Biomath M263 Clinical Pharmacology

Transcription

1 Training Program in Translational Science Biomath M263 Clinical Pharmacology Spring Wednesdays 3 PM room CHS 4/2/2014 Pharmacokinetics (PK) and Pharmacodynamics (PD) Elliot Landaw, MD, PhD 4/9/2014 Opioid Pharmacology Michael Ferrante, MD 4/16/2014 The Early Detection of Ovarian Cancer: Are Biomarkers Joshua Cohen, MD the Answer? 4/23/2014 Studying Tissue Pharmacokinetics by PET; Assessment Caius Radu, MD of Tumor Response to Chemotherapy 4/30/2014 Essentials of Geriatric Psychopharmacology Helen Lavretsky, MD 5/7/2014 TBA 5/14/2014 Pharmacokinetics and Pharmacodynamics in Renal Disease 5/21/2014 Changes in Pharmacokinetics and Pharmocodynamics During Pregnancy 5/28/2014 Drug Therapy in Newborns: Peri- and Postnatal HIV Treatment Anjay Rastogi, MD Carla Janzen, MD, PhD Yvonne Bryson, MD

2 Pharmacokinetics & Pharmacodynamics Basic Concepts Issues in Pharmacokinetics (PK) Clearance Half-lives and Residence Times Distribution Volumes Absorption & Bioavailability Measures Pharmacodynamics (PD) Steady State Models Linking of PK & PD April 2, 2014 (E. Landaw) M263 Clinical Pharmacology

3 Texts Some Resources M Rowland & RN Tozer Clinical Pharmacokinetics 4 th ed., Lippincott Williams & Wilkins 2011 AJ Atkinson et al. (eds). Principles of Clinical Pharmacology, Academic Press, 3rd Edition 2012 Web sites (links to PK/PD resources) Journals: Clinical Pharmacology & Therapeutics ( J. Pharmacokinetics & Pharmacodynamics

4 Basic - Definitions Pharmacokinetics (PK) quantitative analysis of the kinetics (time course) and steady state (SS) relationships of drug What the body does to the drug ADME Absorption Distribution Metabolism Excretion Elimination

5 Basic - Definitions Pharmacodynamics (PD) quantitative analysis of relation of drug concentration at an effect site (C e ) to drug effect (E). What the drug does to the body Understand Dose-Effect relationships SS: C e measured plasma concentration Non-SS: may need to use PK to infer C e

6 Effect Site Concentrations Dosing Regimen dose, frequency, route source: A. Atkinson Concentrations Plasma, urine, tissue, Parent and metabolites EFFECTS Rx, Toxic

7 Steady State vs. Kinetic Studies Steady state (SS) with constant IV infusion conc. not changing with time plasma conc. C SS reflects C tissue (usually) PK (+load) determine time until ~SS SS from Repetitive dosing (oral, IM, etc.) eventually reach constant Profile SS C max = peak ; C min = trough ; average C SS

8 Repetitive Dosing and Profile SS Cmax Cmin source: Rowland & Tozer

9 Steady State vs. Kinetic Studies Many PK/PD concepts are for SS Clearance; Volume of distribution SS PD effect for given SS conc. (time to PD SS may be longer than time to plasma SS) But some studies are kinetic e.g., single oral dose or I.V. bolus Tracer kinetic studies; PET Aim may be infer SS under rep. dosing

10 Linear vs Nonlinear System Linear Pharmacokinetics double the dose concentration doubles AUC proportional to dose Superposition principle (example): If {I.V. bolus} C iv (t) and {oral dose} C oral (t), then {both dosing together} C(t) C iv (t) + C oral (t) holds for small enough doses (microdoses) linearity for large doses if transport, binding, and elimination remain first order

11 Nonlinear Kinetics Example

12 Linear vs Nonlinear System single kinetic study + linearity can predict response to any input, including getting to SS but for NONlinear systems: CL, V, etc. not constant; depend on C SS, Dose requires testing at different doses; models time to SS not predicted by single dose study Common nonlinearities Saturation kinetics (Michaelis-Menten) Saturable plasma protein, tissue binding Threshold effects (e.g., glucose spilling) Induction; Neuro./hormonal regulation

13 Importance of Experiment Design Quality & interpretation of PK/PD data depend critically on design: Dose(s), route, and form (bolus vs infusion) What to sample Plasma, urine, tissue, PET, Total vs. unbound concentrations Parent compound, metabolites PD Effect measures What times to sample in a kinetic study Train team: record what was done, not just asked

14 Basic Concepts Pharmacokinetics & Pharmacodynamics Issues in Pharmacokinetics (PK) Clearance Half-lives and Residence Times Distribution Volumes Absorption & Bioavailability Measures Pharmacodynamics (PD) Steady State Models Linking of PK & PD

