Lecture 20 - dose management

Question 1

why adjust drug doses between human populations?

Answer 1

Reasons for this include the following:
variations in the distribution of the drug in the body (e.g. due to differences between individuals in body size and composition; this may be especially important in infants, children and people who are obese);

variations in metabolism and elimination of the drug (e.g. due to differences between individuals in genetic makeup; protein binding; hepatic and renal function; other organ function due to disease or prior therapy; and concurrent medication such as drugs that stimulate or inhibit the activity of cytochrome P450).

Question 2

what is extrapolation of dose?

Answer 2

stimating or predicting an appropriate dosage for a particular treatment or medication in a population or situation where direct clinical trial data may be limited or unavailable.

The aim of dose extrapolation is to produce appropriate drug exposure to ensure efficacy and safety

Question 3

what us the rational for dosing anticancer drugs?

Answer 3

Scaling of anticancer drug doses from animals to man is based on allometric relationships

Anticancer drugs have narrow therapeutic ranges
- size of patient influences V (linear) and CL (allometric)

BSA has been shown to correlate with cardiac output, total blood volume as well as renal function.

Doses are individualised according to the patient’s BSA - equivalent to an allometric exponent of 0.66

Question 4

Describe dose banding

Answer 4

Alternative to BSA dosing: dose bands often based on BSA ranges

Cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, topotecan all considered for dose banding.

Question 5

explain the dosage regimen design of carboplatin.

Answer 5

Carboplatin dose of 400 mg/m2 effective but patients with reduced GFR had side effects

Question 6

what are schedule dependancies in anticancer therapy?

Answer 6

route and rate of adminsiatrtion often as important as total exposure. optimising the dosage regimens of anticancer drugs may be as important as developing new drugs.

Fluroruacil: 1970s: IV bolus, 1980s: prolonged infusion– better response

Etoposide: giving the same dose over 5 days rather than 24 h increased response rate from 10% to 89%

Paclitaxel: weekly more effective that every 3 weeks

Question 7

what are factors influencing docetaxel and paclitaxel pharmacokinetics?

Answer 7

docetaxel can enter into the hepatocytes via lipophilic - passive diffusion and organic anion transport protein. paclitaxel enters by organic anion transport protein.

Within hepatocytes
Docetaxol metabolised by CYP3A4 and CYP3A5 isoenzymes
Paclitaxol metabolised by CYP3A4, CYP3A5 and CYP2C8

Intestinal efflux proteins excrete taxanes (including docetaxel and paclitaxel) into bile

Question 8

how can we reduce variability in taxmen exposure?

Answer 8

Genotyping
Find single nucleotide polymorphisms (SNPs) that influence PK or PD?
Results inconsistent
Phenotyping
Use probe drug to assess enzyme function; correlate with taxol clearance?
Paclitaxol elimination too complex, docetaxol - inconsistent findings
Therapeutic Drug Monitoring – need PK/PD studies
Docetaxol: response associated with AUC (one study)
Paclitaxel: outcome associated with time >0.05 M or 0.1 M
Limitations: need rapid assay, practical sampling, easy interpretation