Meloxicam Pharmacology and Bioavailability

Meloxicam (MLX)

• Meloxicam is a Non-Steroidal Anti-Inflammatory Drug (NSAID) and is also a good analgesic
• It is a BCS Class II drug meaning it has low solubility but high permeability
• Meloxicam is well absorbed with an absolute bioavailability of 89%
• However, Meloxicam is slow to be absorbed with a tmax (time to reach maximum concentration) of greater than 5 hours
• To obtain a faster analgesic response, a parenteral (injection) formulation of Meloxicam has been developed
• To improve the oral absorption rate of Meloxicam, a solid dispersion formulation has been created
• In the solid dispersion, the drug Meloxicam is incorporated into a water-soluble polymer matrix called polyethylene glycol (PEG)
• The goal of the solid dispersion is to increase the solubility and rate of dissolution of Meloxicam

Relative Bioavailability

• The bioavailability study conducted was a relative bioavailability study
• This is because no intravenous (IV) data was collected in the study
• The relative bioavailability of the Oral Disintegrating Tablet (ODT) formulation of Meloxicam was calculated
• The dose of Meloxicam given in the ODT and Immediate Release Tablet (IRT) was 15mg
• The relative bioavailability is calculated by dividing the Area Under the Curve (AUC) of the test formulation (ODT) by the AUC of the reference formulation (IRT)
• In this case, the relative bioavailability of the ODT formulation is 106% because the AUC of the ODT formulation is 40.189 and the AUC of the IRT formulation is 37.830

Conclusion

• The researchers concluded that the ODT-MLX formulation would be useful to produce an earlier onset of action than the IRT
• This conclusion is supported by comparing the time to reach maximum concentration (tmax) and the maximum concentration (Cmax) of the two formulations
• Statistical tests were conducted to determine if the differences in tmax and Cmax were statistically significant
• The p-value for both tmax and Cmax was less than 0.05 indicating that the differences were statistically significant
• This supports the conclusion that the ODT formulation resulted in a faster onset of drug action.

Bioavailability

• Absolute bioavailability = AUC(extravenous)/Dose(extravenous) divided by AUC(Intravenous)/Dose(Intravenous)
• AUC = Area under the plasma concentration-time curve
• Cmax = Peak height concentration
• tmax = Time to peak concentration
• MTC = Minimum Toxic Concentration
• MEC = Minimum Effective Concentration
• Relative bioavailability = AUC(test)/Dose(test) divided by AUC(standard)/Dose(standard)

Biopharmaceutics Classification System (BCS)

• The BCS classifies drugs according to their solubility and permeability.
• The goal of the BCS is to establish an IVIVC (in vitro-in vivo correlation).
• IVIVC is a mathematical model predicting the correlation between an in vitro property and a relevant in vivo response.

Intravenous (IV) Administration

• IV administration introduces the drug directly into the bloodstream.
• 100% bioavailability is achieved with IV administration.

Oral Administration

• Oral administration requires an absorption process.
• Not all of the drug may reach the blood circulation.
• Absorption and elimination can occur simultaneously.

Absolute Bioavailability

• The percentage of the administered dose of a drug that reaches the systemic circulation intact.
• It's the comparison of non-intravenous (i.e., extravenous) to intravenous routes of administration.

Biopharmaceutics Classification System (BCS) Classes

• Class I - High solubility, High permeability
• Class II - Low solubility, High permeability
• Class III - High solubility, Low permeability
• Class IV - Low solubility, Low permeability

In-Vitro Dissolution Studies

• The U.S. FDA requires dissolution testing data to control pharmaceutical product quality.
• The USP drug monographs provide guidelines for dissolution analysis:
  • Dissolution medium type
  • Volume of dissolution medium
  • pH
  • Ionic strength
  • Apparatus type (Apparatus 1 or Apparatus 2)
• The cumulative amount and percentage of labelled drug content are calculated.
• USP mandates the time for 75% of the labelled amount of drug to dissolve.

USP-approved Dissolution Apparatus

• Apparatus 1 - Rotating basket; rotates at specific rpm, can handle harsh media, 900 mL volume, 0.1 M HCl, kept at 37°C.
• Apparatus 2 - Paddle; rotates at specific rpm, can handle harsh media, 900 mL volume, 0.1 M HCl, kept at 37°C.

