1. PRESENTED BY: ALIAA MOHAMED KHALED PRSENTED TO: DR.NASHAAT LOTFY
Taxanes and Their Derivatives
PRESENTED BY: ALIAA MOHAMED KHALED PRSENTED TO: DR.NASHAAT LOTFY

2. The Taxanes and Their Derivatives (antimicrotubule agent)
Two taxanes are approved for clinical use (paclitaxel and docetaxel)
An albumin-stabilized paclitaxel (Abraxane) is also available for treatment of breast cancer (selective binding of albumin –bound paclitaxel to specific albumin receptors present on tumor cells versus normal cells) approved in 2005
Paclitaxel is first isolated from the bark of the Pacific yew tree
(Taxus brevifolia)
Docetaxel is a semisynthetic analog of paclitaxel
Both docetaxel and paclitaxel bind to the same microtubule site, although the affinity of docetaxel is 1.9-fold higher
Both drugs are cell cycle specific, they are active in the G2/M phase of the cell cycle
(Late G2 & mitotic phase are inhibited and thus cell replication is inhibited)

3. STRUCTURE (both molecules are complex esters)
The structures of paclitaxel and docetaxel differ in substitutions at the C-10 taxane ring position and on the ester side chain attached at the C-13 ring position.
Docetaxel is slightly more water-soluble than paclitaxel and a more potent inhibitor of tubulin .
The substitutions at C-13 position are essential for antimicrotubule activity.

4. MECHANISM OF ACTION
The movement of the replicated chromosomes during mitosis, requires both polymerization of tubulin to form microtubules as well as depolymerization of microtubules.
Microtubules (long chains of the protein tubulin) are highly dynamic, they play a key role during mitosis, they serve to give a cell shape, aid in cellular motility and are very important in cell division.
Taxanes stabilize microtubules (the drug binds to microtubules and prevents their breakdown).
Thus, they shift the depolymerization-polymerization process to accumulation of microtubules. The stable microtubules formed are nonfunctional,This results in death of the cell.

6. Resistance
Like the vinca alkaloids, resistance has been associated with the presence of amplified P-glycoprotein OR a mutation in the tubulin structure.
result in enhanced drug efflux and decreased intracellular accumulation of the drug.

7. Docetaxel
Paclitaxel,nanoparticle albumin-bound (nab)
Paclitaxel
Characteristic
TAXOTERE®
ABRAXANE®
ONXOL® (USA), TAXOL®
COMMON TRADE NAMES
Not absorbed orally
ORAL ABSORPTION
75–100 mg/m2
1h infusion every
3 weeks
260 mg/m2
IV for one dose on day 1 every 3 weeks
135–175 mg/m2
3 h infusion every
DOSE AND SCHEDULE
>95%
<90%
PLASMA PROTEIN BINDING
Extensive binding
Extensive except CNS
Extensive
Extensive except
CNS and testes
TISSUE DISTRIBUTION
Hepatic metabolism via cytochrome P450,biliary/fecal elimination
Doses should be reduced in patients with hepatic dysfunction.
METABOLISM & EXCREATION

8. Docetaxel
Paclitaxel-(nab)
Paclitaxel
Characteristic
<10%
dose modification is not required in patients with renal impairment
RENAL CLEARANCE
1. Breast cancer
(advanced or metastatic)
2. Lung cancer, non-small cell
3. Head and neck cancer
4. Lung cancer, small cell
5. Ovarian cancer
6. Prostate cancer
FDA approved for treatment of breast cancer after failure of combination therapy for metastatic disease or recurrent breast cancer
1. Primary treatment of
ovarian cancer
2. Metastatic ovarian
cancer or metastatic
breast cancer
3. Primary or secondary
treatment of NSCLC (non
-small cell lung cancer)
4. Node positive breast
cancer
5. Overexpression of HER
-2 breast cancer
6. second-line treatment
of AIDS-related Kaposi's
sarcoma.
INDICATION:
Act as a radio sensitizing agent
No experience with the use of Abraxane with radiotherapy
RADIATION:

9. SIDE EFFECTS The dose-limiting toxicity of taxanes is NEUTROPENIA
Patients with fewer than 1500 neutrophils/mm3 should not be given these agents
Treatment with granulocyte colony-stimulating factor (Filgrastim) NEUPOGEN® can help to reverse neutropenia .

