USES OF PHARMACOKINETICS

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1 LINIAL PHARMAOKINETIS Juan J.L. Lertora, M.D., Ph.D. Director linical Pharmacology Program Office of linical Research Training and Medical Education National Institutes of Health linical enter September 9, 2010 USES OF PHARMAOKINETIS Basis for rational dose selection in therapeutics Development and evaluation of new drugs Basic studies of drug distribution (PET Scan) TARGET ONENTRATION STRATEGY ESTIMATE INITIAL DOSE TARGET LEEL LOADING DOSE MAINTENANE DOSE BEGIN THERAPY ASSESS THERAPY PATIENT RESPONSE DRUG LEEL REFINE DOSE ESTIMATE ADJUST DOSE 1

2 RATIONALE FOR PLASMA LEEL MONITORING PROTEIN BOUND METABOLISM PLASMA ELIMINATION PRESRIBED DOSE ABSORPTION FREE RENAL EXRETION ADHERENE MOST TISSUES NONSPEIFI BINDING DISTRIBUTION BIOPHASE REEPTOR BINDING EFFET FIRST DESRIPTION OF THERAPEUTI DRUG MONITORING Wuth O. JAMA 1927;88: RADIOIMMUNOASSAY Rosalyn Sussman Yalow Nobel Laureate 2

3 First Academic linical Drug Analysis Lab Arthur J. Atkinson, Jr., M.D. Northwestern Memorial Hospital hicago, Illinois GAS LIQUID HROMATOGRAPHY HIGH PERFORMANE LIQUID HROMATOGRAPHY 3

4 IROLOGI FAILURE RATE (%) FLUORESENE POLARIZATION IMMUNOASSAY DRUG ANDIDATES FOR TDM Low therapeutic index No physiologic endpoints or biomarkers to guide dosage Pharmacokinetics vary widely between individuals Need to monitor adherence? EFFET OF ADHERENE RATE ON OUTOME IN HI INFETED PATIENTS % 80% - 94% < 80% ADHERENE RATE From: Paterson DL, et al. Ann Intern Med 2000;133:

5 INDIATIONS for Measuring Blood Levels To evaluate suspected toxicity To evaluate actual or potential lack of therapeutic efficacy To monitor prophylactic therapy To guide dose adjustment TARGET ONENTRATION STRATEGY ESTIMATE INITIAL DOSE TARGET LEEL LOADING DOSE MAINTENANE DOSE DIGOXIN Levels in TOXI and NONTOXI Patients * * From Smith TW and Haber E. J lin Invest 1970;49:

6 DIGOXIN: Factors Influencing OUTOME in GREY ZONE Risk of toxicity in patients with coronary heart disease, hypoxemia, and/or hypokalemia, hypomagnesemia EG evidence of toxicity if concurrent therapy with antiarrhythmic drugs TRADITIONAL Guidelines for DIGOXIN Levels THERAPEUTI RANGE: ng/ml POSSIBLY TOXI LEELS: ng/ml PROBABLY TOXI LEELS: > 3.0 ng/ml SURIAL as a function of DIGOXIN LEEL measured after 1 Month Rx* DIG LEELS 1 MONTH WHAT WERE DIG LEELS HERE? * Rathore SS, et al. JAMA 2003;289:

7 PROPOSED Range of DIGOXIN LEELS for OPTIMAL THERAPY in HF New Therapeutic Range: ng/ml Benefit results from INHIBITION OF SYMPATHETI NEROUS SYSTEM rather than INOTROPY BUT DIGOXIN DOSES PRESRIBED FOR PATIENTS WITH THIS RANGE OF DIGOXIN LEELS SHOULD HAE BEEN ASSOIATED WITH HIGHER LEELS? DIGOXIN DOSES for Patients with Levels of ng/ml NUMBER OF PATIENTS DIGOXIN DOSE (mg/day) Rathore SS, et al. JAMA 2003, 289: TARGET ONENTRATION STRATEGY ESTIMATE INITIAL DOSE TARGET LEEL LOADING DOSE MAINTENANE DOSE BASED ON ONEPT OF DISTRIBUTION OLUME 7

