Rutgers University Pharmacology Presentation

1. Research Project video submission. You will create and upload your video (probably voice-over-PowerPoint, but feel free to be creative!) to the course shared drive. This video should give a general introduction to your investigated drug (what it is, what it does, who uses it, and why) and then discuss 1-2 other details you learned about during the course of your semester-long investigations that you found particularly intriguing. This video should be approximately 5 minutes only! Please export your video into a standard format (preferably MPEG-4) and name it Last Name, Drug name.mp4.

As part of this assignment, you will also create two (2) multiple choice questions (with 4-5 possible answers) that ask relevant pharmacologicalquestions about your investigated drug and would be answerable by anyone who 1) watched your video, and 2) fully comprehended the material learned in this class over the course of the semester. Your video should end with a presentation of these two questions (show them, and read the questions and possible answers, but do not indicate the correct answers) Introduction
A radioligand refers to a drug that contains radioactive labels and can closely associate with
receptors, enzymes and other different proteins of interest. The goal of this experiment is to
analyze the binding sites, accessibility and level of affinity to the selected radioligand, [3H]8OH-DPAT.
Section 1
The specific binding equilibrium at a selected radioligand concentrations translates to the
product of fractional occupancy and the total receptor number (B max). The formula used in
this case is;
Specific Binding =Fractional Occupancy *Total receptor number
The total receptor number in this scenario is +100.
[[3H]8-OH-
Non-specific
Specific Binding
CPM
CPM
Total CPM
DPAT] (M)
100
1.00E-11
252.35
225.03
1.00E-09
1.00E-10
471.44
225.29
1.00E-19
3.00E-10
831.28
225.87
3.00E-29
1.00E-09
1465.47
227.9
3.00E-38
2.00E-09
1825.11
230.8
6.00E-47
3.00E-09
1997.48
233.7
1.80E-55
4.00E-09
2099.39
236.6
7.20E-64
5.00E-09
2167.21
239.5
3.60E-72
6.00E-09
2215.97
242.4
2.16E-80
7.00E-09
2252.98
245.3
1.51E-88
8.00E-09
2282.25
248.2
1.21E-96
9.00E-09
2306.15
251.1
1.09E-104
1.00E-08
2326.16
254
1.09E-112
3.00E-08
2493.11
312
3.27E-120
1.00E-07
2737
515
3.27E-127
3.00E-07
3328.97
1095
9.80E-134
1.00E-06
5363.19
3125
9.80E-140
CPMs Vs Radioligand
6000
Binding
4500
3000
1500
0
0.00E+00
2.50E-07
5.00E-07
7.50E-07
Radioligand
Total CPM
Non-speci c CPM
[[3H]8NonOH-
Total
DPAT]
CPM
Specific
specific
Binding
CPM
(M)
0
1.00E-1
252.35
fi
fi
1
225.03
2.40E+00
Speci c Binding
1.00E-06
1.00E-1
471.44
225.29
0
2.67E+00
3.00E-1
831.28
225.87
0
2.92E+00
1.00E-0
1465.47
227.9
9
3.17E+00
2.00E-0
1825.11
230.8
9
3.26E+00
3.00E-0
1997.48
233.7
9
3.30E+00
4.00E-0
2099.39
236.6
9
3.32E+00
5.00E-0
2167.21
239.5
9
3.34E+00
6.00E-0
2215.97
242.4
9
3.35E+00
7.00E-0
2252.98
245.3
9
3.35E+00
8.00E-0
2282.25
248.2
9
3.36E+00
9.00E-0
2306.15
251.1
9
3.36E+00
1.00E-0
2326.16
254
8
3.37E+00
3.00E-0
2493.11
8
312
3.40E+00
1.00E-0
2737
515
7
3.44E+00
3.00E-0
3328.97
1095
7
3.52E+00
1.00E-0
5363.19
3125
6
3.52E-06
Semi-log Graph
Apeci c binding
100
10
1
0
0
5
9
14
18
Log [Radioligand]
The value of Kd represents the ligand concentration which occupies half of the receptors. The
results from the calculation of kd shows that the receptor has a significantly high affinity for
the ligand. Web-based calculator the Kd of [3H]8-OH-DPAT at 5-HT1A under these
experimental conditions is 0.012 nM.