15 Organ Clearance Physiology: organ clearance as SS concept Q blood flow C B_arterial Organ of elimination C B_venous Elim. Flux = Q(C B_art C B_ven ) (mass/time) E = Single pass extraction fraction: E = Elim. flux/ input flux = (C B_art C B_ven )/C B_art Clearance Elim. flux/c ref (vol/time) If use C B_art as C ref, Clearance = E Q

16 Organ Clearance Clearance Elim. flux/c ref Elimination (metabolism, transport) often function of unbound C u (free plasma fraction) C u = f u C (but f u not routine measurement) Clearance = E Q high E (E>0.7), CL sensitive to Q, not f u low E (E<0.3) Q transit time E CL sensitive to f u, CYP induction or inhibition but SS exposure = f u AUC not sensitive to f u

17 Renal Clearance (CL R ) Easiest organ CL to measure e.g. Net CL R = (urine exc. rate)/(mid-collection C) Elim. flux = filtration + secretion reabs. GFR CL creat = 120 ml plasma water/minute CL R due just to filtration = GFR f u

18 Total Clearance (CL T or just CL) SS Clearances add: CL = CL R + CL H + nonrenal/nonhepatic clearance Estimating CL from single dose kinetic study i.v. Dose: CL = Dose/ C(t)dt = Dose/AUC Oral Dose: CL = F Oral Dose/AUC where F = fraction of dose reaching central pool (plasma + tissue in rapid equilibrium with plasma) CL oral CL/F = Oral Dose/AUC 0

19 Trapezoidal rule: C(t) Estimating AUC May need to fit single exponential at end to estimate tail area to Fit model of data to entire C(t). e.g., C(t) = A 1 exp(-λ 1 t) + + A n exp(-λ n t) AUC = A 1 /λ A n /λ n t

20 Using Profile SS to estimate AUC Profile SS after multiple repeated doses: use area under one cycle to estimate single dose AUC single dose AUC (from 0 to ) source: Rowland & Tozer

21 Predicting SS Concentration #1 Constant i.v. flux infusion I (mass/time) SS plasma conc. C SS = C( ) total CL = (total Elim. Flux)/C ref Here C ref is C SS Since patient at steady state, Elim. Flux = I Therefore, C SS = I / CL

22 Predicting SS Concentration #2 For repetitive oral dose D every T units of time, at Profile Steady State: average C SS = (FD/T) / CL. i.e. average C SS = (D/T) / CL oral where CL oral estimated from kinetic study by CL oral = Oral Dose/AUC = CL/F

23 Half-lives and Residence Times 1-compartment approximation for body: Drug distributes in single, well-mixed central pool 1 st order elimination rate k (time -1 ); volume V V logc(t) C(t) = (Dose/V)exp(-kt) k t k = CL/V V = Dose/C(0) t 1/2 = 0.693/k (half-life of drug in whole body) MRT = 1/k (Mean Residence Time in body) V = total drug distribution volume = CL MRT 0....

24 Is this single exponential decay? 40 What s the half-life of this drug? serum concentration (nm) time after IP injection (hours)

25 conc. on LOG scale suggests No! 100 serum concentration (nm) 10 1 initial t 1/2 0.6 hours terminal t 1/2 14 hours time after IP injection (hours)

26 Half-lives and Residence Times multi-compartment approximation for body: Drug distributes in central + peripheral pool(s) C(t) exhibits elimination and distribution kinetics logc(t) C(t) = A 1 exp(-λ 1 t) + A 2 exp(-λ 2 t) V t 2 or more half-lives, but terminal half-life not always the main factor for dosing, accumulation, etc. Relative importance each half-life depends on A i /λ i

27 Caution: Interpreting Terminal t 1/2 Terminal t 1/2 often rate limited by elimination BUT NOT ALWAYS! counterexample: gentamicin CL cr ml/min terminal t 1/2 in all 90 hrs renal impairment affects mainly first half-life avg C SS still (D/T)/CL oral but dosing interval T to achieve desired C max /C min trickier to compute source: Rowland & Tozer Schentag et al. JAMA 238:327-9, 1977

28 Mean Residence Time (MRT) MRT = mean time molecule of drug resides in body before being irreversibly eliminated Assumes linear system May be useful summary measure when there are multiple half-lives Effective (overall) half-life = MRT

29 Mean Residence Time MRT estimated from a kinetic study: Measure plasma concentration C(t) after dose: MRT AUMC/AUC tc(t)dt /AUC MRT = AUMC/AUC requires no peripheral elimination no traps linear PK 0

30 Mean Residence Time 1-compartment model MRT = 1/k = V 1 /CL half-life = MRT time to reach 90% SS following constant flux infusion is 2.3 MRT s = 3.3 half-lives Multi-exponential model AUMC/AUC = w 1 (1/λ 1 ) + + w n (1/λ n ) where w i (A i /λ i ) and w w n = MRT s (i.e., 3.3 effective half-lives) is time to reach at least 84% SS

