PHSC1424 Biopharm - Unit 6 Lecture 1 Oral Drug Absorption Challenges

Very high solubility, low permeability, low bioavailability

solubility, permeability, and bioavailability of Metformin

III

BCS class of Metformin

Approximately 50% to 60%

absolute bioavailability of Metformin under fasting conditions

Decreased absorption

What is the lack of dose exposure proportionality with increasing doses of Metformin due to?

Decreases extent of absorption and slightly delays it

How does food affect Metformin's pharmacokinetics?

40% lower mean peak plasma concentration (Cmax), 25% lower AUC, 35-minute prolongation of Tmax

How are Cmax, AUC, and Tmax of Metformin affected by food?

Basic ionizable functional groups

What does Metformin's structure have contributing to its high solubility yet low permeability?

Organic cation transporter (OCT)

uptake transporter of Metformin from GI lumen to portal vein

OCT transporters could get saturated

In relation to its uptake, why is Metformin not preferred at high concentrations?

Highly water soluble, poor permeability, very low bioavailability

solubility, permeability, and bioavailability of Bisphosphonates

III

BCS class of Bisphosphonates

Hydrophilic phosphate groups that are negatively charged in physiological pH and completely ionized in intestinal lumen

What about the structure of Bisphosphonates contributes to the high water solubility?

0.6 to 3%

the range for the very low oral bioavailability of bisphosphonates

Food intake and posture

What does the oral bioavailability of bisphosphonates highly variable with?

Osteoporosis treatment

What are bisphosphonates and selective estrogen receptor modulators (SERMs) used for?

Poor adherence to drug administration regimens

What is considered one of the main problems that affect the efficacy of bisphosphonates and selective estrogen receptor modulators (SERMs)?

One-third

Approximately how many patients may administer their Bisphosphonates improperly?

Fast before and stay upright after administration

What is it important for patients taking bisphosphonates to do?

Maximizing bioavailability and avoiding esophageal irritation and erosion

What does proper administration of bisphosphonates, including fasting before and staying upright after administration, help with?

Physicians, pharmacists, and dieticians may underestimate impact of food and posture on drug exposure and response

Besides improper administration, what is another general problem with bisphosphonates?

Chelating

What type of agents are oral bisphosphonates, leading to salt formation with multivalent cations?

Form salts with multivalent cations

What do chelating agents like oral bisphosphonates do?

Food, dietary supplements, drugs, mineral water

What might have multivalent cations that form salts with chelating agents?

Insoluble at pH > 5 making bisphosphonates unable to be absorbed in the intestine

What is the issue with salts formed from oral bisphosphonate chelation?

Varies from at least 30 mins to 2 hours

recommended minimum time interval between bisphosphonate administration and the intake of vitamins, dietary supplements, and antacids containing multivalent cations such as calcium, aluminum, magnesium, and chromium

At least 2 hours

time that should separate the administration of bisphosphonates and iron preparations

Calcium

For oral bisphosphonates taken once a week or once a month, it is justified to refrain from administering what type of preparations on the same day?

Absorption

What does chelation impair?

Dairy products

can interfere with certain medications, including antibiotics such as tetracycline, doxycycline, and ciprofloxacin

Tetracycline, doxycycline, and ciprofloxacin

some antibiotics dairy products can interfere with

Antacids

contain trivalent and divalent metal cations like aluminum hydroxide, magnesium carbonate, and calcium carbonate that can bind to antibiotics and other drugs

Aluminum, calcium, magnesium, or iron

Drugs that bind what cations can form an insoluble substance in the stomach and upper small intestine that the body is unable to absorb?

Formation of insoluble substance in stomach and upper small intestine that cannot be absorbed

What is the result of drugs binding to aluminum, calcium, magnesium, or iron?

II

BCS class of posaconazole

During or immediately following a full meal

What is the recommendation for Noxafil (posaconazole) oral suspension administration?

Take with liquid nutritional supplement or acidic carbonated beverage

If someone can't take Noxafil (posaconazole) oral suspension with a full meal, what is the other administration recommendation?

Suppress acid secretion, increasing gastric pH or gastric motility, resulting in lower azole exposure

How do some drugs like PPIs reduce absorption of Noxafil (posaconazole) oral suspension?

Approximately 54%

absolute bioavailability of the posaconazole oral DR tablet under fasting conditions

Increase

Does the Cmax and AUC of posaconazole DR tablets increase or decrease when given with a high fat meal compared to a fasting state?

With food

In order to enhance the oral absorption and optimize plasma concentrations, how should posaconazole delayed-release tablets be administered?

Delayed release tablets

Which form of posaconazole isn't significantly affected by drugs that affect gastric pH or gastric motility?

II

BCS class of Ritonavir, an antiviral

Dissolution

Many drugs, such as Ritonavir, in BCS class II require strategies to improve what?

Pgp efflux pumps

What are several HIV protease inhibitors found in BCS class IV substrates of?

Poor and variable

What is the exposure of antivirals in BCS class IV like? (hint: leads to poor HIV treatment response)

Variable solubility and permeability, substrate for intestinal efflux by transporters, first pass metabolism in GIT or liver

3 reasons current antiretroviral therapies have poor bioavailability

Take with food

a solution to the poor bioavailability of current antiretroviral therapies attributed to variable solubility and permeability

Pgp inhibitor

a solution to the poor bioavailability of current antiretroviral therapies attributed to being a substrate for intestinal efflux transporters

CYP3A inhibitor

a solution to the poor bioavailability of current antiretroviral therapies attributed to first pass metabolism in the GIT or liver

Ritonavir

a potent CYP3A4 inhibitor that acts as a pharmacokinetic booster to result in a clinically relevant increase in the systemic exposure of Darunavir

To increase systemic exposure

How can Ritonavir's inhibition of CYP3A4 be used with Darunavir?

37% to 82%

How does the absolute oral bioavailability of Darunavir change when used alone and then with 100mg Ritonavir twice daily?

By taking with food

Besides using Ritonavir, how can Darunavir exposure also be increased?

IV

semaglutide BCS class

Low permeability, low solubility

permeability and solubility of semaglutide

Poor stability in the stomach and limited absorption

stability and absorption of semaglutide

Using SNAC to enhance absorption

How have oral formulations of semaglutide, like Rybelsus, overcome limitations?

300 mg of salcaprozate sodium (SNAC)

To overcome low permeability and high degradation, what is oral semaglutide co-formulated with?

Salcaprozate sodium (SNAC)

acts as a permeability enhancer, protecting the peptide from enzymatic degradation in the stomach and promoting absorption for semaglutide

Stomach

Where does the absorption of oral semaglutide predominantly occur?

0.4 to 1%

oral semaglutide (Rybelsus) estimated absolute bioavailability

Do not take with more than 4oz of water and no other liquids besides water

Rybelsus or Ozempic tablet administration point

30 minutes

After taking oral semaglutide, how long before it's okay to eat, drink, or take other oral medications?

Increases local pH

How does SNAC prevent oral semaglutide degradation?