fi
Section 2
Semi-log Graph
10000
ϴ
1000
100
10
1
0
750
1500
2250
3000
[Drug]
Series1
Series2
Series3
Series4
Series5
Series6
Series7
Series8
Series9
The data was normalized using the total and non-specific vials which controlled each
individual drug compound. The normalized data was graphed and the axis formatted in the
logarithm scale. To calculate the IC50 and Ki values of each library compound at 5-HT1A
under these experimental conditions; a web server converter was applied. The
The formula applied was Ki=IC50-E/2
From the graph, the inhibitor concentration to produce 50% of inhibition for each drug was
0.0017. the value of E is 0.01.
Ki= 0.017-0.01/2
Ki= 0.012
Discussion
The data obtained from the experiment indicates that binding occurs in scenarios
where the ligand and receptors or the binding sides collide from diffusion. Collusion occurs
in presence of adequate energy and at proper orientation to ensure that the drug binds to the
correct site. The rate of association in the first set of data was determined by multiplying the
ligand by receptor kon, in minutes (Díaz-Asencio et al., 2018). This indicates the rate of
binding per minute when all the experimental conditions are constant. It is easy analyzing the
constant because the ligand and receptor remain together upon binding for some minutes
depending on the affinity. The rate of dissociation is considered as the time that a ligand takes
to separate from the receptor and equals the association rate. This formular used is; [Ligand]
[Receptor]kon=[LigandReceptor]Koff.
The results are further used to calculate Kd which represents the rate of association
and dissociation at equilibrium. In this experiment the value of kd is expressed in moles per
liter. The value of Kd in low thus represents a high affinity for the drug (Sharma et al., 2019).
In the second section of the experiment, the value of IC50 was impacted by three main
occurrences. First, the Ki receptor on the competing drug which involves calculating the
concentration of the unlabeled drug and its ability to bind to half the sites. Second, the
radioligand concentration which is directly proportional to IC50 at constant Ki. This is
evidenced in the results as increasing the radioligand concentration increased the IC50. The
third factor is the affinity of radioligand to the binding site with a lower Kd representing a
higher affinity (Grätz et al., 2020).
Conclusion
The analysis of data in the experiment is based on several assumptions; that binding
occurs in line with the law of mass action at equilibrium. The second assumption is that the
receptors are similar and thus form a single population. The results also indicate that most
part of the ligand does not bind to the receptor to balance the free and added concentration.
The binding effects is independent as association with one site does not affect that of another
site.
References
Díaz-Asencio, L., Clausing, R. J., Rañada, M. L., Alonso-Hernández, C. M., & Bottein, M. Y.
D. (2018). A radioligand receptor binding assay for ciguatoxin monitoring in
environmental samples: Method development and determination of quality control
criteria. Journal of environmental radioactivity, 192, 289-294.
Grätz, L., Tropmann, K., Bresinsky, M., Müller, C., Bernhardt, G., & Pockes, S. (2020).
NanoBRET binding assay for histamine H2 receptor ligands using live recombinant
HEK293T cells. Scientific reports, 10(1), 1-10.
Sharma, S. K., Lyashchenko, S. K., Park, H. A., Pillarsetty, N., Roux, Y., Wu, J., … & Lewis,
J. S. (2019). A rapid bead-based radioligand binding assay for the determination of
target-binding fraction and quality control of radiopharmaceuticals. Nuclear medicine
and biology, 71, 32-38.
A graphical representation of dose response relationship.
A GRAPGH OF DRUG EFFECT AGAINST DOSE
110
100
90
LUMINESCENCE (EFFECT %)
80
70
60
50
40
30
20
10
0
DOSE
Buprenorphine alone (partial agonist) luminescence
Morphine alone (agonist) luminescence
Naloxone alone (neutral antagonist) luminescence
Naloxone + 10 μM morphine luminescence
BNTX alone (inverse agonist) luminescence
BNTX + 10 μM morphine luminescence
Buprenorphine + 10 μM morphine luminescence
Question 1.