10. Docetaxel
Paclitaxel-(nab)
Paclitaxel
Characteristic
1. fatigue
2. Hypersensitivity RXs
3. fluid retension syndrome present as: weight gain, pleural effusion; ascitis. (Incedince increase when total dose more than 400mg/m2)
4. alopecia up to 80% of patient
5. peripheral
neuropathy but less common than in paclitaxel
1. sensory neuropathy 
2. alopecia
3. ocular &
visual
disturbance
4. edema
5. Fatigue &
weakness
6.diarrhea
1. hypersensitivity RXs
2. alopecia; usually complete
3. nail and skin changes, mild, transient
intestinal obstruction
4 . Nausea, vomiting, or diarrhea
5 . peripheral neuropathy (usually sensory in nature)
6 . arthralgia/myalgia (worse with higher doses and shorter infusions)
7. Bradycardia and
Hypotension.
SIDE EFFECTS:

11. Docetaxel
Paclitaxel -(nab)
Paclitaxel
Characteristic
Single-dose vials of concentrated injection containing 20 or 80mg of docetaxel (anhydrous), in 0.5 or 2.0mL polysorbate 80
The suspension consists only of (albumin-bound paclitaxel nanoparticles)
No need for premedication to prevent solvent-based hypersensitivity Rxs
As a result of lowered toxicity, higher doses of paclitaxel may be administered
formulated in
50% alcohol
(may cause drowsiness)
and 50%
polyoxyethylated
castor oil derivative
FORMULATION

12. Docetaxel
(nab)
Paclitaxel
Characteristic
1. Intermittent infusion
in 250 mL NS over 1 h (use non-PVC equipment)
Patient must have received a minimum of 3 doses of dexamethasone® before each treatment.
• slow initiation of infusion is not routinely needed to reduce the risk of allergic reactions
over 30 min
non-PVC bag and tubing are NOT needed
Intermittent infusion
 In appropriate volume of NS or D5W over 1-3 h
dilute in non-PVC bags (e.g., polyethylene) used to minimize leaching
dilute to final concentration of mg/mL
premedication required to prevent hypersensitivity Rx
2.Continuous infusion
as for intermittent infusion except given over 24 h
Administration

13. DRUG INTERACTIONS Management Mechanism Interacting drug
monitor for increased cardiotoxicity OR use docetaxel instead of paclitaxel
(docetaxel does not appear to share this same interaction potential)
Paclitaxel reduces plasma clearance of doxorubicin, increased doxorubicin toxicity
Doxorubicin
Administer paclitaxel 24 hour before platinium compounds.
Myelosuppression is greater when platinum drugs administered before paclitaxel, platinium compounds inhibit plasma clearance of paclitaxel
Cisplatin and Carboplatin
(platinum derivatives)
monitor coagulation parameters during coadministration OR use LMWH during course of chemotherapy OR decrease dose of Coumadin
paclitaxel displaces coumadin from
protein-binding sites
Warfarin

14. Management
Mechanism
Interacting drug
Decrease dose of gemcitabine
Paclitaxel may increase level of gemcitabine by unknown mechanism
Gemcitabine
(Gemzar®)
Preferred method is to give trastuzumab first when administering as sequential infusions
May increase efficacy of paclitaxel by unknown mechanism
Trastuzumab
(Herceptin®)
Separate administration by 24 hours if possible
Toxicity of both agents may be increased when given concurrently, (increased levels of epirubicin metabolites, decreased paclitaxel clearance)
Epirubicin (Pharmorubicin®)
close monitoring OR the combination of these drugs should be avoided.
ketoconazole may inhibit the metabolism of paclitaxel
Ketoconazole

