This presentation includes important factors to be considered prior to deciding anti cancer drugs and dosage

1. Pharmacokinetics & Pharmacodynamics of
Anticancer Drugs
Srigopal Mohanty
DM-Post Graduate
Medical Oncology, KMC

2. Introduction
Pharmacokinetics (PK): A branch of pharmacology to determine
the fate of drugs administered into a living organism.
PK: How an organism affects a drug
Pharmacodynamics (PD): The study of biochemical and
physiologic effects of drugs
PD: How a drug affects an organism

4. Routes of Administration & Absorption
• Administration:
IV
IM
Oral: for targeted therapy (small molecule t/t)
Regional: Intra-pleural/ peritoneal/ CSF/ arterial
• Absorption: The process by which unchanged drug
moves from site of administration to site of measurement
• First pass Effect: Oral intake → GI epithelium → Portal
blood circulation → Liver → Systemic circulation.
Elimination of some amount of drug occurs @ GI
epithelium & Liver.

5. Factors affecting oral Absorption of drugs
• Absorptive surface area
• GI transit time
• GI blood flow
• GI pH
• Intestinal influx/efflux transport
• Intestinal metabolism
• Size of molecule (TKI/MAb)

7. What is Bioavailability?
• Availability/ Bioavailability: Is the fraction of administered drug that is
absorbed intact.
• Calculated by AUC in extra-vascular administration
AUC in IV administration
Value ranges from 0 to 1 (0% to 100%)
• Effective dose = Bioavailability × Administered dose
• Bioavailability depends on;
• Route of administration
• First pass metabolism
• Factors affecting drug absorption

8. Disposition
• Distribution: Is the reversible transfer of a drug to & from
the site of measurement
• Any drug does not return to the site of measurement after
leaving the site means undergone elimination
• Elimination occurs by: metabolism & excretion
• Metabolism: is the conversion of drug to another
chemical
• Excretion: is irreversible loss of chemically unchanged
drug
Distribution Elimination

9. Volume of distribution(Vd)
• “The apparent volume of body tissue into which a drug
distributes at equilibrium”
• VD depends on;
Lipid solubility
Tissue permeability
Plasma protein binding
Local organ blood flow
• Barriers to Vd: Blood brain barrier, blood testes barrier

10. Clearance
It relates drug dose with systemic drug exposure (AUC)
Elimination Rate Constant:
Defined as the fractional rate of drug removal
Half Life:
The time in which body concentration of a drug decreases to half
of its initial value.
Useful to estimate he time required to reach steady state plasma
concentration

11. Dose Proportionality (DP)
• DP a/k/a linear pharmacokinetics
• Drugs with linear pharmacokinetics are dose proportional. i.e
doubling the drug dose doubles the plasma concentration or AUC
• Vd & CL unaffected by drug dose & concentration
• Dose proportionality is clinically important because it means that
dose adjustments will generate predictable changes in systemic
drug exposure
• Factors that can contribute to a lack of dose proportional
pharmacokinetics include saturable oral absorption, capacity-
limited distribution or protein binding, and/or saturable
metabolism.

12. Pharmacodynamics
• Relate clinical drug effects: Therapeutic/Adverse drug effects
• Pharmacodynamic response variation occurs due to:
Age
Sex
Stage of disease
Performance status
Treatment modality received
Chemo sensitivity of the tumor
Plasma protein level
Organ (Liver/Kidney) functions
Co-administration of other drugs

13. Body size and body composition:
BSA is used for drug dose calculation
Dose per sq meter ×BSA
Recent targeted therapy & Mabs are calculated by dose
per kg × weight in kg. i.e Bevacizumab 5mg/kg,
Panitumumab 6mg/kg
Age:
Change in body composition, organ function affect drug
deposition & drug effects in extreme of ages.
Advanced age: Poor tolerance to chemo
Child hood: Increased late effects

14. Effect of Disease
• Malignancies involving liver & kidney shows
reduced drug clearance during initial treatment
period, whereas it increases as disease remission
starts.
• Tumour derived inflammation cause reduced
metabolism of drugs by altering CYP3A4 activity.
• Ex: Docetaxel

15. Renal function status
• Dysfunction of organ of elimination causes delayed drug
clearance, result in drug accumulation & toxicity
• Dose reduction has to be considered in c/o deranged RFT, to
maintain plasma concentration.
• For drugs excreted by glomerular filtration. i.e. carboplatin,
dose calculation done based on creatinine clearance
Effects of Hepatic impairment
• Hepatic dysfunction score is based on serum bilirubin, ALP,
SGOT, SGPT,

16. Effects of serum proteins
• The free (unbound) drug in plasma is available for
distribution and therapeutic response
• Protein binding is a major determinant of drug action
• Liver & Kidney disease can significantly decrease
extent of serum binding, so increased concentration
of free drug, so increased toxicity, although total
plasma drug concentration unaltered
• For Paclitaxel & Etoposide, PB is dependent on dose
& schedule