Morphine.
Emax = 3.00E-5
EC50 = 1.00E-8
Buprenorphine.
Emax = 3.00E-5
EC50 = 3.00E-8
BNTX
Emax = 3.00E-5
IC50 = 2.50E-8
Naloxone
Emax = 0
IC50 = 0
Question 2.
Morphine alone (agonist)
Morphine is a full Mu opioid receptor agonist (Gi), thus binds to the receptor resulting
to a decrease in cAMP (Muntean et al., 2018), overall effect being increase in luminescence.
Therefore, increase in morphine concentration is illustrated by the increase in the level of
luminescence up to a plateau phase where all available receptors become saturated.
Naloxone alone (neutral antagonist)
Naloxone is a neutral antagonist therefore bindings to the GPCR receptor both the
inactive and active conformation preventing the action of agonists from accessing the receptor
site (Krause et al., 2018). The overall effect is that the cell will have constant levels of cAMP
reflected by line with zero gradient i.e., constant luminescence on the graph at all
concentrations in the experiment.
BNTX alone (inverse antagonist)
Acts as an inverse antagonist by binding to the same receptor site which an agonist
bind but eliciting an opposite effect to that of the agonist (Kutsumura et al., 2017). Therefore,
on binding to the receptors of the cells it stimulates the receptors to produce more cAMP
therefore decreasing luminescence as the drug concentration increases till it reaches a
plateau when all the receptors become saturated with the drug.
Buprenorphine alone (partial agonist)
Act as a partial agonist to the opioid receptor, binds to the receptors but elicit partial
effect as opposed to that of a full agonist. In this experiment as the concentration of the drug
increases the levels of cAMP decreases resulting to an increase in luminescence up to a
plateau phase when all the receptors become saturated (Note that this effect is not as much
compared to the effect of a full agonist).
Naloxone + 10 μM morphine
There is initial high plateau luminescence due to the action of morphine (completely
occupy the receptors) on Mu receptors that promotes decreased levels of cAMP. This effect
is however countered by increasing concentrations of Naloxone which competitively displaces
morphine from the receptors and stimulate the increase in levels of cAMP, till a plateau phase
is reached whereby all receptors are completely covered by naloxone (Calabrese & Giordano
2021).
BNTX + 10 μM morphine
There is initial high plateau luminescence due to the action of morphine (completely occupy
the receptors) on Mu receptors that promotes decreased levels of cAMP. This effect is
however antagonized with increasing concentration of BNTX which displaces morphine from
the receptor while stimulating the receptor to increase intracellular levels of cAMP. the
luminescence thus decreases to a plateau level when they are completely occupied by BNTX
Buprenorphine + 10 μM morphine
There is initial high plateau luminescence due to the action of morphine (completely occupy
the receptors) on Mu receptors that promotes decreased levels of cAMP. This effect is
however decreased with increasing levels of Buprenorphine which displaces morphine from
the receptor site while causing partial decrease in CAMP, thus there will be decrease in
luminescence to a plateau level where buprenorphine occupies all the receptors.
References
Calabrese, E. J., & Giordano, J. (2021). Ultralow doses and biological amplification:
Approaching Avogadro’s number. Pharmacological Research, 170, 105738.
Muntean, B. S., Zucca, S., MacMullen, C. M., Dao, M. T., Johnston, C., Iwamoto, H., … &
Martemyanov, K. A. (2018). Interrogating the spatiotemporal landscape of
neuromodulatory GPCR signaling by real-time imaging of cAMP in intact neurons and
circuits. Cell reports, 22(1), 255-268.
Krause, D., Warnecke, M., Schuetz, C. G., Soyka, M., Manz, K. M., Proebstl, L., … & Koller,
G. (2018). The impact of the opioid antagonist naloxone on experimentally induced
craving in nicotine-dependent individuals. European Addiction Research, 24(5), 255265. https://www.karger.com/Article/PDF/494346
Kutsumura, N., Koyama, Y., Nagumo, Y., Nakajima, R., Miyata, Y., Yamamoto, N., … &
Nagase, H. (2017). Antitrichomonal activity of δ opioid receptor antagonists, 7benzylidenenaltrexone derivatives. Bioorganic & Medicinal Chemistry, 25(16), 43754383.
