Therapeutic Drug Monitoring in Oncology: The key to individualised ...

Therapeutic Drug Monitoring
in Oncology: The key to
individualised chemotherapy?
Graham Sewell
Professor of Clinical Pharmacy
Kingston University / Plymouth
Hospitals Trust UK

Contribution of Chemotherapy to 5
year survival in adult malignancies
• 5-year survival rate (1992-97) for 22 adult
malignancies in Australia = 63.4% (CI 95 63.1-
63.6)
• Contribution of “curative and adjuvant”
chemotherapy = 2.3% (USA = 2.1%)
• Main role of chemotherapy is palliation
Morgan G et al Clinical Oncology (2004) 16, 549-560
• Many reasons for chemotherapy failure
including drug resistance and sub-optimal
dosage schedules

Cancer Chemotherapy
• High toxicity
• Low efficacy
• Inter-patient variability
• Narrow therapeutic window
• Dosing usually based on avoidance of
toxicity rather than on ensuring
efficacy.
• Need for therapeutic optimisation

Presentation Outline
• TDM in Pharmacotherapy
• Dose determination in cancer
chemotherapy
• Use of TDM in chemotherapy:
- Opportunities
- Limitations and challenges
• TDM in chemotherapy: Future
developments

Pharmacokinetics
• Describes the process of drug absorption,
distribution and elimination
• Key terms: Bioavailability (F)
Volume of Distribution (Vd)
Protein-binding
Clearance (Cl)
Half –Life (T1/2)
Area Under Cp Vs time curve (AUC)

Clinical Pharmacokinetics
• Many drug doses are empirical
• Drug elimination (and hence efficacy
and toxicity) varies between patients.
• Body wt. and BSA – not always good
indicators of drug clearance
• Some drugs have narrow therapeutic
window E.g. cytotoxic drugs used in
cancer chemotherapy

Therapeutic Drug Monitoring
(TDM)
• Large variation in drug plasma
concentration between individuals for a
given dose;
Formulation
Drug interactions
Life-style (eg diet, smoking)
Disease (renal & hepatic function)
Genetic variation (in metabolism)

Clinical Use of TDM
• Measure plasma concentration of drug to
adjust dose for individual :
- maximises therapeutic effect
- minimises drug – related toxicity
• Monitors on-going therapy
• Checks patient compliance and
administration of medicines to the patient

Requirements for TDM
• No direct clinical measure to provide clear
evidence of drug therapeutic effect or drug
toxicity (or multiple toxicities)
• Drug plasma concentration is related to either
therapeutic or toxic effect
• Drug has low therapeutic : toxicity ratio
• Drug is used as prophylactic (eg. Phenytoin)
• Drug is not extensively metabolised to active
metabolites

Medicines Monitored by TDM
Digoxin Phenytoin Carbamazepine
Cyclosporin Gentamicin Lithium
Theophylline Vancomycin Valproate
Amiodarone Phenobarbitone

TDM : Procedure
• Take sample: - correct time
- correct sample tube
- correct state (plasma or
serum)
• Measure concentration (RIA, HPLC etc)
• Interpret concentration and consider
confounding factors

Examples of Non-Oncology TDM
“therapeutic range”
• Digoxin; 1 – 3.8 nmol/L (gives therapeutic
effect – avoids ADR’s of malaise,
anorexia,vomiting,confusion)
• Gentamicin; to achieve bactericidal effect
min plasma conc = 5ug/ml
To avoid toxicity, max plasma conc =
10ug/ml and max trough conc = 2ug/ml

TDM- “The Old Way”
• Give standard dose
• Check plasma level
• React to plasma level
• If high- lower the dose and re-check
• If low- increase dose and re-check
• No differentiation between upper and
lower ends of therapeutic range
• Tend to “treat the level, not the patient”

Is Dose Important in Cancer
Chemotherapy?
• Yes – for toxicity
• Yes for efficacy?????
• Inter-patient variability
• Bonadonna: Reduced survival in breast
cancer patients receiving < 85% of
target dose in CMF regimen
Bonadonna etal, N Engl J Med (1995), 332, 901

How Accurate/Relevant is
BSA-Based Dosing ?
• Use of BSA arises from interspecies dosing
(animals to humans) in Phase 1 studies.
• BSA does not correlate well to drug clearance
plasma or tumour levels.
• Errors in BSA calculation (DuBois and
DuBois, Arch. Int.Med 1916 : 17 :863-71)
• No basis for physiological scaling within
species

Further Reading on BSA in
Cancer Chemotherapy
• Reilly JJ, Workman P . Normalisation of
anticancer drug dosage using body weight
and surface area; is it worthwhile ? Cancer
Chemotherapy and Pharmacology 1993, 32,
411-418
• Ratain MJ. Body surface area as a basis for
dosing of anticancer agents; science myth or
habit. J Clin Oncol 1998, 16, 2297-2298
• Egorin M Editorial 2003, J Clin Oncol, 21, 182