31 Distribution Volumes Volume of Central Pool (V 1 ) V 1 = i.v. Dose/C(0) C(0) estimated by back-extrapolating from early concentrations V 1 = plasma + tissues in rapid equilibrium by time of earliest plasma sample determines (transient) peak plasma concentration following i.v. dose

32 multi-compartment approximation for body: Drug distributes in central + peripheral pool(s) C(t) exhibits elimination and distribution kinetics logc(t) C(t) = A 1 exp(-λ 1 t) + A 2 exp(-λ 2 t) V t Back-extrapolated C(0) = A 1 + A 2 V 1 = Dose/C(0)

33 SS Total Distribution Volume (V SS, V D or just V) Assume at SS A( ) = total amount of drug in body at SS Define V = A( ) / C SS Hypothetical volume SS mass would have to occupy to yield same concentration as C SS V = CL MRT Provides insights into distribution, permeation, tissue binding, etc. back-extrapolated C(0) from terminal decay (i.e., V extrap ) may overestimate V

34 source: Rowland & Tozer t 1/2 depends on CL and V

35 Absorption & Bioavailability source: A. Atkinson

36 Bioavailability Measures of extent and rate of absorption from admin. site to measurement site (latter usually central pool, i.e. plasma) i.v. administration is gold standard for complete and instantaneous absorption single oral dose: informal measures are: C peak t peak

37 Bioavailability formal measures F estimates extent of absorption Separate i.v. and oral studies F = (Dose iv /Dose oral ) AUC oral /AUC iv fraction of administered dose reaching plasma MAT (mean absorption time) AUMC oral /AUC oral - AUMC iv /AUC iv Absorption rate constant (compart. model) Absorption flux time course (deconvolution)

38 Example: Rifampicin pretreatment reduces oral digoxin bioavailability

39 Pharmacokinetics & Pharmacodynamics Basic Concepts Issues in Pharmacokinetics (PK) Clearance Half-lives and Residence Times Distribution Volumes Absorption & Bioavailability Measures Pharmacodynamics (PD) Steady State Models Linking of PK & PD

40 Dose-Effect Relationships Drug Dose C(t) PD Effect(s) PK Covariates age sex body size organ function disease other drugs genes/markers

41 Dose-Effect Endpoints Graded Continuous scale (dose effect) Measured in a single biologic unit Relates dose to intensity of effect Quantal All-or-none pharmacologic effect Population studies Relates dose to frequency of effect source: Frank M. Balis

42 Simplest PD Model: Binary, 2-State Graded Effect 1 0 Drug-Receptor complex Drug Drug-Receptor Complex Ligand-binding domain k 1 Effector domain Receptor k 2 Effect Effect = Maximal effect [Drug] K D + [Drug] source: Frank M. Balis (K D = k 2 /k 1 )

43 Graded Dose-Effect Curve 100 Maximal effect (efficacy) 80 % of Maximal Effect source: Frank M. Balis EC 50 [Drug]

44 Comparing Dose-Effect Curves Drug A Drug B % of Maximal Effect Drug C source: Frank M. Balis 20 0 Effect = Maximal effect [Drug] K D + [Drug] [Drug]

45 Empirical Pharmacodynamic Models Fixed effect model Linear model Log-linear model E max model Sigmoid E max model Effect = E 0 + S [Drug] Effect = I + S Log([Drug]) E max [Drug] H Effect = H EC50 + [Drug] H source: Frank M. Balis

46 Sigmoid E max PD Model Effect (%) Effect (%) H = 5 H = 2 H = H = H = EC EC [Drug] source: Frank M. Balis

47 Concentration and Effect vs Time Non-Steady State Central Compartment Conc./ Amount 6 4 Peripheral Compartment Effect Effect [% of E MAX ] 2 Effect Compartment source: Frank M. Balis Time

48 Hysteresis and Proteresis Loops Intensity of Drug Effect Hysteresis Loop (Counterclockwise) Equilibration delay in plasma and effect site conc. Formation of active metabolite Receptor up-regulation Intensity of Drug Effect Tolerance Proteresis Loop (Clockwise) Receptor tachyphylaxis Plasma Drug Concentration source: Frank M. Balis

49 PK/PD Applications Drug discovery/development Scaling (cell culture animal human) Feasible dosing, drug delivery Predict and quantify inter- & intra-patient variability Regulatory issues (FDA) Basic and Clinical Sciences Understand in vivo mechanisms Quantify PK and PD study endpoints Design of clinical studies Dosing regimens Timing of samples Identify important covariates

50 PK/PD Applications Therapy Optimal treatment strategies Individualization of therapy Clinical monitoring (PD) or predicting (PK/PD) efficacy and toxicity endpoints Pharmacogenetics/pharmacogenomics Hereditary variations in response (PK or PD) Identification of genes or loci Genome-based drug discovery Predict efficacy and potential adverse effects