PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx

Transcription

1 PHRMCOKINETICS IN PTIENTS REUIRING RENL REPLCEMENT Rx PRT 1: PK IN PTIENTS REUIRING HEMOILYSIS rthur J. tkinson, Jr., M.. junct Professor epartment of Molecular Pharmacology an Biochemistry Feinberg School of Meicine Northwestern University JOHN JCOB BEL FIRST ESCRIPTION OF HEMOILYSIS IN NIMLS* * From: bel JJ, et al. J Pharmacol Exp Ther 1914;5:

2 WILLEM J. KOLFF, M.. ( ) ELIMINTION BY IFFERENT ROUTES MESUREMENTS RENL HEPTIC ILYSIS BLOO FLOW +* +* + FFERENT CONC EFFERENT CONC ELIMINTE RUG *not actually measure in routine PK stuies T SOURCES FOR FICK EUTION V RECOVERE RUG 2

3 IMPCT OF E R NR CRITERION FOR ILYSIS EFFICCY* EC > 30% [ R + NR ] BUT ERNCE ESTIMTES MUST BE COMPRBLE * Levy G. m J Me 1977;62: GOLS OF ILYSIS ISCUSSION ISCUSSION OF ILYSIS ERNCE MECHNISTIC - RENKIN PPROCH EMPIRICL RECOVERY ERNCE FICK EUTION INICL STUIES OF ILYSIS PK MOEL PROSPECTIVE STUY TRETMENT OF RUG TOXICITY PHYSIOLOGIC CHNGES URING ILYSIS USE OF KINETIC METHOS FOR NLYSIS PTHOPHYSIOLOGIC CONSEUENCES 3

4 EUGENE RENKIN PROFESSOR EMERITUS T UC VIS RENKIN ILYSIS EUTION* (1 e P S/ ) = ILYZER BLOO FLOW P S = PERMEBILITY COEFFICIENT-SURFCE RE PROUCT OF ILYZING MEMBRNE NEGLECTS: BOUNRY EFFECTS, ULTRFILTRTION * From Renkin EM. Tr m Soc rtific Organs 1956;2:102-5 ETERMINNTS OF PERMEBILITY TERM (P or P S) ILYZER MEMBRNE CHRCTERISTICS - MEMBRNE SURFCE RE - MEMBRNE THICKNESS - MEMBRNE POROSITY RUG BINING TO PLSM PROTEINS SOLUTE SIZE N IFFUSIVITY 4

5 ILYZER PERMEBILITY VS. FREE WTER IFFUSION COEFFICIENTS PROCINMIE/NP: RTIO OF ILYZER PERMEBILITY COEFFICIENTS* RTIO OF FREE WTER IFFUSION COEFFICIENTS 1.23 * From Gibson TP et al. Clin Pharmacol Ther 1976;20: ILYSIS ERNCE VS. ILYZER BLOO FLOW* * From Renkin EM. Tr m Soc rtific Organs 1956;2:102-5 POSSIBLE USE FOR INTR-ILYZER TRNSFER OF RESULTS PERFORM PRELIMINRY IN VITRO STUY TO OBTIN P S RTIO FOR RUG & STNR COMPOUN FOR ILYZER BEING USE IN ILYSIS STUY (RECOR & RBC/PLSM). THIS RTIO CN BE USE TO ESTIMTE RUG FOR OTHER ILYZERS N OTHER VLUES IF P S OF STNR COMPOUN FOR THT ILYZER IS KNOWN. NEE TO SELECT PPROPRITE STNR COMPOUN (? CRETININE). 5

6 GOLS OF ILYSIS ISCUSSION ISCUSSION OF ILYSIS ERNCE MECHNISTIC - RENKIN PPROCH EMPIRICL RECOVERY ERNCE FICK EUTION INICL STUIES OF ILYSIS PK MOEL PROSPECTIVE STUY TRETMENT OF RUG TOXICITY PHYSIOLOGIC CHNGES URING ILYSIS USE OF KINETIC METHOS FOR NLYSIS PTHOPHYSIOLOGIC CONSEUENCES RECOVERY ERNCE THE GOL STNR C Vol t C Vol UC -V IFFERENCE METHO [FICK EUTION] E So - V - V E = ILYZER BLOO FLOW = CONCENTRTION IN BLOO COMING TO ILYZER V = CONCENTRTION IN BLOO LEVING ILYZER E = EXTRCTION RTIO 6

7 EXTRCTION RTIO Renkin Equation : E E 1 - e - V -P S/ Fick Equation : In Each Case : E TWO ILYSIS MYTHS NEE TO USE BLOO CONCENTRTIONS WHEN CLCULTING BLOO ERNCE BUT PLSM CONCENTRTIONS PROPORTIONL TO BLOO CONCENTRTIONS, SO MKES NO IFFERENCE IN /[ + V] RTIO NEE TO USE PLSM FLOW WHEN CLCULTING PLSM ERNCE PLSM VS. BLOO ERNCE RECOVERY : P U V P B U V B FICK : P PK -V B B -V IF P B : P, SO : B PK B P 7

