821 Sainte Croix Ave,

Saint-Laurent, Quebec H4L 3X9

The Pharmacokinetics of Oxycodone

Épreuve Synthèse de Programme

201-HTL-VA DIFFERENTIAL EQUATIONS

sect. 00001

Ivan T. Ivanov

Athavan Sukumar Vallipuranathan

Monday, May 1, 2023
Abstract

Oxycodone is a semi-synthetic opioid that comes in two variations: immediate-release

and extended-release. This project aims to demonstrate the differences between both iterations

by comparing them through the lens of the two-compartment model defined by a set of

differential equations. The blood-brain model, used assumes that the body is split into two

compartments. The model also assumes that drug distribution between these compartments is

governed by first-order kinetics. Concentration graphs of the two compartments are plotted

using python and after doing some initial comparisons, more concrete values can be extracted

from the graphs such as termination of action, minimum effective concentration and duration.

Abstract 1
Introduction to Drugs 2
Basics of Pharmacology 2
Overview of Pharmacokinetics 3
Bioavailability Measurements 4
Effects of Conditions on Drug Disposition and Absorption 4
Dosage Adjustment of Drugs in Disease States 4
Correlation of Pharmacological Responses with Administered Doses 5
Evaluation of Drug Interactions 5
Clinical Prediction 5
Terms of Pharmacodynamics 6
Oxycodone 7
Pharmacokinetics of Oxycodone 8
Two-compartment Model 9
Blood-Brain Pharmacokinetic Model of Oxycodone 9
Pharmacokinetic Parameters 10
Differential Equations, Formulas, and Parameter Estimates 10
Amount of Oxycodone in Gastrointestinal Tract 12
Concentration of Oxycodone in the Blood and Brain 13
ER Oxycodone Comparison 14
Pharmacodynamics: Drug Action and Duration 17
Conclusion 19
References 19
Image References 21
Appendix A 22
Appendix B 29

1
Introduction to Drugs

Drugs have been used to remedy illnesses since the annals of history. Since drugs are

compounds that are foreign to the body, they have the potential to cause harm rather than treat

ailments. This notion is exasperated when they are used inappropriately such as giving an

individual the wrong dose. The renaissance physician Paracelsus once said, “Solely the dose

determines that a thing is not a poison.” This is especially true when that “thing” is a

xenobiotic— a chemical compound that is foreign to the body (Breen & Jambhekar, 2009).

Most drugs fall into five categories: central nervous system depressants, central nervous

system stimulants, opiates, psychedelics, and cannabis. These different types of drugs can

have a variety of effects on the human body. These effects can range from having audiovisual

hallucinations to feeling lethargic to being in a state of absolute euphoria (University of

Washington, 1993). Prescribed medicine aims to treat and manage illnesses and conditions

whilst minimising the negative effects that the medicine may cause. For the reasons stated

above, it is important to have a deep understanding of the drug at hand.

Basics of Pharmacology

Pharmacology is the study of drugs and is a science that is concerned about the

properties and effects of drugs. It encompasses the sciences of pharmaceutics, the preparation

of drugs, therapeutics, the treatment of illnesses with the use of drugs, and toxicosis, the

adverse effects that emanate with therapeutic interventions (Magoma, 2012). Pharmacology can

be divided into five processes.

The pharmaceutical process of drugs involves the chemical synthesis, formulation and

distribution of drugs. The pharmacokinetic process deals with the time course of drug

concentration in the body. This process will be expanded upon later. The pharmacodynamic

process deals with the mechanism of drug action, meaning the interaction of drugs with the

molecular structures in the body. The therapeutic process deals with the clinical response

2
arising from the pharmacodynamic process. Finally, the toxicologic process deals with adverse

effects of drugs arising from either over dosage or interference of biochemical pathways

unrelated to the intended drug target (Magoma, 2012).

