Principles of Biopharmaceutics & Kinetics 2, Fall 2024 Non-Linear Kinetics PDF

Principles of Biopharmaceutics & Kinetics 2 Non-Linear Kinetics & PK PD Principles Hailey Kwiatkowski, PhD Assistant Professor of Pharmaceutical Sciences [email protected]...

Principles of Biopharmaceutics & Kinetics 2 Non-Linear Kinetics & PK PD Principles Hailey Kwiatkowski, PhD Assistant Professor of Pharmaceutical Sciences [email protected] Fall 2024 Non-Linear Pharmacokineti cs Introduction Most drugs have constant elimination rate constants (and half- life), apparent volume of distribution, and systemic clearance *no change from varied dose, RoA, multiple administrations for most drugs Most drugs exhibit first order absorption and elimination kinetics and are described as linear pharmacokinetics (aka dose independent). Cp AUC Dose Dose 3 Introduction IV Bolus Drug A o Same ROA o Same dose Drug B o Different Drug C relationship between dose and AUC o Drug B demonstrates linear pharmacokinetics o Drug A and Drug C demonstrate non-linear pharmacokinetics Drug A may be due to saturation of metabolism/excretion Drug C may be due to saturation of absorption mechanisms 4 Possible Causes of Non-Linear PK o Many process of drug absorption, distribution, metabolism, and excretion involve enzymes or carrier- mediated systems At therapeutic levels, this may or may not be applicable o Possible causes: Drug saturation of plasma protein=binding Drug saturation of carrier-mediated systems Pathologic alteration in ADME (ex: aminoglycosides causing renal nephrotoxicity, or a gallstone obstruction of bile duct altering biliary drug excretion) o Outcome: Change in apparent elimination rate constant  change systemic exposure (AUC) 5 Relevance of Non-Linear PK 6  Causes of Non-Linear PK Saturation Process Mechanism Examples Outcome Saturated uptake Less absorption Ribflavin Absorptio transporters n Saturated efflux More absorption Propranolol transporters Saturated plasma Higher free Prednisone proteins fraction Naproxen Distributio Cellular n uptake/saturable Varies Methotrexate transport into or out of tissues Lower clearance, Metabolis Saturated hepatic Phenytoin slower m enzymes Ethanol elimination Lower clearance, Saturation of renal Penicillin The most clinically important type of nonlinear Excretion pharmacokinetics is saturable slower transporters Naproxen metabolismelimination 7 Mechanism of Dose-Dependent, Non-Linear PK Behavior: Absorption Concentration-dependent saturation of a carrier or enzyme involved in the drug’s ADME process Increased Drug Concentration 8  Characteristics of Dose- Dependent Non-Linear PK o Non-linear PK = dose or time dependency of PK processes o CL, half-life, and F will depend on dose of the drug o Shape of PK curve changes as a function of dose o Dose-dependent absorption or elimination: increased absorption/elimination half-lives 9 Characteristics of Time- Dependent Non-Linear PK o CL, half-life, and F will depend on dose of the drug o Shape of PK curve changes as a function of time o Example: Autoinducers such as carbamazepine o Solution: Administer dose more frequently for same effect 10  Non-Linear Kinetic Drug Administration Cp Dose o AUC and Cp do not increase proportionally to dose administered 11 Impact of Non-Linear Elimination-Chronic Drug Administration oCp change is not proportional to changes in rate of administration 12 Non-Linear Kinetic Drug Administration High drug concentration low drug concentration 13 Non-Linear Kinetic Drug Administration Example drug administered at lower doses intravenously exhibits linear kinetics at lower doses, but non-linear kinetics at higher doses  elimination rate not directly proportional to plasma concentration S. L. Plot Higher doses Cp Low doses (mcg/mL) Time (h) 14 Michaelis-Menten Kinetics All active drug transport processes are capacity limited (saturable) and exhibit Michaelis-Menten kinetics: Vmax= maximum metabolism rate; when Cp >> Km, Vmax is the amount of drug removed per unit time Km = Michaelis-Menten constant (concentration that produces 50% of V ) 15 Concept Check A patient has been using phenytoin 100 mg three times daily. The phenytoin level was drawn and found to be 8.8. ug/mL (reference range 10-20 ug/mL). The prescriber doubled the dose to 200 mg three times daily. The patient started to slur her words, felt fatigued and returned to the clinic. The level was repeated and found to be 23.7 ug/mL. Which of the following statement is accurate regarding the most likely reason for the change in phenytoin level? A. Phenytoin half-life is reduced at higher doses B. Phenytoin volume of distribution increases at higher doses. C. Phenytoin bioavailability decreases at high doses D. Phenytoin metabolism is saturated at higher doses. 