Permeation Across Biomembranes

• The intestinal mucosa is the site of absorption.
• Biological membranes are complex structures made of lipids and proteins.
• Most drugs permeate by simple diffusion.
• A drug's ability to partition into the lipophilic membrane environment indicates its ability to cross the biomembrane.

Bioavailability

• Bioavailability is the amount of drug that reaches the bloodstream intact
• The two parameters that govern drug absorption are solubility and permeability
• Solubility refers to the ability of a drug to dissolve in a solvent (usually water in the body)
• Permeability refers to the ability of a drug to pass through biological membranes
• The Biopharmaceutics Classification System (BCS) classifies drugs based on these two parameters
• Drugs with high solubility and high permeability are classified as Class I (e.g. Metoprolol)
• Drugs with low solubility and high permeability are classified as Class II (e.g. Nifedipine)
• Drugs with high solubility and low permeability are classified as Class III (e.g. Cimetidine)
• Drugs with low solubility and low permeability are classified as Class IV (e.g. Tirofiban)

In Vitro Dissolution Studies

• Dissolution testing is an important quality control measure for pharmaceutical products
• The United States Pharmacopeia (USP) provides specific guidelines for dissolution testing
• The USP guides specify the type of dissolution medium, volume of dissolution medium, pH, ionic strength, and type of apparatus (Apparatus 1 or Apparatus 2)
• For each drug, the USP drug monographs provide detailed guidelines on how to conduct the dissolution analysis
• The USP requires the time for 75% of the labeled amount of drug dissolved

Dissolution Apparatus

• There are two main dissolution apparatuses: Apparatus 1 (rotating basket) and Apparatus 2 (paddle)
• Apparatus 1 (rotating basket) is a rotating basket that stands harsh media
• Apparatus 1 (rotating basket) has a volume of 900 mL and maintains a 0.1 M HCl medium at 37°C
• Apparatus 2 (paddle) is a rotating paddle that stands harsh media
• Apparatus 2 (paddle) has a volume of 900 mL and maintains a 0.1 M HCl medium at 37°C

Cell Culture Based Model for Drug Permeation

• Caco-2 monolayer is a cell culture based model for studying drug permeation
• Caco-2 monolayer consists of a single layer of differentiated human colon adenocarcinoma cells
• Caco-2 monolayer is a suitable in vitro model for studying drug permeation because it resembles cells in the small intestine
• Caco-2 monolayer cells have microvilli structure, transporter systems, and tight junctions between cells
• The monolayer requires 15-21 days to form properly
• The monolayer integrity can be checked by the non-permeation of a marker molecule or by measuring transepithelial electrical resistance (TEER)

Factors Affecting Oral Bioavailability

• Physiological factors, drug factors, and excipients can affect the bioavailability of drugs
• pH variation within the gastrointestinal tract (e.g., stomach) can affect drug ionization and therefore dissolution and absorption
• Food consumption can trigger changes in the gastrointestinal tract that affect drug absorption
• Lipinski’s Rule of Five describes molecular properties important for a drug's pharmacokinetics, but does not predict if a compound is pharmacologically active
• Lipinski's Rule of Five is a rule of thumb for orally administered compounds
• Lipinski’s Rule of Five indicates that poor oral absorption is more likely to occur when there are more than 5 hydrogen bond donors, 10 hydrogen bond acceptors, a molecular weight greater than 500, or a calculated Log P (cLogP) greater than 5
• Excipients are usually considered inert but some excipients can modify the extent and/or the rate of absorption of drugs
• Drug types of varying degree of complexities, molecular masses, intestinal permeability include small molecules, monoclonal antibodies, peptides, proteins, and nucleic acid therapeutics
• Excipients can be diluents, lubricants, and disintegrants

Approaches to Improve Oral Bioavailability

• Improve drug solubility by decreasing the particle size of the drug
• Improve drug dissolution by formulating the drug into solid dispersions or using co-solvents
• Improve drug permeability by formulating the drug into liposomes or using absorption enhancers
• Avoid first-pass metabolism by using alternative routes of administration or using prodrugs
• Use appropriate dosage forms for the desired rate and extent of drug absorption

This quiz explores the pharmacological properties of Meloxicam, a Non-Steroidal Anti-Inflammatory Drug (NSAID). It covers aspects like its solubility, absorption rates, and formulation strategies to enhance bioavailability. Test your knowledge on Meloxicam's characteristics and its relative bioavailability study.