17. Sex Dependence
• Various anti cancer drugs shows sexual dimorphism
• Male sex is associated with greater elimination
capacity of anticancer drugs i.e Paclitaxel and
increased clearance i.e Imatinib

18. Drug Interactions
• Pharmacokinetic of one drug is altered by the other
• May result in favorable or unfavorable outcome
• Interactions are more common for combinations of TKI with
cytotoxic chemotherapeutics
• If two highly plasma protein-bound drugs are co-administered,
one drug can displace the other from its protein binding site and
cause an increased concentration of the unbound drug.1 The
unbound drug is biologically active because it can exert its
pharmacological effect, while plasma protein binding limits the
activity of the bound drug.2

19. Co-administration of Non-chemotherapeutic Drugs
• Cytochrome P450 (CYP): An imp enzyme of metabolism of
majority of anticancer drugs
• Increase CYP activity (induction), translated into a more rapid
metabolic rate, result in a decrease in plasma concentrations and
loss of therapeutic effect.
• Example: anticonvulsant drugs such as phenytoin,
phenobarbital, and carbamazepine can induce drug-
metabolizing enzymes and thereby increase the clearance of
various anticancer agents.
• Inhibition of CYP activity, for example with ketoconazole may
trigger a rise in plasma concentrations and can lead to
exaggerated toxicity commensurate with overdose.

20. Effect of Food on Exposure to Select Oral Anticancer Agents

21. Co-administration of Complementary and Alternative Medicine
• Prevalence of complementary and alternative medicine (CAM)
use in oncology patients to be as high as 87%, and in many
cases
• A number of clinically important pharmacokinetic interactions
involving CAM and cancer drugs have now been recognized,
although causal relationships have not always been established.
• Most of the observed interactions point to the herbs affecting
several iso-forms of the CYP family, either through inhibition or
induction.
• Because of the high prevalence of herbal medicine use,
physicians should include herb usage in their routine drug
histories.

23. Inherited Genetic Factors
• Pharmacogenetics describes differences in the Pharmacokinetics
and Pharmacodynamics of drugs as a result of inherited
variation in drug metabolizing enzymes, drug transporters,
and drug targets between patients.
• Occasionally responsible for extensive inter patient variability
in drug exposure or effects.
• Elimination is critically dependent on a rate-limiting
breakdown by a polymorphic enzyme (e.g., 6-mercaptopurine
by thiopurine- S-methyl transferase; 5-fluorouracil by dihydro-
pyrimidine dehydrogenase.

24. PHARMACOGENOMICS
• Pharmacokinetic processes are highly dependent on the
interplay with drug transport in organs such as the
intestines, kidneys, and liver.
• The most extensively studied class of drug transporters are
those encoded by the family of ATP–binding cassette
(ABC) genes, some of which play a role in the resistance
of malignant cells to anticancer agents.
• Drugs influence the oral absorption and disposition of
a wide variety of drugs.
– ABCB1 (P-glycoprotein),
– ABCC1 (multidrug resistance–associated protein 1 [MRP1])
– ABCC2 (multidrug resistance–associated protein 2 [MRP2]
– ABCG2 (breast cancer resistance protein [BCRP])

25. PHARMACOGENOMICS
• Few individual are susceptible to certain
anticancer drug–induced side effects, interactions,
and treatment efficacy(for example, in the case of
genetic variation in ABCG2 in relation to Gefitinib-
induced diarrhea)
• Functionally relevant polymorphisms in these
influx transporters may contribute to inter
individual and interethnic variability in drug
disposition and response (example, in the case of the
impact of polymorphic variants in the OCT1 gene
SLC22A1 on the survival of patients with chronic myeloid
leukemia receiving treatment with Imatinib).

26. Therapeutic Drug Monitoring (TDM)
• Measurement of drug concentration in blood
• Indications of TDM:
– Experimentally determined relationship between plasma
drug concentration and pharmacological effect
– Knowledge of drug level influence management
– Narrow therapeutic window
– Drug dose cant be optimized by clinical observation alone
• Affected by time/route/dose/storage condition/accuracy of
analytical methods/co-medications/clinical status of patient

27. TDM…
• Methotrexate plasma concentrations are routinely monitored to
identify patients at high risk of toxicity and to adjust leucovorin
rescue in patients with delayed drug excretion. This monitoring
has significantly reduced the incidence of serious toxicity,
including toxic death, and in fact, has improved outcome by
eliminating unacceptably low systemic exposure levels.
• TDM is currently under investigation for several more recently
developed anticancer drugs, including Imatinib.

28. Feedback-Controlled Dosing
• Adaptive dosage with feedback control
• In this approach, patients are first treated with standard dose,
and, during treatment, pharmacokinetic information is estimated
by a limited-sampling strategy and compared with that predicted
from the population model with which treatment was initiated.
• On the basis of the comparison, more patient-specific
pharmacokinetic parameters are calculated, and dosage is
adjusted accordingly to maintain the target exposure measure
producing the desired Pharmacodynamic effect.
• Helps in maintaining high precision control of plasma drug
concentration.

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31. THANK YOU