16 Michaelis-Menten Kinetics – PK Parameters Total body clearance Half-life Dose at steady state 17 Calculation Check Drug T has a VMAX of 600 mg/d and a KM of 12 mg/L. What is the clearance for Drug T when Cp = 100 mg/L? 18 Clinical Scenario C.R. is a 45-year-old 85-kg male, who experiences simple partial seizures. He has normal liver and renal function and is not taking any other medications. A patient is to begin taking phenytoin. A steady plasma concentration of 15 mg/L is desired. Assuming a Vmax of 400 mg/day and a Km value of 4 mg/L, what rate of administration of phenytoin sodium (S = 0.92 and F = 1) should be used? 19 Pharmacokinetics vs. Pharmacodynamics PD PK What does the drug What does the body PK-PD do to the organism? do to the drug? Drug Effect: -Absorption concen -desirable (ex: tration antimicrobial -Distribution and activity inhibition) -Metabolism effect -undesirable -Excretion Graphi (adverse effects) Graphically: Cp vs t cally: Effect Graphically: Cp vs vs t effect 20 PK/PD Modeling Creates quantitative model to predict relationship between: o Administered dose o Drug concentration vs time profile o Drug effect vs time profile 21 Concentration-Response Relationships o Concentration-response relationship typically described by a sigmoidal shape (S-shaped) o Emax = the maximal effect (associated with the activation of all receptors in the system) o EC50 = the concentration that produces 50% the maximal response Lower the EC50 = higher drug potency 22 Hill Equation o Describes effect as function of drug concentration (C) o Blood is typically use as a surrogate for concentration at the site of action for practical reasons 𝐸 𝑚𝑎𝑥 ∗ 𝐶 𝐸= o Assumes a saturable drug response 𝐸 𝐶 50 +𝐶 (effect approaches Emax asymptotically as concentration increases) o To determine ED50, substitute dose for concentration 23 Hill Coefficient, N 𝑁 𝐸 𝑚𝑎𝑥 ∗ 𝐶 o Hill coefficient, N, is a 𝐸= 𝑁 𝑁 shape factor that 𝐸 𝐶 50 +𝐶 estimates the slope of the S-curve o N is drug specific o Large N values ( >6) correspond to “on/off” effects o Clinically, smaller slope is desirable to allow for dose titration 24  Regions of Cp-Response Curve I II III 25 Drug Effect and Region 26 Concept Check The pharmacological response is directly proportional to the log plasma drug concentration. A. True B. False 27 Time-Dependent Responses Effect Blood Brain Mostly attributed to the fact that the time course of the change in plasma drug concentrations not always reflects the time course of the change in concentrations at the site of action Concentration-response profile appears as hysteresis loop Examples: cefodizime, cisplatin, fluorouracil, heparin, ketoprofen, mequitzine, theophylline 28 Counterclockwise Hysteresis Counterclockwise loop indicates that the site of drug action is outside of the blood compartment Cause: 1. The site of action is in a peripheral compartment 2. Response requires time (protein synthesis) 3. Response is mediated by an active metabolite (prodrugs) 29 Clockwise Hysteresis 1. Common for drugs that exert their effect on highly regulated physiological parameters (BP): caffeine, nitroglycerin 2. Fentanyl (lipid soluble drug) - due to lipid partitioning 3. Indicative of acute tolerance – ex intranasal cocaine 30 Estimating Duration of Action The slope of the linear plot (-mk) is a function of the drug’s half-life and the slope of the concentration-effect profile M is related to N 31 Calculating Duration of Action Limitations: IV Bolus input One compartment model Effect is within the log-linear region of the S curve 32 Calculations Check A patient is administered tubocurarine prior to surgery for the purpose of establishing neuromuscular blockade. The half-life of this drug is 150 min, Vd = 20 L/kg, and MEC = 0.5 mg/L. Calculate a dose which will maintain the blockade for 60 min (td = 60 min). 33 Relationship Between Dose and Td IV bolus (one-compartment model) Important clinical implications: Doubling the dose  doubling of the duration of action Half-life doubling (or halving K) = doubling duration of action 34 Calculations Check The MEC in plasma of new antibiotic is 0.1 ug/ml. The drug follows a one-compartment open model and has an apparent volume of distribution of 10 L and a first order elimination rate constant of 1/hour. What is the duration of action for single 100 mg IV dose of this antibiotic? 35