In the United States, Humira is an abbreviation for the drug Adalimumab. It’s biological,
which is a class of medication. In rheumatoid arthritis and some other disorders, the body
produces an abnormal amount of a protein called TNF. This results in inflammation,
discomfort, and joint degeneration. Anti-TNF medications such as Adalimumab inhibit TNF
and hence lessen inflammation. In patients with mild to severe rheumatoid arthritis (RA),
Adalimumab reduces swelling, pain, and fatigue in the joints. For the rehabilitation of psoriatic
arthritis and ankylosing spondylitis, juvenile arthritis, Crohn’s disease, and uveitis, it has been
approved by the Food and Drug Administration (FDA) and the European Medicines Agency
(EMA).
Adalimumab is a biological disease modifier injected subcutaneously for the management
of rheumatoid arthritis and other severely debilitating diseases caused by tumour necrosis
factors. It was initially introduced in the United States by AbbVie and received FDA approval
in 2002. It is synthesised by recombinant DNA technique in mammalian cells. This medication
is available in prefilled syringes and a handy pen for self-administered subcutaneous doses.
Adalimumab was the first entirely human monoclonal antibody to receive FDA approval. It
was constructed via a phage display. Adalimumab has been licensed by the Food and Drug
Administration (FDA) to treat rheumatism, psoriatic arthritis, ankylosing spondylitis, Crohn’s
disease, mild to severe persistent psoriasis, and juvenile idiopathic arthritis since 2008.
Although the FDA just licensed it in late 2012 to treat ulcerative colitis, it has been used for
various years in patients with Crohn’s disease that did not respond to standard therapies at
regular doses.
Several phases of clinical trials were carried out to establish the efficiency and safety of
Adalimumab in treating various conditions. Adalimumab is an entirely human IgG1
monoclonal antibody. It binds specially to tumour necrosis factor (TNF)-alpha. The mechanism
of action is double: it inhibits TNF-alpha bioactivity while also inducing apoptosis in TNFexpressing mononuclear cells. Adalimumab’s efficacy in psoriasis was suggested earlier by a
sub-group evaluation of patients registered in PsA trials who also had psoriasis and was
officially confirmed by the phase II trial and findings obtained from phase 3 trials in patients
with severe to moderate psoriasis. These results show that Adalimumab is an operational
treatment for psoriasis and overall quality of life, with effects lasting for a one-year treatment
period. The safety profile from psoriasis research findings was consistent with those from other
diseases. The danger of adverse occurrences did not show up to escalation with long-term
Adalimumab exposure.
Adalimumab was found as a consequence of a partnership between the Bioresearch
Corporation (BASF) and Cambridge Antibody Technology in the United Kingdom, which was
the outcome of a 1993 collaboration between a Medical Research Council which was funded
by the government and three professors. Initially, Adalimumab was available exclusively under
the brand Humira. However, as other types of biological therapies become available, you may
receive Adalimumab under a different label, such as Amgevita, Hulio, Hyrimoz, or Imraldi.
These drugs are referred to as biosimilar and function similarly to the original. Humira is
supplied in a single-use or vial prefilled syringe that contains 40 mg of the active ingredient in
0.8 mL of a buffered mixture composed of citric acid monohydrate, mannitol, and sodium
phosphate dihydrate, sodium citrate, sodium dihydrogen phosphate dihydrate, Polysorbate 80,
and sodium chloride.
Adalimumab can be recommended to people with rheumatoid arthritis, juvenile idiopathic
arthritis, psoriatic arthritis, and ankylosing spondylitis. Adalimumab is a prescription
medication that is used to:
● Treat adults with mild to extreme rheumatoid arthritis (RA). Adalimumab may be used
alone, combined with methotrexate, or blended with several other medications.
