Vyvanse - A Modern Example of Genius Drug Design
A discussion on the effectiveness of objective-centered drug design.
A Modern Example of Genius Drug Design
The treatment of ADHD (Attention-Deficit Hyperactivity Disorder) in children and adults like any medical treatment, don't come without risks. Even more so when the first-line treatment in both cases involve the use of stimulant medication.
In New Zealand, the stimulant medications approved for the treatment of ADHD in both adults and children are Ritalin/Rubifen (Methylphenidate) and Vyvanse Lisdexamfetamine). Both medications have varying degrees of efficacy and affect different patients in different ways, partly due to their medicinal chemistry and drug design.
In this article, I will be discussing the case of Vyvanse/Lisdexamfetamine and how it's a great illustration of objective-centred drug design.
ADHD's relationship with Dopamine
The pathology of ADHD is widely theorised to be due to mismanagement of dopamine and dopaminergic activity in the synapse. As a result, most pharmaceuticals approved for the treatment of ADHD increase dopaminergic activity, hence they have psycho-stimulant effects.
Adderall and Vyvanse belong to the amphetamine-based class of stimulants, whilst the first-line treatment in children is methylphenidate (traded as Rubifen/Ritalin) - a non-amphetamine based stimulant.
Methylphenidate works as a dopamine re-uptake inhibitor. Similar to SSRI anti-depressants (such as Prozac/Fluoxetine or Zoloft/Sertraline), the mechanism of action for Methylphenidate is the blocking of a neuorotransmitter transporter, which in this case is the Dopamine Transporter (DAT) protein that sits on presynaptic dopaminergic neurons.
The blocking of DAT prevents the re-uptake of synaptic dopamine, allowing it to stay in the synapse for longer, resulting in more dopaminergic action.
Adderall (Dexamfetamine/levoamphetamine mixture) and Vyvanse (Lisdexamfetamine sulfate) are, as their name suggests, amphetamine-based stimulants. Amphetamines, unlike methylphenidate, is actually taken up by the DAT in the presynaptic neuron. Once through the transporter, it disrupts a certain vesicle known as VMAT2, which contains both dopamine and noradrenaline. The destruction of VMAT2 causes these neurotransmitters (and to a certain extent, serotonin) to be released from the vesicles to the cytoplasm.
Amphetamines continue to work its magic by switching on the TAAR1 GPCR (G-protein coupled receptor) which essentially modifies DAT to reduce its re-uptake capabilities.
Fundametally, amphetamine stimulants both induce the release of dopamine, and reduce the re-uptake of dopamine, which makes it very effective in the treatment of ADHD and narcolepsy.
However, these benefits come coupled with their drawbacks. A significant risk in the usage of these medications is the risk of abuse.
Stimulant Abuse and the genius of Vyvanse
Farre & Cami (1991) published studies that state the risk of addiction for a substance is highly influenced by its pharmacokinetics. Specifically, the risk increases alongside:
- Short onset of action
- High rate of absorption
- High lipid solubility for crossing the CNS barrier easily
Reasons like this is why heroin is the more addictive, nefarious cousin of morphine. Or why methamphetamine is a class A narcotic, but amphetamine salts are approved as treatments.
Rather than emerging primarily through serendipitous discovery, Vyvanse was developed around a single defined objective: reducing the abuse potential of stimulant pharmacotherapy while preserving its therapeutic effect. The pharmacological properties reflect this.
Recommended dosing regimen for Vyvanse
Vyvanse comes in capsule form and is taken orally. It reaches its peak plasma concentration around 1-2 hours after administration, and its effects lasts for 12 to 14 hours. This long-acting profile means the patient will only have to take it once a day and are likely to suffer from sleep disturbance side effects.
If taken orally via the recommended regime, it also makes it hard for drug-seekers to achieve their wanted euphoria or "high". Other ADHD treatments also have their long-acting dosage forms. Ritalin ER comes in a slow-release capsule, Rubifen SR attributes its slow-release profile to its unique matrix formulation, same with Adderall XR.
Drug seekers can crush tablets to destroy the matrix or open the capsules to essentially nullify the extended-release profile of those medications. They could also experiment with intranasal administration (snorting) or IV administration (needles) to achieve a high bioavailability from bypassing first-pass metabolism, and decrease its onset of action, giving the user a sharp, intense high minutes after administration.
Although Vyvanse comes in capsule form, opening the capsule and snorting the contents DO NOT give the user a sharp high.
Lisdexamfetamine sulfate is an inactive compound that is not lipophilic, therefore it cannot cross into the CNS. For any psychoactive function, it needs to be metabolised into its active compound Dexamfetamine, which can cross into the CNS.
Interestingly, the metabolism process - which is the most rate-limiting step of Vyvanse's mechanism of action - is not catalysed via traditional CYP450 liver enzymes. Rather, it is metabolised by amino-peptidase enzymes found primarily in erythrocytes (red blood cells). Another common way for drug seeking addicts to grant a longer/stronger high is by consuming CYP450 inhibitors/inducers to augment the metabolism process. Vyvanse does not let the user do this due to the fact that it's not metabolised by CYP450 enzymes.
There is also no known way to induce the amino-peptidase that is responsible for the metabolism of Lisdexamfetamine into its active form, partly because researches don't know the exact enzyme target.
Erythrocytes do not have a nucleus, meaning it doesn't make any of the amino-peptidase enzymes. They are made during the early stages of erythrocyte formation in the bone marrow. What's in the cell is what it has until the end of its life-cycle.
Doping/increasing the number of erythrocytes circulating your body will not affect the metabolism of Vyvanse either. Studies show that Vyvanse only requires ~20% of the readily available erythrocytes in a healthy human adult. Meaning, by doping/increasing the blood, there will be little to no effect on the metabolism Vyvanse.
Conclusion
Vyvanse is a particularly elegant example of what can happen when drug development begins with a clearly defined problem. Amphetamines are highly effective for the treatment of ADHD, but their pharmacology also gives them considerable potential for misuse when the active drug can be delivered rapidly to the CNS. Vyvanse addresses this problem at the molecular level by chemically attaching the dexamfetamine to lysine, and forcing the drug through an erythrocyte-dependent conversion step before it even becomes pharmacologically active, hence its a biological bottleneck that cannot be altered or bypassed effectively via simple means.
Vyvanse does still have risks of abuse, and amphetamines are not rendered completely harmless. What it does well is significantly reduce the rewards of increasing the rate of drug delivery to the brain. Unlike other stimulants which rely on patient's behaviour and physical barriers to the medication, Vyvanse has incredible abuse-deterrent properties built into the molecule itself, which makes it a compelling example of objective-centered drug design.
The genius of Vyvanse is that its safety mechanism is the drug itself, and not an add-on or afterthought around the drug.