The process of pharmacodynamics includes understanding the different routes of drug

administration. Topical application, oral administration (mucosal and intestinal), rectal

administration, and parenteral administration (subcutaneous, intramuscular, and intravenous)

are all different kinds of methods of administration and they all have their own benefits and

drawbacks (Favaro & Asperheim, 2012). Generally, the properties of a certain drug determines

the route that it must be used for (Magoma, 2012). Pharmacokinetics, which refers to the

movement of a drug into, through, and out of the body, also plays a major role in determining the

effects of a drug.

Overview of Pharmacokinetics

‘‘Pharmacokinetics is the study of kinetics of absorption, distribution, metabolism and

excretion (ADME) of drugs and their corresponding pharmacologic, therapeutic, or toxic

responses…’’ (European Medicines Agency, 2015).

Pharmacokinetics helps to determine the optimal dosage and frequency of drug administration

for different individuals and conditions. It also helps to identify drug interactions, adverse effects,

and therapeutic outcomes. Pharmacokinetics studies have several applications including

measuring bioavailability, evaluating the effects of physiological and pathological conditions on

drug disposition and absorption, adjusting drug dosage in disease states when necessary,

correlating pharmacological responses with administered doses, evaluating drug interactions,

and using pharmacokinetic parameters to individualise drug dosing regimens and provide the

most effective drug therapy (Breen & Jambhekar, 2009).

3
Bioavailability Measurements

Bioavailability measurements are important for evaluating the pharmacokinetics and

efficacy of drugs. They indicate the fraction of the administered dose that reaches the systemic

circulation and the target site of action. Bioavailability measurements can be performed using

various methods, such as plasma concentration-time curves, urinary excretion rates, or

pharmacodynamic endpoints (Chow, 2014).

Effects of Conditions on Drug Disposition and Absorption

Effects of physiological and pathological conditions on drug disposition and absorption:

This refers to how different characteristics of the body can alter the pharmacokinetics of a drug.

For example, age, gender, weight, genetics, organ function, disease, infection, inflammation and

food intake can affect how a drug is absorbed, distributed, metabolised and excreted (Gandhi et

al., 2012).

Dosage Adjustment of Drugs in Disease States

Dosage adjustment of drugs in disease states is the process of modifying the dose,

frequency or route of administration of a drug based on its pharmacokinetics in different clinical

situations. For instance, some drugs may need to be given at lower or higher doses, more or

less often, or through different ways depending on the patient's status and response (Gandhi et

al., 2012).

Correlation of Pharmacological Responses with Administered Doses

Correlation of pharmacological responses with administered doses: This means how the

amount of a drug given to a person affects how the drug works in their body. Different drugs can

have different ways of changing the body's functions depending on how much is taken. For

example, some drugs may show a direct proportion between dose and effect, while others may

show a more complex or limited proportion (Peper, 2009).

4
Evaluation of Drug Interactions

Evaluation of drug interactions: This is the study of how the actions and effects of a drug

can change when it is taken with other drugs or substances. For instance, some drugs can alter

the activity of the enzymes that break down other drugs in the body, resulting in higher or lower

drug concentrations and outcomes (Breen & Jambhekar, 2009).

Clinical Prediction

Clinical prediction is the application of pharmacokinetic parameters to tailor drug dosing

for optimal therapy. It accounts for the large inter-individual differences in how drugs are

absorbed, distributed, metabolised and excreted, which depend on various factors such as

weight, kidney function or genetic makeup (Breen & Jambhekar, 2009).

Terms of Pharmacodynamics

Figure 1: A typical plot of plasma concentration versus time

following the administration of a drug.
MTC, minimum toxic concentration; MEC, minimum effective concentration

5
 Onset of action refers to the time it takes for a drug to start producing a noticeable

therapeutic effect after it has been administered. It represents the period between drug

administration and the beginning of its intended action. Termination of action refers to the point

at which the pharmacological effect of a drug ceases or diminishes to a significant extent. It

signifies the end of the drug's desired therapeutic action. The term duration of action refers to

the length of time that a drug exerts its pharmacological effect in the body. Lastly, the

therapeutic range represents the concentration range of a drug in the body that is considered

effective and safe in producing the desired therapeutic effect. It defines the concentration at

which the drug is most likely to provide its intended benefits without causing significant adverse

effects (Breen & Jambhekar, 2009).

