kinetics 4.7 Drug Product Design and Dosage Calculations

Drug Product Design Considerations

• Importance of understanding drug design in pharmacy and pharmacology.

• Key elements to consider when designing a drug:

  • Physicochemical properties of the drug: Stability, solubility, and interaction with excipients.

  • Formulation characteristics: Dosage form (tablet, injectable, etc.), delivery method, excipient roles, and how they impact bioavailability.

Case Study - Phenytoin Dosage

• A case analysis of a patient with a seizure disorder stabilized with diazepam.

• Two important calculations: Loading dose and Maintenance dose.

  • Key parameters given:

  • Population Vmax = 7 mg/kg

  • Population Km = 4 mg/L

  • Salt Factor = 0.92 (for phenytoin Sodium)

  • Volume of Distribution (Vd) = 0.65 L/kg

• Loading Dose Calculation:

  • Formula:
    Loading\, Dose = \frac{Desired\, Concentration \times V_d}{Salt\, Factor}

  • For a desired concentration of 20 mg/L and a patient weighing 75 kg:

  • Loading\, Dose = \frac{20\, mg/L \times (0.65\, L/kg \times 75\, kg)}{0.92} = 1060\, mg

• Maintenance Dose Calculation:

  • For steady-state concentration desired at 15 mg/L:

  • Maintenance\, Dose = \frac{V{max} \times Dosing\, Rate}{(Salt\, Factor \times Km)}

  • Given Vmax is 7 mg/kg for a 75 kg patient, the required daily maintenance dose turns out to be around 450 mg/day.

Pharmacokinetics and Steady-State Achievements

• Discusses the time taken to achieve steady-state concentrations based on differing dosages of phenytoin.

  • 300 mg, 350 mg, 400 mg dosages lead to different times to reach steady-state, illustrating saturation kinetics.

  • Critical to draw samples at appropriate times to determine effectiveness of dosing strategy.

Patient-Specific Vmax Determination

• A case to determine if the population parameters apply to a specific patient after an inadequate response (level obtained was 6 mg/L instead of the target 15 mg/L).

• Patient-specific Vmax was calculated using:

  • Patient's\, V{max} = \frac{Dosing\, Rate \times Salt\, Factor}{C{ss}}

• New dosing recommendations are updated based on patient's unique pharmacokinetic response.

Biopharmaceutical Considerations in Drug Formulation

• Factors affecting drug absorption and delivery:

  • Disintegration: The drug must break down into smaller particles to be absorbed.

  • Dissolution: The process of dissolving the disintegrated particles into solution.

  • Excipients Use: Role of excipients such as stabilizers, disintegrants, lubricants, and their impact on pharmacokinetic profiles.

Equations Governing Drug Dissolution

• Noyes-Whitney Equation: Governs the rate of dissolution and includes factors like surface area, stagnant layer thickness, and concentration gradients.

  • Rate = \frac{D \times A \times (C_s - C)}{H}

  • Where D is the diffusion coefficient, A is the area, Cs is saturated concentration, C is concentration in bulk solvent, and H is stagnant layer thickness.

Excipients and Their Role

• Discusses the basics of excipients used in drug formulation, such as:

  • Diluents: Increase volume.

  • Disintegrants: Increase disintegration speed for faster absorption.

  • Binders: Help to form granules.

  • Coating Agents: Protect the drug from degradation; for example, enteric coatings prevent release in the stomach.

Stability and Release Rates

• Stability of the drug formulation is important for efficacy and safety.

• Release Rate Considerations:

  • Tailored formulations depending on whether drug therapy is for acute conditions or chronic use.

• Importance of adjusting release to improve adherence to medication regimen.

Pharmacodynamics and Dosing

• Illustrates the relationship between drug concentration and therapeutic effect.

  • Importance of considering route of administration and its impact on drug response.

  • Adherence considerations including taste, size, and frequency of dosing needs are critical for patient compliance.

These notes summarize considerations and examples in drug product design and dosing based on patient pharmacokinetics. They provide a foundational understanding of critical pharmacologic principles necessary for effective drug design and administration.

Importance of understanding drug design in pharmacy and pharmacology.

Key elements to consider when designing a drug:

• Physicochemical properties of the drug: Critical characteristics include stability, solubility, and how the drug interacts with excipients. Stability ensures that the drug maintains its efficacy and safety over its intended shelf life, while solubility affects bioavailability, i.e., how much of the drug becomes available at the site of action.

• Formulation characteristics: This includes selecting the appropriate dosage form (such as tablets, injectables, or topical preparations), determining the delivery method, and understanding excipient roles. Each of these factors impacts the drug's bioavailability and patient compliance. For example, the selection of a liquid formulation over a solid may facilitate faster absorption for certain patients.

Case Study - Phenytoin Dosage

A case analysis of a patient with a seizure disorder stabilized with diazepam.

Two important calculations in this scenario are: Loading dose and Maintenance dose.