Adalimubab may help prevent further bone and joint damage and improve your ability
to function normally.
● Polyarticular juvenile idiopathic arthritis (JIA) ranges from mild to severe in children
two years and older. Adalimumab is available alone or in combination with
methotrexate.
● Adult psoriatic arthritis (PsA). Adalimumab may be used singly or combined with other
medications. Adalimumab may help prevent further bone and joint damage and
improve your functional capacity.
● Adult-onset ankylosing spondylitis (AS). In individuals 12 years of age and older, mild
to severe hidradenitis suppurativa (HS).
● To treat children and adults six years’ age and older who have moderate to extreme
Crohn’s disease (CD).
● To treat children and adults five years of age and older that have moderate to severe
ulcerative colitis (UC). It is unknown whether HUMIRA helps treat those who have
ceased responding to or cannot tolerate anti-TNF medications.
● Treating adults with symptomatic chronic plaque psoriasis (Ps) that are prepared for
phototherapy or systemic therapy and are under the lookout of a physician that will
determine whether different systemic therapies are more effective.
● Treating children and adults two years of age and older suffering from non-infectious
transitional, posterior, and pan uveitis eye problems.
Prescription of Adalimumab is avoided if one’s arthritis is not active, one already has an
infection, or other treatments appropriate for the condition have not been tried. Before
prescribing Adalimumab, doctors may use a ranking system to determine the severity of your
arthritis. The approach may vary according to the ailment you have, but you will typically be
asked to rate your overall health on a scale of 0 to 10, and your doctor will note if any of your
muscles are tender and swollen. Blood tests are also required before treatment administration
to assess the condition and viability of the drug. If one has had multiple sclerosis, cancer,
repeated infections, severe heart conditions, hepatitis B, tuberculosis, and lung fibrosis, the
doctor may decide against offering Adalimumab treatment.
Before commencing Adalimumab, a chest x-ray and blood tests will be performed to
determine if you have previously been subjected to tuberculosis (TB). You may need to be
treated for tuberculosis (TB) before receiving Adalimumab if it is present in your body but not
causing symptoms. Additionally, you will be tested for prior hepatitis infection, as
Adalimumab may raise the risk of recurrent hepatitis. Additional blood tests will be required
to monitor your response to Adalimumab.
Adalimumab is administered via a subcutaneous injection. You, your spouse, or some other
family member can learn how to help the shots in the comfort of your own home. Because
Adalimumab is a lengthy treatment, it is critical to continue taking it unless you experience
severe adverse effects:
● even if it initially appears to be ineffective, and
● Even if the health will improve because this will assist in maintaining management of
your disease. If you miss an Adalimumab dose, notify your rheumatology team. They’ll
be able to guide you on the next time you should take it.
The most common adverse reactions include redness, swelling, or discomfort at the injection
site. Changing the location of your injections regularly will assist lessen the likelihood of this.
Due to the way Adalimumab attacks the immune system, it may make you more susceptible to
infection. Additionally, it can make them more challenging to notice. Consult your physician
or rheumatology nurse immediately if you develop any new disease symptoms, including throat
infection, fever, diarrhoea, or coughing up green phlegm. If any of these concerns are severe,
contact your doctor immediately.
The results of a real-world analysis indicate that Adalimumab provides adequate control of
the disease in the majority of the patients and that some patients achieve long-term disease
control. These research results confirmed the importance of Adalimumab in attaining and
sustaining long-term disease control in patients with rheumatoid arthritis and are reliable with
long-term clinical trial results.
REFERENCES
Bang, L.; Keating, G. Adalimumab. BioDrugs 2004, 18 (2), 121-139
Hu, S.; Liang, S.; Guo, H.; Zhang, D.; Li, H.; Wang, X.; Yang, W.; Qian, W.; Hou, S.; Wang,
H.; Guo, Y.; Lou, Z. Comparison Of The Inhibition Mechanisms Of Adalimumab And
Infliximab In Treating Tumour Necrosis Factor Α-Associated Diseases From A Molecular
View. Journal of Biological Chemistry 2013, 288 (38), 27059-27067.