As the title and abstract suggest, this paper’s primary focus is on oxycodone and its

pharmacokinetics. To apply the theories of pharmacokinetics one must first understand the drug

that is being studied.

Oxycodone

Oxycodone is a synthetic opioid that is derived from thebaine, a substance found in the

opium poppy. It was first synthesised in 1916 by German chemists, Martin Freund and Edmund

Speyer, who were looking for a less addictive alternative to morphine (Sneader, 2005).

Oxycodone is used to treat moderate to severe pain, and it works by binding to opioid receptors

in the brain and spinal cord, blocking the transmission of pain signals (Kalso, 2005). Oxycodone

can also produce euphoria, relaxation, and sedation, which can make it prone to abuse and

addiction (Centre for Addiction and Mental Health, 2023).

OxyNEOTM is a brand name for oxycodone hydrochloride extended-release tablets,

which are designed to release the drug slowly over 12 hours (Purdue Pharma, 2020).

OxyNEOTM was introduced in Canada in 2012 as a replacement for OxyContin, which was

6
discontinued due to concerns about its high abuse potential. OxyNEOTM has a different

formulation and appearance than OxyContin, and it is supposed to be more resistant to

crushing, chewing, snorting, or injecting (Centre for Addiction and Mental Health, 2023).

Oxycodone is a powerful and potentially dangerous drug that should only be used as

prescribed by a doctor. It can cause serious side effects such as respiratory depression,

constipation, nausea, drowsiness, confusion, and dependence. They can also interact with other

medications and substances, such as alcohol, benzodiazepines, antidepressants, and

antihistamines, which can increase the risk of overdose and death (Centre for Addiction and

Mental Health, 2023).

Figure 2: Molecular structure of oxycodone

When oxycodone is metabolised in the liver it becomes nor-oxycodone and when

nor-oxycodone is metabolised further it becomes nor-oxymorphone. They are called metabolites

and they are weaker than oxycodone in terms of pain suppressant ability but still have pain

relieving effects (Fang et al., 2013).

Oxycodone tablets have a duration range of three to six hours for immediate-release or

twelve hours in controlled-release formulations (Sadiq et al., 2022). The onset of action is ten to

thirty minutes for the immediate-release formulation and about one hour for controlled-release

(Sadiq et al., 2022).

7
 The immediate-release tablets come in 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg

strengths. Capsules are available in 5 mg strength. Controlled-release tablets come in 10 mg,

15 mg, 20 mg, 30 mg, 40 mg, 60 mg and 80 mg strengths (Sadiq et al., 2022).

Pharmacokinetics of Oxycodone

Oxycodone is generally administered orally and there are several pharmacokinetic (PK)

models that can be used to describe its pharmacokinetics. One such model is the

one-compartment model with first-order absorption and elimination. This model assumes that

the drug is absorbed into a single compartment from the gastrointestinal tract and then

eliminated from the body at a constant rate. Another model is the two-compartment model with

first-order absorption and elimination. This model assumes that the drug is absorbed into two

compartments from the gastrointestinal tract and then eliminated from the body at a constant

rate (Agema et al., 2021).

Two-compartment Model

The two-compartment PK model is a way of describing the distribution and elimination

of a drug in the body using two connected compartments. The central compartment

(compartment 1) consists of the plasma and tissues where the drug reaches quickly and

uniformly. The peripheral compartment (compartment 2) consists of tissues where the drug

reaches more slowly and unevenly. The drug can move between the two compartments

following first-order kinetics, meaning that the rate of transfer depends on the concentration

difference between them. The drug can also be eliminated from the central compartment

following first-order kinetics, meaning that the rate of elimination depends on the concentration

in the central compartment (University of Turku, 2016). The two-compartment PK model can be

used to estimate various pharmacokinetic parameters, such as the volume of distribution,

clearance, half-life, and bioavailability of a drug (Talevi, 2021).

