Pharmaceutics of Low and High dose Methotrexate (MTX) Flashcards
What is MTX? 14:15
Antimetabolite antineoplastic:
- Antagonist of folic acid
- Immunosuppressant properties
- Inhibits dihydrofolate reductase (DHFR)
- Preventing formation of tetrahydrofolate (THF); necessary for purine and pyrimidine synthesis
- Cell cycle specific (inhibition of DNA and RNA synthesis)
What cases is MTX used?
- Management of ALL (Acute Lymphoblastic Leukaemia)
- Prophylaxis and treatment of meningeal leukaemia
- Psoriasis (not UK) and RA (lower dose)
Why is Oral MTX rarely associated with toxicity?
- Absorption of MTX is an active process; active transport (specific pathway)
- Pathway saturated in overdose
At what doses is MTX given IV and PO respectively?
- Doses > 100mg given partly/wholly IV over < 24 hours
- PO dosing for low individual dosing; < 100 mg/m^2
What are the issues with MTX dosing control?
- Effects of varying doses v. different
- Drug properties v. different at different pH
- Low permeability (C log P = 0.53)
- Poor aqueous solubility (0.01 mg/mL)
- Prolonged exposure to drug needed; MTX only kills actively dividing cells
- But; short plasma half-life (2-10 hrs)
- Nonspecific delivery
- Development of resistance; particularly w/sub-therapeutic doses
How does the salt form of MTX differ in solubility to the OG form?
- Salt form is much more soluble in the blood; Log P = -1.85
- COOH of MTX is protonated in OG form = not soluble
- But deprotonated (COO-) in sodium salt form
How do MTX PO tablets compare to MTX IM?
Oral Tablets:
- Low doses more commonly used for arthritic conditions
IM Injection:
- Used for RA (lower doses than anti-cancer)
- Better absorption than by PO (avoids receptors in stomach)
- Peak conc. similar to IV
- Slower drug absorption and more prolonged exposure to drug than with IV (muscles well perfused, drug will get transported to blood stream)
What route of administration is required for high-dose MTX anti-cancer therapy? Why?
- Parenteral route needed to achieve high dose; oral route is saturable
- Must be administered parenterally to achieve desired plasma concentrations
How does bioavailability of MTX change with increasing dose when administered orally? Plateau? Limits?
- Bioavailability does not increase w/increasing doses above a threshold level
- At doses less than 30mg/m^2, absorption of MTX is 90% of the dose
- Whilst at doses greater than 80mg/m^2, absorption is less than 20% of the dose
- Thus oral route becomes saturable; parenteral routes required for higher dosing.
What forms does MTX injection come in? What constraints does this place on formulation?
- Solution
- Powder for Solution
- Injectable
»> Complicated to prepare; sterility, stability etc
Why is lose dose MTX PO rapidly absorbed from the GI tract?
Specific receptors for folic acid (folate) in the gut.
How can MTX IM act as a depot, and possibly enhance toxicity?
- IM MTX distributes to tissues and extracellular fluid quickly
- However, it penetrates ascitic fluid and effusions; hence being to act as a depot, and enhance toxicity
»> Not controlling dosing as desired
What is the clearance like for MTX?
Triphasic (binds to plasma proteins, takes longer):
- Terminal elimination (half-life) = 3 - 10 hours (doses less than 30mg/m^2)
- Half-life = 8 - 15 hours (high-dose parenteral therapy)
What are the consequences of MTX forming polyglutamate conjugates intracellularly after uptake via active transport?
- Conjugate form MTX-pGlu is not actively exported
- Intracellular processing of this conjugate can liberate MTX; delayed action
- Thus MTX can remain in body for several months, particularly in liver
- Risk of overdose in injectable form (residual MTX post-liberation from polyglutamate conjugates)
Why are the pharmacokinetics of MTX highly variable?
Affected by:
- Age
- Renal and hepatic function
> Limited lipid solubility; does not diffuse across lipid membranes
Not transported into CSF after oral or IV
What is the main route of elimination for MTX?
Renal:
- Glomerular filtration
- Active tubular secretion
What is MTX toxicity dependent on? Administered dose?
- More dependent on duration of exposure
- Due to accumulation of polyglutamate conjugate
MTX can bind to proteins. What are the practical issues surrounding this w/treatment?
- Approximately 50% MTX bound to plasma proteins (IM)
- Variation between PO (takes time for MTX to reach bloodstream and IV early elimination rates)
> First pass metabolism vs. renal excretion
> Protein-bound MTX excreted less quickly; long circulation of proteins
What effects does taking aspirin/other NSAIDs have with taking MTX?
Negative:
- Displaces MTX from protein increased serum levels of free MTX
- Inhibits MTX secretion in PCT (kidney); reducing renal clearance = greater toxicity risk (greater exposure)
- Reduces renal clearance as a result, increasing serum level
- Increase in duration of MTX exposure hence increase in toxicity
What are the practical issues with high-dose MTX treatment? What can it result in?
- Can result in supersaturation of the urine with MTX & metabolites
- But this can cause crystal formation; which can cause intrarenal obstruction, possible AKI.
- MTX salt (COO-) non-protonated = crystal formation (esp. in acidic urine; acts as conjugate base)
What are the risk factors with crystal formation in high dose MTX, and how can these be minimised?
Risk factors:
- Acid urine
- Volume depletion
- Renal impairment
Minimise nephrotoxicity w/hydration + urinary alkalinisation:
- Sodium bicarbonate or acetazolamide
- Hydration
How can MTX overdose come about? PO or IM/IV?
- Acute oral dosing rarely causes ADRs; absorption of MTX is an active process; saturated in overdose (in the gut), F falls with increasing doses
- Thus, overdose is in injectables (IM/IV)
How is MTX overdose treated? What is of importance?
- Antidote folinic acid (Leucovorin) given IV
- Competitive for receptor
- Timing critical; efficacy drops rapidly with time after overdose
- Need to maintain high hydration (avoid acidic urine)
Why is the timing critical in administering Leucovorin (antidote folinic acid) for MTX overdose?
- MTX overdose = accumulation in cell as polyglutamate analogue
- This antidote needs to be given early to prevent depot effect; MTX eventually liberated from conjugate by intracellular processes
- Thus hit receptors with Leucovorin early
What barrier can MTX cross in high doses? Implications?
- Can cross the BBB
- Danger of severe damage/death if incorrectly dosed
What are the implications for MTX formulations given the dangers of overdose in IM/IV etc?
- Solubility (avoid crystal formation)
- pH (want to keep MTX as Na+ salt; avoid crystal formation)
- Sterility
How can resistance develop against MTX treatment?
- Intervention in DNA and RNA synthesis pathways can select for resistant phenotypes
»> MTX acts by inhibiting DHFR (dihydrofolate reductase) and thymidylate synthase (or 5FU?); dose at MTD - Impairment of drug import into cells and increase in drug export can generate resistance
What can the local administration of soluble TMX sodium lead to?
- Rapid transport through capillaries
- And into circulatory system; overdose risk
> Possible therapeutic failure in patients?