Liu, M.; Degner, J.; Davis, J.; Idler, K.; Nader, A.; Mostafa, N.; Waring, J. Identification Of
HLA-DRB1 Association To Adalimumab Immunogenicity. PLOS ONE 2018, 13 (4),
e0195325.
McInnes, Iain, B.; Jaclyn, K.; Marina, M.; Joseph, F.; Merola, Yi, L. Trial of upadacitinib and
adalimumab for psoriatic arthritis. New England Journal of Medicine 2021 384, (13), 12271239.
Navarro-Sarabia, F.; Ariza-Ariza, R.; Hernandez-Cruz, B.; Villanueva, I. Adalimumab For
Treating Rheumatoid Arthritis. Cochrane Database of Systematic Reviews 2005.
1
Introduction
Adalimumab is a drug that is used to treat severe ulcerative colitis (UC). It is normally
used for patients who are above 5 years old and adults. It is also known as HUMIRA. It has
several effects on the human body and as seen before used to treat inflammatory conditions. It
is a TNF blocker medicine that has been approved though lowers the ability of a patient’s
immune system to fight infections. This paper shows several properties of this drugs alongside
how it can be administered.
Properties of the Drug: ADALIMUMAB
Formulation
HUMIRA is administered as a single-use syringe that needs to be prefilled. It contains
40mg of active substance that is comprised of 0.8ml of a citrate or phosphate-buffered solution.
The formulation of ADALIMUMAB also comprises Polysorbate 80. Here, the active substance is
adalimumab which is a recombinant monoclonal antibody that is directed to humans (TNF-α).
Routes of administration
Adalimumab can be administered via various means. It can be administered as a 20-40
mg dose through a subcutaneous injection that may be provided either weekly or on a weekly
basis. This subcutaneous mode of administration is favorable to infliximab which requires
infusion. IN conjunction with the same, one can inject themselves in the abdomen or front thigh.
Mostly, the preferred place for administering the injection is the abdomen because it is the least
painful. This drug cannot be taken orally because the human digestion system would destroy it.
Instead, a doctor or nurse who is experienced in the treatment of ID will administer the drug
through injections which is the preferred mode of administration.
Distribution patterns in the body
Adalimumab is referred to as a TNF blocker. This means that it works through binding to
TNF molecules and also blocking them. This binding and blocking process helps reduce the
2
inflammation that may result in symptoms of Crohn’s disease or, rather, ulcerative colitis.
HUMIRA can take up to around six months for the last dose to leave the body. This means that
some effects may appear even after treatment is over.
General PK parameters (Vd, t1/2, Clearance rate, etc.)
An analysis of thirty patients treated for RA was done, and the following pharmacokinetic
and PK-PD parameters were estimated: apparent volume of distribution (Vd/F) = 10.8 l (92%);
apparent clearance (CL/F) = 0.32 l day−1 (17%); first-order absorption rate (ka) = 0.28 day−1; CRP
input (kin) = 22.0 mg l−1 day−1 (65%); adalimumab concentration leading to a 50% decrease
in kin (C50) = 3.6 mg l−1 (88%); baseline DAS28 (DAS0) = 5.5 mg l−1 (11%); and adalimumab
concentration leading to 50% decrease of DAS0 (IC50) = 11.0 mg l−1 (71%). Simulations showed
that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and
DAS28 after the first injection (Levi, Grange & Frey, 2013).
Metabolism & excretion of drugs, including key interactions with CYPs/transporters/etc.
Drug metabolism is the chemical changing of a drug by the body. This chemical altering
of the body may result in substances either active or inactive and either similar or dissimilar to
the original drug. Some drugs are administered in an inactive form and metabolized by the body
into an active form. This active form then produces the desired results. These drugs may also
be metabolized further instead of being excreted from the body. The resulting drug forms are
then eliminated from the body. Excretion is this active process of removal of drugs from the
body and can be through urine or bile.