8
Blood-Brain Pharmacokinetic Model of Oxycodone

Figure 3: Visual representation of the

two compartment pharmacokinetic model

Pharmacokinetic Parameters
AGI→ amount of oxycodone in the gastrointestinal tract (mg)
A1 → amount of oxycodone in the central compartment (mg)
A2 → amount of oxycodone in the peripheral compartment (mg)

ka → rate of absorption of oxycodone (h-1)

k12→ rate of distribution from central compartment to peripheral compartment (h-1)
k21→ rate of distribution from peripheral compartment to central compartment (h-1)
k10→ rate of elimination (h-1)

C1 → concentration of oxycodone in central compartment (mg/L)

C2 → concentration of oxycodone in peripheral compartment (mg/L)

V1 → volume of central compartment (L)

V2 → volume of peripheral compartment (L)

D → dose of drug (mg)

S → salt factor, ratio of administered dose that is made up of pure drug
F → bioavailability factor, ratio of dose that reaches the systemic circulation

With all the parameters defined, the next step is to design a set of differential equations that

express the pharmacokinetic model above.

9
Differential Equations, Formulas, and Parameter Estimates
𝑑𝐴𝐺𝐼(𝑡)
1. 𝑑𝑡
=− 𝑘𝑎 · 𝐴𝐺𝐼(𝑡)
𝐴𝐺𝐼(0) −𝑘𝑎𝑇
2. 𝐴𝐺𝐼(𝑇) = 𝑘𝑎
(1 − 𝑒 )

3. 𝐴𝐺𝐼(0) = 𝐷 · 𝑆 · 𝐹
𝑑𝐶1(𝑡) 𝑘𝑎𝐴𝐺𝐼(𝑡)
4. 𝑑𝑡
= 𝑉1
− (𝑘10 + 𝑘12)𝐶1(𝑡) + 𝑘21𝐶2(𝑡)
𝑑𝐶2(𝑡)
5. 𝑑𝑡
= 𝑘12𝐶1(𝑡) − 𝑘21𝐶2(𝑡)

Equation 1 represents the rate at which the amount of drug in the gastrointestinal system

is decreasing with time. Equation 2 is the integral of the first and it plots out the amount of drug

in the system over time. Formula 3 gives the initial amount of drug in the gastrointestinal system

if the drug is ingested orally. Differential equations 4 and 5 represent the rate of concentration of

the two compartments (University of Turku, 2016).

𝐴𝐺𝐼(0) −𝑘𝑎𝑇 𝑇 𝑇
6. 𝐶1(𝑇) = 𝑘𝑎𝑉1
(1 − 𝑒 ) − (𝑘10 + 𝑘12) ∫ 𝐶1(𝑡)𝑑𝑡 + 𝑘21 ∫ 𝐶2(𝑡)𝑑𝑡
𝑜 0
𝑇 𝑇
7. 𝐶2(𝑇) = 𝑘12 ∫ 𝐶1(𝑡)𝑑𝑡 − 𝑘21 ∫ 𝐶2(𝑡)𝑑𝑡
0 0
Functions 6 and 7 are integrals of the differential equations 3 and 4 and they plot out the

centration of the two compartments over time (University of Turku, 2016).

10
With the differential equations set up, the next step is to give numeric values to the constants

found in them. The values below were taken from a study where 302 pharmacokinetic samples

were collected from 28 patients that had cancer related pains (Agema et al., 2021). Certain

values were changed to accentuate the differences between both variations of oxycodone

(seen below in italics).

