Pharmacokinetics: IV Bolus, Infusion, and Oral Admin

• Intravenous (IV) bolus administration involves direct injection of a drug into systemic circulation, leading to immediate distribution and elimination at a rate constant KE, without an absorption phase.
• IV infusion administers the drug constantly into systemic circulation, balancing infusion and elimination rates.

Oral Administration

• Oral drug administration involves the drug entering the gastrointestinal (GI) tract before systemic circulation, being eliminated at rate constant KE.
• The absorption rate is proportional to the drug amount in the GI tract, while elimination rate is proportional to the drug amount in systemic circulation.
• The rate of change of drug amount in systemic circulation considers both absorption (KA) and elimination (KE), following first-order kinetics.

Pharmacokinetics of Oral Administration

ADME Process

• Concentration-time profiles for oral drug administration reflect absorption, distribution, metabolism, and excretion (ADME).
• Initially, the absorption rate exceeds the elimination rate until peak plasma concentration (Cmax) is reached at time Tmax.
• After absorption, distribution into tissues causes plasma concentration to decrease, followed by metabolism and excretion.
• Drug elimination typically follows first-order kinetics.

Bateman Equation

• The Bateman Equation is an analytical solution describing drug concentration over time after a single oral dose, combining absorption and elimination processes.
• This equation assumes a one-compartment model, first-order kinetics for absorption and elimination, and no lag time.
• The Bateman Equation considers bioavailability (F), administered dose (D), absorption rate constant (KA), volume of distribution (VD), and elimination rate constant (KE)
• The equation consists of a constant part multiplied by a term representing the net change in drug concentration due to absorption and elimination, expressed as e^(-KEt) - e^(-KAt).

Bioavailability (F)

• Bioavailability is the fraction of an administered drug dose that reaches systemic circulation in its active form; it equals Fabs * Fgut * Fhepatic.
• Fabs is the fraction absorbed from the GI tract into the portal circulation.
• Fgut is the fraction escaping gut metabolism.
• Fhepatic is the fraction escaping hepatic first-pass metabolism.
• A lower Fhepatic significantly impacts bioavailability due to extensive hepatic first-pass metabolism, which can be bypassed through pro-drug development or alternative routes of administration.

Flip-Flop Kinetics

• The defining differential equation includes KA and KE.
• In flip-flop kinetics, absorption (KA) is slower than elimination (KE).
• Normal kinetics have KA > KE, where the terminal phase is driven by KE. With flip-flop kinetics, KA < KE, the terminal phase is dominated by KA.
• In flip-flop, the effect of KE in the exponential decay term diminishes more rapidly because KE has a larger value than KA.

Feathering (Residual Method)

• Feathering separates different phases of the concentration-time profile on a semi-logarithmic scale.
• The method involves extrapolating the linear terminal phase back to earlier time points, and then subtracting these concentrations from the total concentrations to isolate the absorption phase.
• This isolated phase is used to estimate the rate constant.

Comparison of Normal vs. Flip-Flop Kinetics

• Modified-release formulations release drugs slowly, prolonging therapeutic effects or reducing dosing frequency.
• In flip-flop kinetics, the terminal slope reflects KA.
• AUC is independent of KA and inversely proportional to KE for both normal and flip-flop kinetics.

Half-Life, Tmax, and AUC

Half-Life (t1/2)

• Half-life is the required for drug concentration in the body to decrease by 50%.
• t1/2 = ln(2) / λz (λz is the rate constant).
• In normal kinetics: t1/2 = ln(2) / KE; In flip-flop kinetics: t1/2 = ln(2) / KA

Tmax

• Tmax is the time needed to reach the maximum concentration (Cmax).
• A smaller KA results in a later Tmax, as seen in modified-release formulations.
• Tmax is independent of dose and bioavailability.
• Tmax is the time when the rate of change of drug concentration is zero, derived by differentiating the Bateman Equation and setting it to zero.

Area Under the Curve (AUC)

• AUC represents the total drug exposure: AUC = (Dose * Bioavailability) / Clearance
• AUC is proportional to the dose and bioavailability, and inversely proportional to clearance and KE.
• AUC is independent of KA.
• For IV bolus: AUC = Dose / Clearance

Multiple Oral Dosing

• Multiple dosing causes drug accumulation in plasma until steady-state is reached.
• Steady-state occurs when the rate of drug administration equals the rate of drug elimination, typically reached in four to five half-lives.
• At steady-state, the concentration-time profile in each dosing interval is consistent.
• The AUC between dosing intervals at steady-state equals the AUC of a single dose from time zero to infinity.
• Key assumptions: linear pharmacokinetics, no saturated absorption or metabolism, and first-order kinetics for elimination.

Average Concentration at Steady-State (Cavg,ss)

• Cavg,ss describes the time-average drug concentration during one dosing interval.
• Cavg,ss = AUC / τ or (Dose * Bioavailability )/ (Clearance * τ)
• Cavg,ss is proportional to the dose and bioavailability, and inversely proportional to clearance and the dosing interval (τ).
• It's used to assess whether the drug level remains within the therapeutic window; maintaining a target Cavg,ss is critical for drugs with a narrow therapeutic index.