Drug metabolism is a primary function that happens in the liver. There are enzymes that
convert inactive drugs to active ones or active drugs to inactive forms. This metabolism in the
liver is through some cytochrome P-450 enzymes. The level of these enzymes regulates the
rate at which the drugs are metabolized. These enzymes have a limited capacity to metabolize.
Therefore, the enzymes can become overloaded when blood levels of a drug are high. Drugs
affect these cytochrome P-450 enzymes. They affect the enzymes in that if they decrease the
3
ability of these enzymes to break down a drug, then the drug’s effects are increased. Similarly, if
the substances increase the enzymes’ ability to break down a drug, then the effects of the drug
are decreased.
Drug metabolism is affected by age. When people are younger, metabolic enzyme
systems have not yet been fully developed. Therefore, newborns have difficulty metabolizing
drugs. However, it is also true that as people age, their enzymatic activity decreases. For
example, older people cannot metabolize drugs as well as younger people.
Drug metabolism is, however, ultimately the final goal of any drug. These drugs may be
eliminated after use or even eliminated while still intact. The drugs are mostly eliminated by the
kidney in urine, while others are eliminated through bile. However, drug elimination is not a
constant factor and is affected by several things. For a drug to be excreted through the kidney, it
has to be water-soluble and also not bound too tightly with the proteins found in the body’s
bloodstream. The condition of the kidneys will also affect how they excrete drugs. Other drugs
are eliminated by the liver through bile. These ones remain unchanged. When they are excreted
through bile, they enter the digestive tract and are either eliminated through feces or recycled
and reabsorbed into the bloodstream. Drugs can also be excreted through saliva, sweat, and
even exhaled air. When they are excreted in these forms, they are excreted in small amounts.
Important drug-drug PK interactions?
Drug-to-drug interactions are one of the most common causes of adverse drug
reactions. PK drug-to-drug interactions occur when a drug alters the conditions of an agent it
has been administered with. These PK interactions may result in an increase or decrease in
plasma drug concentrations. Some drug-drug PK interactions include; drug-metabolizing
enzymes, drug transporters, and even orphan nuclear receptors that regulate the level of
expression of enzymes and transporters.
Absorption, distribution, metabolism, and excretion are some of the important drug-todrug interactions. All these processes are associated with treatment failure or toxicity in the
4
body. PK drug-to-drug interactions are the foundation of the knowledge of each drug and are
known by moderating the patient’s clinical manifestations. Drug-to-drug reactions affect the
metabolism, inhibition as well as excretion of other drugs. It is a sort of competition between the
drugs and which one is strong enough to elicit a reaction in the body. These processes will
affect the drug concentrations and their effects on the body. In PK, there are simple systems
that can be easily understood, and the potency of a drug can be easily predicted. This can be
done through dose adjustment to measure the extent of a drug interaction. This is unlike PD
interactions, where one has to carefully weigh which drugs groups produce which effects. PK
drug-drug interactions are simpler and can be easily predictable, unlike PD drug-to-drug
interactions (Zhang, Gao & Liu, 2020).
Sites of drug action and metabolism
This drug is injected into the front thigh or preferably the abdomen where it is less
painful. This drug’s target is the TNF alpha which causes inflammation in the human body. The
drug’s metabolism is completed when it binds with TNF alpha. Metabolism occurs when it is
removed by opsonization through the reticuloendothelial system.
Biological Targets of the Medication and the Mechanism(S) of Action
Efficacy? Potency? Selectivity?
The target for drugs can be approached through direct biochemical methods or genetic
interactions. Many mechanisms are used to determine the target of drugs and their effects on
the desired area. Confirmation of biological targets is done by understanding the protein
structure of the target area. There are usually small molecules that selectively regulate the
functions of target proteins. These molecules are found in nature and are usually used for
regulating the mechanism or target area. The molecules undergo biological screening for the
effects of purified proteins. This is done so as to determine the efficacy of the drug on the
5
targeted area. It can also be used to identify whether the drug will be potent in the required area
or not. After a target area for a drug is identified, there need to be additional studies that
establish the roles of the protein in the required area. These studies may establish things such
as the side effects which were not warranted or even the new roles that this specific protein
might play in the target area. Characterization of these drug proteins is done by use of
manipulation of their genetic sequence. Manipulating a drug’s genetic sequence will determine
its funct6ioning in the body. These genetic engineering processes will determine the efficacy of
a drug and also look into its potency.