Parameter Unit Parameter Estimate

Ka (IR) h-1 3.61

Ka (ER) h-1 1.67

V1 (IR) L 6.5

K12 (IR) h-1 0.086

K21 (IR) h-1 1.36

K10 (IR) h-1 0.24

V1 (ER) L 11

K12 (ER) h-1 0.086

K21 (ER) h-1 1.87

K10 (ER) h-1 0.07

D mg 40

S - 0.9

F (IR) - 0.64

F (ER) - 0.55
Table 1: Experimental values of variables (Agema et al., 2021)

11
Amount of Oxycodone in Gastrointestinal Tract

Assuming that 40mg tablets are the basis for the following examples, the function
𝐴𝐺𝐼(0) −𝑘𝑎𝑇
𝐴𝐺𝐼(𝑇) = 𝑘𝑎
(1 − 𝑒 ) will be plotted with python. The initial value of the graph will be

𝐴𝐺𝐼(0) = 40 · 0. 90 · 0. 64= 23.04.

Figure 4: Amount of oxycodone in the GI tract over time (IR)

The simple graph shown in Figure 4 demonstrates how the amount of oxycodone in the

gastrointestinal tract decreases over time as it is absorbed into the blood. This graph will later

be compared to the extended release version of oxycodone also known as OxyNEOTM.

More interesting observations can be made by looking at the graphs that the functions of C1(t)

and C2(t) produce. The following graphs will compare the concentrations of IR oxycodone in the

two compartments over time.

12
Concentration of Oxycodone in the Blood and Brain

Figure 5: Concentration of oxycodone in the blood (IR)

Figure 6: Concentration of oxycodone in the brain (IR)

13
 Figure 7: Concentration of oxycodone (IR) in both compartments

In Figure 5, the concentration of oxycodone in the blood is shown to spike early on and

dissipates over time. Figure 6 is similar in structure to Figure 5 but the concentration is much

smaller. The drug reaches a maximum concentration of 1.096mg/L in the blood only after 0.912

hours of ingestion. Oxycodone only reaches a maximum concentration of 0.00218mg/L in the

brain after 0.31 hours. Maximum concentration occurs at the same time in both compartments

but the vast difference in peak concentrations is shown in Figure 7.

14
ER Oxycodone Comparison
Using the same functions and formulas from before and swapping out certain values, the

amount of ER oxycodone in the body overtime can be graphed and compared to the amount of

IR oxycodone.

Figure 8: Comparison of the amount of IR/ER oxycodone in the body over time

The graph of both of the lines very clearly shows that the ER oxycodone stays in the

gastrointestinal tract for much longer. It is absorbed into the body at a much slower rate than IR

oxycodone which allows it to also stay active in the body for longer.

15
Figure 9: Concentration of oxycodone (ER) in both compartments

Figure 10: Comparison of the concentration in the blood

of both IR and ER oxycodone

Figure 11: Comparison of the concentration in the brain

of both IR and ER oxycodone

16
 As the graphs in Figure 10 and 11 show, there is a major difference between IR

oxycodone concentration and the ER variation. This difference is most visible at the maximum

concentration of both iterations of the drug. ER oxycodone has a maximum concentration of

1.09 mg/L in the blood and 0.0462 mg/L in the brain. ER oxycodone reaches a higher peak

concentration and is eliminated from the body slower than its IR counterpart. In the following

section, the drug action and duration of the drug’s effects will be looked into in more depth. As

shown in Figure 8, ER oxycodone is absorbed at a slower rate as its graph is not as steep. The

higher maximum concentration of ER oxycodone also contributes to the reason why it lasts for

so much longer. Since both iterations of the drug are metabolised and eliminated at similar

rates, it is the rate of absorbance that acts as a sort of limiting parameter. The absorbance rate

of the drug determines the maximum concentration which when coupled with the elimination

and distribution rate, determines how slow or fast the drug is metabolised.

In an earlier section, it was mentioned that the onset of action for ER oxycodone was

one hour while the onset of action for IR oxycodone was only 10 minutes. The reason why the

onset of action of ER oxycodone is so much longer is because the absorption actually varies

over time instead of being a constant like the rate of absorption of IR oxycodone. In this paper,

the process is simplified by keeping the absorption rate of ER oxycodone constant, but doing so

makes the theoretical onset of action of one hour invalid. In the following section, an onset of 10

minutes will be used for ER oxycodone.