8 RUG IN RBC IS ILYZE! FLOW PRMETER MEN VLUE ml/min PK 223 MES 195 (p < 0.2) EFF * 217 (p > 0.2) * EFF = [ (1 - HCT) + (RBC/P) (HCT) ] MES ILYSIS STURTION VS. RECOVERY ERNCE ILYSIS STURTION ( S BUT : V RECOVERY ERNCE : U V P C /C ) : C C C V C p SO EXPRESSIONS RE EUIVLENT p p GOLS OF ILYSIS ISCUSSION ISCUSSION OF ILYSIS ERNCE MECHNISTIC - RENKIN PPROCH EMPIRICL RECOVERY ERNCE FICK EUTION INICL STUIES OF ILYSIS PK MOEL PROSPECTIVE STUY TRETMENT OF RUG TOXICITY PHYSIOLOGIC CHNGES URING ILYSIS USE OF KINETIC METHOS FOR NLYSIS PTHOPHYSIOLOGIC CONSEUENCES 8

9 T SOURCES FOR FICK EUTION V RECOVERE RUG KINETIC MOEL USE TO NLYZE HEMOILYSIS T* * From Stec GP, et al. Clin Pharmacol Ther 1979;26: KINETIC MOEL USE TO NLYZE HEMOILYSIS T* V * From Stec GP, et al. Clin Pharmacol Ther 1979;26:

10 FICK ERNCE EUTION V V - V V TWO PROBLEMS WITH FIXE- PRMETER MOEL* 1. URING ILYSIS: [] N [V] ROP MORE THN EXPECTE FROM RUG RECOVERY 2. FTER ILYSIS: CONCENTRTION REBOUN IS LESS THN EXPECTE * From Stec GP, et al. Clin Pharmacol Ther 1979;26: KINETIC MOEL USE TO NLYZE HEMOILYSIS T* Cl S G * From Stec GP, et al. Clin Pharmacol Ther 1979;26:

11 REUCTION IN S URING N FTER HEMOILYSIS* 77% in S * From Stec GP, et al. Clin Pharmacol Ther 1979;26: CONUCT OF PK STUIES IN HEMOILYSIS PTIENTS Chapter 6 Principles of Clinical Pharmacology tkinson J Jr, Umans JG: Pharmacokinetic Stuies in Hemoialysis Patients. Clin Pharmacol Ther 2009;86: CER, F: raft Guiance for Inustry Pharmacokinetics in Patients with Impaire Renal Function Stuy esign, ata nalysis, an Impact on osing an Labeling. ( ownloas/rugs/guiancecomplianceregulatory Information/Guiances/UCM pf) GOLS OF ILYSIS ISCUSSION ISCUSSION OF ILYSIS ERNCE MECHNISTIC - RENKIN PPROCH EMPIRICL RECOVERY ERNCE FICK EUTION INICL STUIES OF ILYSIS PK MOEL PROSPECTIVE STUY TRETMENT OF RUG TOXICITY PHYSIOLOGIC CHNGES URING ILYSIS USE OF KINETIC METHOS FOR NLYSIS PTHOPHYSIOLOGIC CONSEUENCES 11

12 ILYSIS CSE HISTORY 67 year-ol woman became lethargic an confuse an evelope hypotension, renal insufficiency, junctional tachycaria an intraventricular conuction elay after ingesting an estimate 7gm of procainamie (P). Plasma P an NP concentrations were 57 μg/ml an 55 μg/ml, respectively. ILYSIS CSE HISTORY (cont.) Hemoialysis was performe for 4 hr. By the en of the secon hour BP was maintaine in the range of 110/80 mm Hg without vasopressor therapy. t the en of ialysis, the patient was alert an oriente although only 340 mg of P an 470 mg of NP ha been remove by this proceure. ILYSIS CSE HISTORY (cont.) Fifteen hours after ialysis, P an NP levels were 9.2 μg/ml an 33 μg/ml, respectively. The patient ha returne to normal sinus rhythm with RS = 0.12 sec. 12

13 KINETIC NLYSIS OF HEMOILYSIS FOR PROCINMIE TOXICITY* * From: tkinson J Jr, et al. Clin Pharmacol Ther 1976;20: CRITERION FOR ILYSIS EFFICCY* EC > 30% [ R + NR ] * Levy G. m J Me 1977;62: WS ILYSIS EFFICCIOUS? ILYSIS INCRESE RUG ERNCE P TWO FOL NP 3.8 FOL BUT 4 hr OF ILYSIS REMOVE < 1 gm of 7 gm OSE 340 mg P 470 mg NP HOWEVER, BLOO LEVELS FELL SUBSTNTILLY P: 25.7 µg/ml 15.5 µg/ml NP: 47.0 µg/ml 35.5 µg/ml N PTIENT S CONITION STBILIZE 13