Pharmacodynamics drug interactions are more complex than PK
Drug interactions and may include a direct effect on receptor function, interference with a
biological control process, and additive or opposed pharmacological effects. In PD interactions,
drugs affect each other directly. They either produce an additive effect or an antagonistic effect
on each other. These drug interactions involve mechanisms of cause and effect. These drug
interactions are sometimes difficult because one drug can make the other potent. For example,
combining inhibitors and diuretics will increase the body’s potassium retention and therefore
increase the chances of life-threatening hypoleukemia. It can also cause cardiac risk. For
example, patients who are taking prophylactic drugs should not take ibuprofen at the same time.
These two drugs will interact to bring adverse effects to the cardiac system. PD drug
interactions require a careful weighing of which drug groups’ cause what adverse effects,
whether desired or undesired. One can also check whether these drug groups weaken or
potentiate each other. This is unlike PK interactions, where one can demonstrate a simple
mechanism of the drugs’ interaction with each other and the body.
Conclusion
6
As seen from the above factors, HUMIRA or adalimumab is referred to as a tumor
necrosis factor which is a blocker medicine that can minimize the ability of a person’s immune
system to fight infections. The drug should be taken alongside doctors’ instructions. Serious
infections may occur in people who are taking HUMIRA. It can be concluded that, the
formulation of ADALIMUMAB also comprises Polysorbate 80. Here, the active substance is
adalimumab which is a recombinant monoclonal antibody that is directed to humans (TNF-α).
7
References
Bartelds, G. M., Wijbrandts, C. A., Nurmohamed, M. T., Stapel, S., Lems, W. F., Aarden, L., …
& Wolbink, G. J. (2007). Clinical response to adalimumab: relationship to antiadalimumab antibodies and serum adalimumab concentrations in rheumatoid
arthritis. Annals of the rheumatic diseases, 66(7), 921-926.
Kivitz, A., & Segurado, O. G. (2007). HUMIRA® pen: a novel autoinjection device for
subcutaneous injection of the fully human monoclonal antibody adalimumab. Expert
Review of Medical Devices, 4(2), 109-116.
Levi, M., Grange, S., & Frey, N. (2013). Exposure‐Exposure Relationship of Tocilizumab, an
Anti–IL‐6 Receptor Monoclonal Antibody, in a Large Population of Patients With
Rheumatoid Arthritis. The Journal of Clinical Pharmacology, 53(2), 151-159.
Ternant, D., Mulleman, D., Degenne, D., Willot, S., Guillaumin, J. M., Watier, H., … &
Paintaud, G. (2006). An enzyme-linked immunosorbent assay for therapeutic drug
monitoring of infliximab. Therapeutic drug monitoring, 28(2), 169-174.
Zhang, E., Xie, L., Qin, P., Lu, L., Xu, Y., Gao, W., … & Liu, S. (2020). Quality by Design–
Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to
Humira®. The AAPS Journal, 22(3), 1-14.
1.
2.
3.
4.
Ellis, C. R.; Azmat, C. E. Adalimumab. StatPearls 2021.
Marušič, M.; Klemenčič, A. Adalimumab-General Considerations. J Pharmacol Clin Toxicol 2018, 6 (2),
1104–1111.
Sinha, S.; Ghosh, B.; Bandyopadhyay, S.; Fatima, F.; Bandi, V. K.; Thakur, P. Comparative Evaluation of Efficacy,
Pharmacodynamics, and Safety of Hetero’s Adalimumab (Mabura®, Hetero Biopharma Ltd.) and Reference
Adalimumab (Humira®, Abbvie Inc.) in Patients with Active Rheumatoid Arthritis on Concomitant Methotrexate
Therapy. BMC rheumatology 2020 (1), 1–11.
Bang, L. M.; Keating, G. M. Adalimumab. BioDrugs 2004, 18, 121–139