Pharmacodynamics: Drug Action and Duration

Significant details about a substance’s pharmacodynamics can be revealed by marking

points on concentration curves, similar to those shown in Figure 1. The onset of action is known

to be 10 minutes and the minimum toxic concentration is said to be around 1.23 mg/L (Purdue

Pharma, 2020) (Spiller, 2003). The other points can be deduced from these values. It is

important to remember that these values vary greatly between individuals and the values stated

17
above are merely averages. It is also important to note that the values above are taken from the

concentration of oxycodone in the blood plasma and not a peripheral compartment.

Figure 12: Concentration of IR oxycodone in the blood plasma

with important drug action lines

Figure 13: Concentration of ER oxycodone in the blood plasma

with important drug action lines

18
 By first plotting a vertical line that represents the onset of action; a horizontal line can

then be plotted depicting the minimum effective concentration. The part of the graph that falls

between the MTC and the MEC is the therapeutic range otherwise known as the effective range.

The second point of intersection of the MEC line marks where the termination of action line will

fall. Figure 12 depicts IR oxycodone concentration in the blood and the graph suggests that the

drug is effective for 3.38 hours while Figure 13, which shows ER oxycodone, suggests that the

drug is effective for 11.37 hours. These numbers coincide with the theoretical values presented

by Purdue Pharma for how long IR and ER oxycodone should be effective; 4 hours and 12

hours respectively.

Conclusion

In sum, this project presented a mathematical model of the pharmacokinetics of

oxycodone. The model used differential equations to describe the absorption, distribution,

metabolism and elimination of oxycodone in two compartments: blood (central) and brain

(peripheral). The model also compared the pharmacokinetic profiles of immediate-release (IR)

and extended-release (ER) formulations of oxycodone, which differ in their duration and peak of

action. The model was implemented in Python and validated by plotting graphs of the plasma

concentration of oxycodone over time. Plotting graphs and making comparisons aided in

demonstrating the differences between IR and ER oxycodone. Therefore with mathematics, the

pharmacokinetics of a drug can be studied.

19
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22
Appendix A

#amount GI tract (IR)

import numpy as np
import matplotlib.pyplot as plt
from scipy.integrate import odeint

def dydt(y, t):

return -3.61 * y

t = np.linspace(0, 24, 100)

y0 = 23.04
y = odeint(dydt, y0, t)

plt.plot(t, y)
plt.xlabel('Time (h)')
plt.ylabel('Amount of oxycodone in the GI tract (mg)')
plt.title('Amount of oxycodone in the GI tract (IR)')
plt.show()

#C1(IR)
k01 = 3.61 #ka IR
k02 = 0.329 #ka ER

k12 = 0.086
k21 = 1.36
k10 = 0.24

v01 = 6.5

k99 = 23.04 #A[gi](0)

t0=0
tf=24
npoints=1000
dt = (tf-t0)/npoints
T = np.linspace(0, 24, npoints+1)

y0 = 0
g0 = 0

y = np.zeros((npoints))
y[0] = y0
sumy = y0

23
g = np.zeros((npoints))
g[0] = g0
sumg = g0

for i in range(1, npoints):

y[i] = k99/(k01 * v01)* (1-np.exp(-3.61*(i*dt))) - (k10+k12) * sumy + k21 *
sumg
g[i] = k12 * sumy - k21 * sumg
sumy += y[i]*dt
sumg += g[i]*dt

plt.plot(T[:-1], y, color='g')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone in the blood (mg/L)')
plt.title('Concentration of oxycodone in the blood (IR)')
plt.legend()
plt.show()

#C2 (IR)
plt.plot(T[:-1], g, color='y')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone in the brain (mg/L)')
plt.title('Concentration of oxycodone in the brain (IR)')
plt.legend()
plt.show()

#comparison C1 and C2 (IR)

plt.plot(T[:-1], y, color='g', label='C1')
plt.plot(T[:-1], g, color='y', label='C2')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone (mg/L)')
plt.title('Concentration of oxycodone (IR)')
plt.legend()
plt.show()