8 DIGOXIN LEELS after I Dose INITIAL DIGITALIZATION DIGITALIZING DOSE 0.75 mg = 750 x 10 3 ng 750 x 10 3 ng d = = 536 L 1.4 ng/ml 1.4 ng/ml 3 DISTRIBUTION OLUMES d (extrap.) d (area) d (ss) 1 t DOSE 1/2 L E 0... n 8

9 ΔLET (msec) FRATION OF DIGOXIN DOSE DISTRIBUTION DELAYS ONSET of DIGOXIN hronotropic Action* * From Gold H, et al. J Pharmacol Exp Ther 1953;109: DISTRIBUTION DELAYS ONSET of DIGOXIN Inotropic Action* HOURS TARGET ONENTRATION STRATEGY ESTIMATE INITIAL DOSE TARGET LEEL LOADING DOSE MAINTENANE DOSE BASED ON ONEPTS OF ELIMINATION HALF LIFE AND LEARANE 9

10 ELIMINATION HALF-LIFE ELIMINATION HALF-LIFE IS THE TIME REQUIRED FOR THE PLASMA ONENTRATION (OR TOTAL BODY STORES) OF A DRUG TO FALL TO HALF OF THE ONENTRATION (OR AMOUNT) PRESENT AT SOME PREIOUS TIME. ELIMINATION PARAMETERS t k 1/2 L E L t 1/2 k E t 1/2 = elimination half life k = elimination rate constant L E = elimination clearance d d MAINTENANE DIGOXIN THERAPY MAINTENANE DOSE 0.25 mg NORMAL DAILY LOSS: = 1/3 Total Body Stores = 1/3 (0.75) mg = 0.25 mg 1.4 ng/ml DAILY LOSS 0.25 mg 10

11 DIGOXIN UMULATION.25 x 2/3 =.17 DOSE # DOSE #2.42 x 2/3 = DOSE #3.53 x 2/3 = DOSE #4.61 x 2/3 = DOSE #5.66 x 2/3 = DOSE #6.69 x 2/3 = DOSE #7.71 UMULATION FATOR F k e τ = dose interval k = elimination rate constant ELIMINATION RATE ONSTANT k t 1/2 11

12 LOADING & MAINTENANE DOSES 90% SS in 3.3 x t ½ TIME-OURSE OF DIGOXIN UMULATION 14 DAYS 7 DAYS DIGOXIN ASE HISTORY A 39 year-old man with mitral stenosis was hospitalized for mitral valve replacement (October 1981). He had a history of chronic renal failure resulting from interstitial nephritis and was maintained on hemodialysis. His mitral valve was replaced with a prosthesis and digoxin therapy was initiated postoperatively in a dose 0.25 mg/day. 12

13 DIGOXIN ASE HISTORY (cont.) Two weeks later, he was noted to be unusually restless in the evening. The following day, he died shortly after he received his morning digoxin dose. Blood was obtained during an unsuccessful resuscitation attempt, and the measured plasma digoxin concentration was 6.9 ng/ml. TARGET ONENTRATION STRATEGY ESTIMATE INITIAL DOSE TARGET LEEL LOADING DOSE MAINTENANE DOSE BEGIN THERAPY ASSESS THERAPY PATIENT RESPONSE DRUG LEEL REFINE DOSE ESTIMATE ADJUST DOSE TARGET ONENTRATION STRATEGY ESTIMATE INITIAL DOSE TARGET LEEL LOADING DOSE MAINTENANE DOSE BEGIN THERAPY ASSESS THERAPY PATIENT RESPONSE DRUG LEEL REFINE DOSE ESTIMATE ADJUST DOSE 13

