Platinium drugs Flashcards
Give an example platinium drug
Carboplatin and cisplatin form the same activated end product.
Carboplatin forms the final adduct slower than cisplatin.
Mechanism of action of carboplatin
Once carboplatin enters cell, it undergoes hydrolysis therefore binding of activated platinium drug to DNA to form platinum DNA adducts (can be intrastrand or interstrand DNA crosslinks)
Metabolism of carboplatin
Carboplatin is metabolised slowly and to a small extent: Carboplatin exhibits lower reactivity and slower DNA binding kinetics, although it forms the same reaction products in vitro at equivalent doses with cisplatin.
Exposure to non-protein bound drug is important: The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).
Carboplatin, a widely used cancer chemotherapeutic agent, is excreted mainly by glomerular filtration. Maintaining efficacy and avoiding toxicity requires determination of glomerular filtration rate (GFR) for accurate dosing.
Toxicity of carboplatin vs cisplatin
Near its maximum tolerated dose (MTD) of 400 mg/m2, carboplatin is less nephrotoxic, neurotoxic and ototoxic, and much less emetogenic, than is cisplatin when approaching its own MTD of around 100 mg/m2
How does drug resistance to carboplatin develop?
- Reduced cellular uptake by CTR 1 transporters for example
- Increased efflux of drug out of tumor cell due to altered localisation ATP7A/7B transporters
- Increased DNA repair via activation of Nucleotide Excision Repair pathway
- MLH1 hyper-methylation - methylation in the MLH1 promoter decreases MMR performs an important role in the resistance
Tumor types acted on by carboplatin?
Germ cell tumors
Ovarian cancer
Childhood cancer
How do we determine individualised effective dose of carboplatin (PK)?
It was found that exposure (AUC) to carboplatin was useful in determining toxicity and clinical effect.
Calvert 1989 found that higher carboplatin clearance was associated with high GFR rate and therefore dose given to patients should be AUC x (GFR + 25)
Thomas et al 2000, also found that using GFR to monitor renal function allows children to be treated more effectively and achieve their targeted exposure (AUC) compared to when dosing based on body surface area.