#amount GI tract (ER) comparison

def dydt(y, t):
return -0.329 * y

t = np.linspace(0, 24, 100)

y0 = 23.04
y = odeint(dydt, y0, t)

plt.plot(t, y, label='ER')

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def dydt(y, t):
return -3.61 * y

t = np.linspace(0, 24, 100)

y0 = 23.04
y = odeint(dydt, y0, t)

plt.plot(t, y, label='IR')
plt.xlabel('Time (h)')
plt.ylabel('Amount of oxycodone in the GI tract (mg)')
plt.title('Amount of oxycodone in the GI tract')
plt.legend()
plt.show()
#comparison C1 (IR & ER)
k01 = 3.61 #ka IR
k02 = 1.67 #ka ER

k12 = 0.086
k21 = 1.36
k10 = 0.24

k47= 0.086
k74= 1.87
k40= 0.07

v01 = 6.5
v02 = 11

k99 = 23.04 #A[gi](0)

t0=0
tf=24
npoints=1000
dt = (tf-t0)/npoints
T = np.linspace(0, 24, npoints+1)

y0 = 0
g0 = 0
y = np.zeros((npoints))
y[0] = y0
sumy = y0
g = np.zeros((npoints))
g[0] = g0
sumg = g0

25
u0 = 0
v0 = 0
u = np.zeros((npoints))
u[0] = u0
sumu = u0
v = np.zeros((npoints))
v[0] = v0
sumv = v0

for i in range(1, npoints):

y[i] = k99/(k01 * v01)* (1-np.exp(-3.61*(i*dt))) - (k10+k12) * sumy + k21 *
sumg
g[i] = k12 * sumy - k21 * sumg
sumy += y[i]*dt
sumg += g[i]*dt

for i in range(1, npoints):

u[i] = k99/(k02 * v02)* (1-np.exp(-3.61*(i*dt))) - (k40+k47) * sumu + k74 *
sumv
v[i] = k47 * sumu - k74 * sumv
sumu += u[i]*dt
sumv += v[i]*dt

plt.plot(T[:-1], u, label='C1 ER')

plt.plot(T[:-1], y, label='C1 IR')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone (mg/L)')
plt.title('Concentration of oxycodone in the blood')
plt.legend()
plt.show()

#comparison C2 (IR & ER)

plt.plot(T[:-1], v, label='C2 ER')
plt.plot(T[:-1], g, label='C2 IR')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone (mg/L)')
plt.title('Concentration of oxycodone in the brain')
plt.legend()
plt.show()

#comparison C1 and C2 (IR)

plt.plot(T[:-1], u, color='r', label='C1')
plt.plot(T[:-1], v, color='m', label='C2')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone (mg/L)')

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plt.title('Concentration of oxycodone (ER)')
plt.legend()
plt.show()

#C1 (IR) drug action value plots

k01 = 3.61 #ka IR

k12 = 0.086
k21 = 1.36
k10 = 0.24

v01 = 6.5
v02 = 11

k99 = 23.04 #A[gi](0)

t0=0
tf=24
npoints=1000

dt = (tf-t0)/npoints
T = np.linspace(0, 24, npoints+1)
y0 = 0
g0 = 0

y = np.zeros((npoints))
y[0] = y0
sumy = y0
g = np.zeros((npoints))
g[0] = g0
sumg = g0

for i in range(1, npoints):

y[i] = k99/(k01 * v01)* (1-np.exp(-3.61*(i*dt))) - (k10+k12) * sumy + k21 *
sumg
g[i] = k12 * sumy - k21 * sumg
sumy += y[i]*dt
sumg += g[i]*dt

plt.plot(T[:-1], y, label='C1 IR')

plt.axvline(x=1/6, color='r', linestyle='--', label='Onset of action')
plt.axvline(x=3.552, color='m', linestyle='--', label='Termination of action')
plt.axhline(y=1.23, color='g', linestyle='--', label= 'MTC')
plt.axhline(y=0.4393475, color='c', linestyle='--', label='MEC')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone in the blood (mg/L)')