15. Special precautions Paclitaxel Hypersensitivity reactions (HSR)
it may result from either the Cremophor EL in the paclitaxel injection or from the paclitaxel itself.
HSR most often occur in the first hour of an infusion (75% occur within the first 10 minutes)
The frequency and severity of these reactions are not affected by the dose or schedule of paclitaxel administration.
Incidence of HSR are significantly reduced by premedication
Corticosteroids (e.g., dexamethasone), histamine H1-antagonists (e.g., diphenhydramine) and H2-antagonists (e.g., ranitidine) should be administered prior to paclitaxel administration to minimize the potential for anaphylaxis.
The following is one suggested regimen for adults
45 minutes before paclitaxel, dexamethasone 20 mg IV
30 minutes before paclitaxel, diphenhydramine 50 mg IV and ranitidine 50 mg IV.

16. Is not recommended due to the potential secretion into breast milk.
2. Pregnancy:
FDA Pregnancy Category D(There is positive evidence of human fetal risk)
3. Breastfeeding
Is not recommended due to the potential secretion into breast milk.
4. Use with caution in patient with
History of chronic ischemic heart disease, myocardial infarction, DM,alcoholism, abnormal liver function
5. Elderly patients
Are at an increased risk for developing toxicities (e.g., arthralgia, myalgia, neutropenia, neuropathy).

17. Docetaxel
1 . Contraindicated in patients with a history of hypersensitivity reaction to docetaxel or to drugs formulated with polysorbate 80, Patients hypersensitive to paclitaxel may also react to docetaxel
2. Preexisting effusions:
Patients with preexisting effusion should be closely monitored from the first dose for the possible exacerbation of the effusions
3. Alcohol abuse: When docetaxel is used in patients who abuse alcohol, or have abused alcohol, the risk of severe neurotoxic reactions may be increased
4. Pregnancy: FDA Pregnancy Category D

18. 5. Treatment with docetaxel is usually accompanied with steroids
In order to prevent severe fluid retention. However, fluid retention still occurs in some cases.
weekly regimen A commonly used regimen consists of
dexamethasone 8 mg PO twice a day for 3 consecutive days
starting one day prior to each docetaxel infusion.
Patients must receive a minimum of 3 doses of
dexamethasone prior to docetaxel treatment.
6. Liver impairment: Patients treated with docetaxel 100 mg/m2 are at a higher risk of developing severe adverse reactions if they have elevated transaminase (ALT and/or AST greater than 1.5 times the upper limit of normal [ULN])

19. Abraxane
1. It has not been studied in patients with hepatic or renal dysfunction, use with caution with patient of liver
dysfunction (higher risk of toxicity)
2. No premedication is required to prevent hypersensitivity
3. Abraxane can't be substituted for or with other paclitaxel formulations as the albumin form of paclitaxel may alter the drug activity
4. Pregnancy category D
5. Breast feeding should be avoided

20. Common regimens in clinical practice
BREAST CANCER: ACT Doxorubicin 60 mg/m2 iv on day 1 Cyclophosphamide: 600 mg/m2 iv on day 1 Docetaxel: 100 mg/m2 iv on day 1 Repeat cycle every 21 days for a total of four cycles, followed by surgery. Single agents Paclitaxel 175 mglm2 , over 3 hours (every 21 days ) OR 250mg/m2 over 3 hours-24hours (every 21 days) Docetaxel mg/m2, over 1 hour Repeat cycle every 3 weeks

21. Trastuzumab –paclitaxel
HER-2 +VE BREAST CANCER
Trastuzumab –paclitaxel
Trastuzumab mg/kg i.v loading dose, and then 2mg/kg weekly
Paclitaxel mg/m2 i.v over 3 hours on day 1
Repeat cycle (every 21 days)
CANCER OF UNKNOWN PRIMARY
PCE
Paclitaxel mg/m2 iv on day 1 over 1 hour
Carboplatin AUC of 6,IV on day1
Etoposide mg alternating with 100 mg PO on days 1-10
Repeated every 21 days
CERVICAL CANCER:
Paclitaxel + Cisplatin
Paclitaxel mg/m2 iv over 24 hours on day 1
Cisplatin mg/m2 iv on day 2
Repeat cycle every 21 days.

22. Thank you