14 PHARMAOKINETI ANALYSIS OF DIGOXIN ASE HISTORY ESTIMATED T 1/2 : 4.3 days (k = 0.16 day -1 ) TIME TO 90% STEADY STATE: 3.3 x 4.3 = 14.2 days STEADY STATE PEAK LEEL: 6.2 ng/ml (post distribution phase) MEASURED LEEL: 6.9 ng/ml (pre distribution) STEADY STATE ONENTRATION ONTINUOUS INFUSION: SS I L E INTERMITTENT DOSING: SS DOSE L E τ STEADY STATE ONENTRATION NOT DETERMINED BY LOADING DOSE MEAN STEADY STATE ONENTRATION NOT DETERMINED BY d PEAK AND TROUGH ARE AFFETED BY d 14

15 d AFFETS PEAK AND TROUGH BUT NOT MEAN LEELS FOR MOST DRUGS, ss IS PROPORTIONAL TO DOSE (Dosing Rate) ONTINUOUS INFUSION: SS I L E INTERMITTENT DOSING: SS DOSE L E τ STEADY STATE ONENTRATION NOT DETERMINED BY LOADING DOSE MEAN STEADY STATE ONENTRATION NOT DETERMINED BY d HANGES IN MAINTENANE DOSE RESULT IN DIRETLY PROPORTIONAL HANGES IN SS FOR MOST DRUGS 15

16 PHARMAOKINETI MODELS WHAT PHARMAOKINETI PARAMETERS ARE PRIMARY? SINGLE OMPARTMENT MODEL DOSE d L E ELIMINATION HALF-LIFE t d (area) 1/2 L E THEREFORE, t ½ IS NOT A PRIMARY PHARMAOKINETI PARAMETER 16

17 3 DISTRIBUTION OLUMES d (extrap.) d (area) d (ss) 1 t DOSE 1/2 L E 0... n SOME DRUGS NOT ELIMINATED BY FIRST ORDER KINETIS PHENYTOIN (DILANTIN) ETHYL ALOHOL AETYLSALIYLI AID (ASPIRIN) PHENYTOIN HYDROXYLATION O H N YP 29 O H N OH H N O H N O PHENYTOIN p - HPPH 17

18 SATURATION OF DPH HYDROXYLATION PHENYTOIN KINETIS in Normal Subjects STEADY STATE EQUATIONS FIRST ORDER KINETIS DOSE /τ DOSE /τ L MIHAELIS - MENTEN KINETIS K E m max SS SS SS 18

19 RELATIONSHIP OF PLASMA LEEL TO PHENYTOIN DOSE* PHENYTOIN DOSE PLASMA LEEL (mg/day) µg/ml (THERAPEUTI RANGE: μg/ml) * From: Kutt H, McDowell F: J Am Med Assoc 1968;203: PATIENT WHO BEAME TOXI ON A PHENYTOIN DOSE OF 300 mg/day THERAPEUTI DOSE PHENYTOIN ASE HISTORY After inpatient evaluation for a generalized seizure, a 28-year-old woman was discharged on phenytoin therapy at a dose of 300 mg/day. After 5 days of therapy, she presented to the hospital s emergency department with marked ataxia. Her phenytoin plasma concentration was found to be 27 μg/ml. She was sent home on a reduced phenytoin dose of 200 mg/day. 19

20 [PHENYTOIN] μg/ml PHENYTOIN ASE HISTORY (cont.) Two days later, she returned to the emergency department with more severe ataxia. Her phenytoin plasma concentration was now 32 μg/ml. Noncompliance was suspected but a clinical pharmacology evaluation was requested. PATIENT with ERY LOW MAX MAX = 132 mg/day DOSE mg/day BASIS OF APPARENT FIRST-ORDER KINETIS If d dt K m d dt : K K m max m max "k" 20

21 PHARMAOKINETIS PRATIE PROBLEMS AT END OF HAPTER 2 WITH ANSWERS IN APPENDIX II EQUATIONS DERIED IN PRINIPLES OF LINIAL PHARMAOLOGY TEXTBOOK 21