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plt.title('Concentration of oxycodone in the blood (IR)')
plt.legend()
plt.show()

#C1 (ER) drug action value plots

k01 = 3.61 #ka IR
k02 = 1.67 #ka ER

k12 = 0.086
k21 = 1.36
k10 = 0.24

k47= 0.086
k74= 1.87
k40= 0.07

v01 = 6.5
v02 = 11

k99 = 23.04 #A[gi](0)

t0=0
tf=24
npoints=1000
dt = (tf-t0)/npoints
T = np.linspace(0, 24, npoints+1)

y0 = 0
g0 = 0
y = np.zeros((npoints))
y[0] = y0
sumy = y0
g = np.zeros((npoints))
g[0] = g0
sumg = g0

u0 = 0
v0 = 0
u = np.zeros((npoints))
u[0] = u0
sumu = u0
v = np.zeros((npoints))
v[0] = v0
sumv = v0

28
for i in range(1, npoints):
y[i] = k99/(k01 * v01)* (1-np.exp(-3.61*(i*dt))) - (k10+k12) * sumy + k21 *
sumg
g[i] = k12 * sumy - k21 * sumg
sumy += y[i]*dt
sumg += g[i]*dt

for i in range(1, npoints):

u[i] = k99/(k02 * v02)* (1-np.exp(-3.61*(i*dt))) - (k40+k47) * sumu + k74 *
sumv
v[i] = k47 * sumu - k74 * sumv
sumu += u[i]*dt
sumv += v[i]*dt

plt.plot(T[:-1], u, label='C1 ER')

plt.axvline(x=1/6, color='r', linestyle='--', label='Onset of action')
plt.axvline(x=11.544, color='m', linestyle='--', label='Termination of action')
plt.axhline(y=1.23, color='g', linestyle='--', label= 'MTC')
plt.axhline(y=0.56173, color='c', linestyle='--', label='MEC')
plt.xlabel('Time (h)')
plt.ylabel('Concentration of oxycodone in the blood (mg/L)')
plt.title('Concentration of oxycodone in the blood (ER)')
plt.legend()
plt.show()

Appendix B
#max coordinates of C1 IR
max_y_index = np.argmax(y)
max_y_value = y[max_y_index]
corresponding_x_value = T[max_y_index]

print("The maximum value of y is", max_y_value)

print("The corresponding x value is", corresponding_x_value)

#max coordinates of C2 IR
max_y_index = np.argmax(g)
max_y_value = g[max_y_index]
corresponding_x_value = T[max_y_index]

print("The maximum value of y is", max_y_value)

print("The corresponding x value is", corresponding_x_value)

#max coordinates of C1 ER
max_y_index = np.argmax(u)

29
max_y_value = u[max_y_index]
corresponding_x_value = T[max_y_index]

print("The maximum value of y is", max_y_value)

print("The corresponding x value is", corresponding_x_value)

#max coordinates of C2 ER
max_y_index = np.argmax(v)
max_y_value = v[max_y_index]
corresponding_x_value = T[max_y_index]

print("The maximum value of y is", max_y_value)

print("The corresponding x value is", corresponding_x_value)

#onset of action intersection IR

idx = (np.abs(T - 1/6)).argmin()
intersection_y = y[idx]
print(f"The intersection point is at (1/6, {intersection_y})")

#mec intersections IR
intersection_points = []

for i in range(npoints):
if abs(y[i] - 0.43514) < 1e-3:
intersection_points.append(T[i])

print(f"The horizontal line y=0.4393475 intersects the function at

x={intersection_points}")

#onset of action intersection ER

idx = (np.abs(T - 1/6)).argmin()
intersection_y = u[idx]
print(f"The intersection point is at (1/6, {intersection_y})")

#mec intersections ER
intersection_points = []

for i in range(npoints):
if abs(u[i] - 0.56353) < 1e-3:
intersection_points.append(T[i])

print(f"The horizontal line y=0.56173 intersects the function at

x={intersection_points}")

30