14 P & NP KINETICS IN TOXIC PTIENT NORML PTIENT P NP P NP t 1/2 (hr) E (ml/min) (ml/min) V β (L/kg) ESTIMTION OF V uestion: Why was istribution volume estimate so much lower in patient than in normal subjects? USUL V ESTIMTE : V OSE GIVEN Δ CONCENTRT ION ILYSIS V ESTIMTE : V RUG REMOVE Δ CONCENTRT ION SEUESTRTION OF RUG IN SOMTIC TISSUES BIOPHSE 14L 7L ILYSIS E 83L 14

15 EFFICCY OF EXTRCORPOREL TRETMENT OF RUG TOXICITY TOTL EXTENT OF RUG REMOVL MY BE COMPROMIZE BY S. S FROM SOMTIC TISSUES CN CCELERTE IN RUG CONCENTRTION TO WHICH VITL ORGNS (CNS, HERT) RE EXPOSE N RESULT IN BENEFICIL INICL RESPONSE > EXTENT OF RUG REMOVL. S FROM SOMTIC TISSUES LSO TTENUTES POST-ILYSIS REBOUN. GOLS OF ILYSIS ISCUSSION ISCUSSION OF ILYSIS ERNCE MECHNISTIC - RENKIN PPROCH EMPIRICL RECOVERY ERNCE FICK EUTION INICL STUIES OF ILYSIS PK MOEL PROSPECTIVE STUY TRETMENT OF RUG TOXICITY PHYSIOLOGIC CHNGES URING ILYSIS USE OF KINETIC METHOS FOR NLYSIS PTHOPHYSIOLOGIC CONSEUENCES WHY OES S URING ILYSIS? (1 e P S/ ) POSSIBILITIES: CPILLRY BLOO FLOW () ECRESES CPILLRY P S PROUCT ECRESES BOTH ECRESE 15

16 MULTICOMPRTMENTL MOEL OF INULIN N URE KINETICS* INULIN URE * From tkinson J Jr, et al. Trens Pharmacol Sci 1991;12: BSIS FOR KINETIC HETEROGENETIY OF INTERSTITIL FLUI SPCE EFFECTIVE PORE SIZE CPILLRY STRUCTURE PRIMRY LOCTION LRGE FENESTRTE SPLNCHNIC BE SMLL CONTINUOUS SOMTIC TISSUES ENOTHELIL FENESTRE IN HEPTIC SINUSOIS 16

17 INTERENOTHELIL CELL JUNCTION IN CONTINUOUS CPILLRY URE ( ) N INULIN ( ) KINETICS URING N FTER HEMOILYSIS* URE INULIN URE INULIN * From Bowsher J, et al. J Lab Clin Me 1985;105: RELTIONSHIP BETWEEN BLOO FLOW () N I * * From Bowsher J, et al. J Lab Clin Me 1985;105:

18 URE N INULIN KINETICS URING N FTER HEMOILYSIS PRMETER BEFORE URING FTER BLOO FLOW PS S (ml/min) F (ml/min) * 2965* C.O. (ml/min) INULIN (ml/min) URE (ml/min) * ESTIMTE S C.O. - S RENIN-NGIOTENSIN SYSTEM CTIVTION URING N FTER HEMOILYSIS* * From Bowsher J, et al. J Lab Clin Me 1985;105: IFFERENT MICROCIRCULTORY CTIONS OF NGIOTENSIN II N VP* * From tkinson J Jr: The Pharmacologist 1989;31:

19 EFFECT OF RGININE VSOPRESSIN (VP) ON P S* * From tkinson J Jr: The Pharmacologist 1989;31: HEMOILYSIS-SSOCTE SKELETL MUSE CRMPS COMPLICTE MORE THN 20% OF HEMOILYSIS SESSIONS PTHOGENESIS UNER SYMPTOMTIC THERPY: NaCl, MNNITOL PREVENTIVE THERPY: NaCl INFUSION OCCUR MORE FREUENTLY IN SOME PTIENTS THN OTHERS SUSPECT YSREGULTION OF MICROVSCULR RESPONSE TO VOLUME STRESS. CONUING PK THOUGHT LTHOUGH NON-COMPRTMENTL NLYSIS OF PK T IS CURRENTLY IN VOGUE, IT IS UNBLE TO PROVIE INSIGHT INTO SOME IMPORTNT PHENOMEN: - IMPCT OF ILYSIS-SSOCITE HEMOYNMIC CHNGES ( S ) - IMPCT OF SPLNCHNIC BLOO FLOW ( F ) ON BIOVILBILITY 19