Key parameters given:

• Population Vmax = 7 mg/kg

• Population Km = 4 mg/L

• Salt Factor = 0.92 (for phenytoin Sodium)

• Volume of Distribution (Vd) = 0.65 L/kg

Loading Dose Calculation:

Formula:
Loading\, Dose = \frac{Desired\, Concentration \times V_d}{Salt\, Factor}

For a desired concentration of 20 mg/L and a patient weighing 75 kg:
Loading\, Dose = \frac{20\, mg/L \times (0.65\, L/kg \times 75\, kg)}{0.92} = 1060\, mg

Maintenance Dose Calculation:

For steady-state concentration desired at 15 mg/L:
Maintenance\, Dose = \frac{V{max} \times Dosing\, Rate}{(Salt\, Factor \times Km)}

Given Vmax is 7 mg/kg for a 75 kg patient, the required daily maintenance dose turns out to be around 450 mg/day. This calculation is vital for achieving therapeutic efficacy without toxicity.

Pharmacokinetics and Steady-State Achievements

Discusses the time taken to achieve steady-state concentrations based on differing dosages of phenytoin—demonstrating the principle of saturation kinetics. Dosages of 300 mg, 350 mg, and 400 mg each lead to different times to reach steady-state, illustrating that higher doses may not equate to faster steady-state achievement.

Critical to draw samples at appropriate times to determine effectiveness of dosing strategy—this is essential for therapeutic drug monitoring to prevent subtherapeutic or toxic levels.

Patient-Specific Vmax Determination

A case was examined to determine if the population parameters apply to a specific patient after an inadequate response (with a level obtained of 6 mg/L instead of the target 15 mg/L).

Patient-specific Vmax was calculated using:
Patient's\, V{max} = \frac{Dosing\, Rate \times Salt\, Factor}{C{ss}}

New dosing recommendations are updated based on the patient's unique pharmacokinetic response, highlighting the importance of personalized medicine in optimizing therapy.

Biopharmaceutical Considerations in Drug Formulation

Factors affecting drug absorption and delivery:

• Disintegration: The drug must break down into smaller particles to be absorbed effectively. This can be influenced by compaction during tablet formation.

• Dissolution: The process of dissolving the disintegrated particles into solution. Formulation strategies can enhance dissolution rates, such as using solubilizers or nanosizing the active pharmaceutical ingredient.

• Excipients Use: Role of excipients such as stabilizers, disintegrants, and lubricants, which can greatly impact pharmacokinetic profiles. For instance, poor choice of excipients could result in variability in drug release and bioavailability.

Equations Governing Drug Dissolution

• Noyes-Whitney Equation: Governs the rate of dissolution and includes factors like surface area, stagnant layer thickness, and concentration gradients:
  Rate = \frac{D \times A \times (C_s - C)}{H}
  Where:

• D is the diffusion coefficient,

• A is the area,

• C_s is saturated concentration,

• C is concentration in bulk solvent, and

• H is stagnant layer thickness. This equation is critical for understanding how formulation changes affect drug release rates.

Excipients and Their Role

Discusses the basics of excipients used in drug formulation, such as:

• Diluents: Increase volume and bulk for tablet formulations.

• Disintegrants: Increase disintegration speed for faster absorption; the right choice can enhance drug bioavailability significantly.

• Binders: Help to form granules, ensuring consistency and integrity of the dosage form.

• Coating Agents: Protect the drug from degradation; for example, enteric coatings prevent release in the stomach, crucial for stability of acid-sensitive drugs.

Stability and Release Rates

Stability of the drug formulation is critical for efficacy and safety, often influenced by environmental factors like humidity and temperature.

Release Rate Considerations involve tailoring formulations based on whether drug therapy is for acute conditions or chronic use. This underscores the importance of adjusting release profiles to improve adherence to medication regimens, thus enhancing patient outcomes.

Pharmacodynamics and Dosing

Illustrates the relationship between drug concentration and therapeutic effect, emphasizing dose-response relationships.

Importance of considering the route of administration and its impact on drug response is paramount, as pharmacodynamics can vary significantly. Adherence considerations, including taste, size, and frequency of dosing needs are critical for patient compliance, which ultimately affects therapeutic success.

These notes summarize considerations and examples in drug product design and dosing based on patient pharmacokinetics. They provide a foundational understanding of critical pharmacologic principles necessary for effective drug design and administration.

1. What are the effects of excipients on the biopharmaceutics profile of a drug formulation?

   • Excipients can significantly influence the biopharmaceutics profile by affecting the solubility, stability, and bioavailability of the active pharmaceutical ingredient. They can enhance drug release rates, improve absorption, and modify the drug's pharmacokinetic properties. Proper selection of excipients is crucial for ensuring the effectiveness and safety of the formulation.

2. How do a drug’s physico-chemical properties affect its biopharmaceutics profile?

   • The physico-chemical properties of a drug, such as solubility, stability, and molecular weight, directly impact its absorption and overall bioavailability. For instance, a drug must be soluble to be absorbed effectively at the site of action, and its stability ensures that it retains therapeutic efficacy throughout its shelf life.

3. What is dissolution and what law governs it?

   • Dissolution is the process through which a solid form of a drug releases into solution, becoming available for absorption. It is governed primarily by the Noyes-Whitney equation, which describes the rate of dissolution as influenced by factors such as surface area, concentration gradients, and stagnant layer thickness around the dissolving particle.

4. What is the impact of drug product properties on therapeutic outcomes?

   • The properties of a drug product, including formulation characteristics and release rates, can influence therapeutic outcomes significantly. For instance, the choice of dosage form and the rate of drug release can affect patient adherence, the onset of action, and the overall therapeutic effect. Tailoring these properties based on individual patient needs is essential to optimize efficacy and improve health outcomes.