Problems with TDM in Oncology
• Plasma level does not reflect tumour level of
drug or drug level in sensitive healthy tissues
• Lag time between exposure of tumour to
drug and therapeutic effect
• Often no clear relationship between Cp and
toxicity/therapeutic effect
• Tumours (and metastasis) are heterogenious

Examples of TDM (1)
Methotrexate
• High-dose MTX therapy
• Monitor plasma MTX 24-48 hours postdose
• Folinic acid rescue until plasma level

Examples of TDM (2)
5-Fluorouracil
• Colorectal cancer (in combination)
• Toxicity: Haematological and mucositis
• Predicted toxicity if AUC > 30,000
ug/L.hr
Milano G et al, Int J Cancer (1988), 41, 537-541

2- 13 C-Uracil Breath Test
• Estimates DPD activity
• Give test dose of 2- 13 C-Uracil
• Measure 13 CO 2 levels in exhaled breath
• 13 CO 2 levels correspond to DPD activity
• Can identify patients with DPD deficiency
• Use these data to adjust and optimise 5-FU
dose

Example of TDM (3)
Mercaptopurine
• Children with ALL (repeated sampling)
• Relapse associated with Cp max
363ng/hr.ml
Hayder S etal, Ther drug Monit 1989, 11, 617-
622

Genetic Polymorphisms in
Metabolizing Enzymes
www.sciencemag.org/feature/data/1044449.shl
Science 1999;286:487-91

Mercaptopurine Catabolism
Liver
GI Tract
Target Cell
6-MP
HGPRT
TIMP
TGTP
TPMT
Thiouric Acid
Me-MP
Me-TIMP
Catabolism

TDM in Oncology: Confounding
Factors
• Genetic polymorphism
• Drug resistance
• Drug interactions
• Assay difficulties
• Active metabolites
• Some drugs are pro-drugs (e.g.
cyclophosphamide)

PK-PD Relationships in Cancer
Chemotherapy
• Difficult to select a reliable and relevant
PD measure
• PD measure is usually a key toxicity
• Case Study: Change of schedule of
Carboplatin from short-infusion to
prolonged continuous infusion

PK-PD Relationship in change of
Schedule
• Example:
Carboplatin by short IV infusion
Change to:
Carboplatin by prolonged continuous
infusion (+RT)

Carboplatin dose for manageable
haematological toxicity
Dose(mg) = Target AUC x (GFR + 25)
(Calvert Equation)
Target AUC values;
4 - 6 mg.ml/min (pre-treated patients)
6 - 8 mg.ml/min (untreated patients)

Carboplatin continuous infusion with
Synchronous Radiotherapy
Carboplatin 25-40mg/day x 5days x 4
courses
by continuous infusion + radiation (40Gy) ,
fractionated

Carboplatin Continuous Infusion PK-
PD Study: Conclusion
• Dose – GFR relationship for short-infusion of
carboplatin is not valid for prolonged infusion
• PK-PD relationship for prolonged infusion
enables dose calculation from pre-treatment
platelet count.
• The PK-PD model ensures maximum dose –
intensity, but with acceptable toxicity.
Allsopp and Sewell, Journal Oncology Pharmacy Practice
(1995), 1 (3), 23-32

TDM – The New Way
• Collect informative data, apply to Baysian
models (model “learns” from this)
• Identify central tendency and dispersion of
pk parameters.
• Identify useful co-variates (BSA, GFR etc)
• Apply Bayesian adaptive control strategy
• Predict outcome and Control therapy

Bayesian Theory
Rev. Thomas Bayes, 1702 - 1762
• Maximal a posteri Bayesian estimation
• Dose adjustment based on most relevant
exposure index (Cp, Cp max , AUC etc)
• Estimates made for each patient using
limited individual data (demographic,
clinical, [drug], pharmacogenomic, etc)

Bayesian Adaptive Dose
Bayesian
Approach:
Prior
probability
New Info
Objective
function
Posterior
probability
Goals
Control
therapy
In
Practice:
Population
model
Drug
levels
Prior +
New info.
Individual
model
Patient
specific
Calculate
dose

Bayesian Adaptive Dosing
Prospective Review
Genetic Factors for Drug Disposition
/Response/Toxicity
Test – dose TDM
Conventional Medication Review
Patient Specific Factors (eg organ function,drug –
drug interactions, cautions, life-style influences etc
etc)
Combination = Optimal Pharmacotherapy?

Conclusions
• Expectation of TDM + other parameters
for reduced inter-patient variability and
reduced toxicity and improved efficacy.
• Little evidence that TDM actually
achieves this.
• Need large, prospective Phase III
studies using Bayesian approach