a headache, migraine,
palpitations, and the rebound effect can be explained based on the moment and
height of the peak concentration.

No previous studies were found comparing the pharmacodynamic (Pd) and
pharmacokinetic (Pk) profile of Tentin with magistral dexamphetamine.

The primary objective is to compare the pharmacological profile of the
magistral form of dexamphetamine sulphate to the pharmacological profile of the
brand-name form of dexamphetamine (Tentin©) in adult patients diagnosed with
attention deficit hyperactivity disorder (ADHD) and assess whether there is a
difference between the pharmacodynamic (Pd) and pharmacokinetic (Pk) profile of
Tentin and magistral dexamphetamine.

The secondary objective is to assess how pharmacokinetic variability influences
the objective and subjective (side) effects experienced by adult patients with
ADHD.

Double blinded randomised crossover-controlled trial

The study includes a (digital) screening and two intervention days.
Participants will receive one intervention on each intervention-day. All
participants will receive GD and Tentin©, dosed as prescribed by the
practitioner, in a randomised order for two intervention-days. At three moments
(0, 60 and 120 minutes after drug administration) on each intervention-day,
participants will complete the QbTest to assess objective performance and the
QbPerformance to assess subjective performance. At eight moments (0, 45, 60,
75, 90, 120, 150 and 180 minutes after drug administration) on each
intervention-day, participants will fill out questionnaires to assess
subjective experiences. At eight moments (0, 45, 60, 75, 90, 120, 150 and 180
minutes after drug administration) on each intervention-day, participants will
undergo blood sampling to determine dexamphetamine plasma-concentrations and
vital sign measurements for safety monitoring and possible outcome-effects.

The burden of participating in this study include:
I. General time spent on participation
- One (digital) meeting: participant informing, informed consent and screening.
- Two visits to the outpatient clinic: two intervention days.
II. Activities and sampling
- Filling out questionnaires
- Take six QbTests in total over two days (3 tests on each day).
- Taking a total of sixteen blood samples (2ml per sample) over a period of two
days (eight samples on each intervention-day).

The therapy given during this study is based on the treatment as usual (TAU).
Participants will receive Tentin© and magistral dexamphetamine as prescribed by
their practitioner. The burden for each participant is considered minor and the
risk of adverse events very low. Participants will undergo a total of sixteen
blood samples (2ml per sample), eight per intervention day. The risk of
complications and adverse events regarding blood sampling is acceptable in
relation to the possible benefits that may be gained from this study, i.e.,
improved pharmacotherapy guidelines for adult patients with ADHD. A benefit for
the participant lies in the fact that his or her personal response to
stimulants is documented and as such can be used for future pharmacotherapeutic
decisions.