PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx
description
Transcript of PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx
![Page 1: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/1.jpg)
PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx
Arthur J. Atkinson, Jr., M.D.Senior Advisor in Clinical Pharmacology
Clinical Center, NIHGregory M. Susla, Pharm. D.
Clinical Science SpecialistThe Bayer Corporation
![Page 2: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/2.jpg)
FIRST DESCRIPTION OF HEMODIALYSIS IN ANIMALS*
* From: Abel JJ, et al. J Pharmacol Exp Ther 1914;5:275-317.
![Page 3: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/3.jpg)
ELIMINATION BY DIFFERENT ROUTES
MEASUREMENTS RENAL HEPATIC DIALYSIS
BLOOD FLOW +* +* +
AFFERENT CONC. + + +
EFFERENT CONC. 0 0 +
ELIMINATED DRUG + 0 +
*not actually measured in routine PK studies
![Page 4: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/4.jpg)
GOALS OF DIALYSIS DISCUSSION
DISCUSSION OF DIALYSIS CLEARANCEMECHANISTIC - RENKIN APPROACHEMPIRICAL
FICK EQUATIONRECOVERY CLEARANCE
EFFECTS OF DIALYSIS ON PHARMACOKINETICS
HEMODYNAMIC CHANGES DURING DIALYSISUSE OF KINETIC METHODS FOR ANALYSISPATHOPHYSIOLOGIC CONSEQUENCES
![Page 5: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/5.jpg)
IMPACT OF CLD
DNRREClClClCl
![Page 6: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/6.jpg)
RENKIN DIALYSIS EQUATION*
)eQ(1Cl P/QD
* From Renkin EM. Tr Am Soc Artific Organs 1956;2:102-5
![Page 7: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/7.jpg)
EFFECT OF MOLECULAR WEIGHT (M) ON SOLUTE DIFFUSIVITY (D)*
* From Henderson LW: In: Brenner BM, Rector FC Jr. The kidney. 1976, p. 1643-71.
INULIN
![Page 8: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/8.jpg)
DIALYZER PERMEABILITY VS. FREE WATER DIFFUSION COEFFICIENTS
* From Gibson TP et al. Clin Pharmacol Ther 1976;20:720-6.
RATIO OF DIALYZER PERMEABILITY COEFFICIENTS* 1.29 0.22
RATIO OF FREE WATER DIFFUSION COEFFICIENTS 1.23
![Page 9: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/9.jpg)
DIALYSIS CLEARANCE VS. DIALYZER BLOOD FLOW*
* From Renkin EM. Tr Am Soc Artific Organs 1956;2:102-5
![Page 10: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/10.jpg)
FICK EQUATION
Q = DIALYZER BLOOD FLOWA = CONCENTRATION IN BLOOD COMING TO DIALYZERV = CONCENTRATION IN BLOOD LEAVING DIALYZERE = EXTRACTION RATIO
![Page 11: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/11.jpg)
FICK EQUATION
EQCl So
A
V-AE
A
V-AQCl
![Page 12: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/12.jpg)
CALCULATION OF RECOVERY CLEARANCE
U = DIALYSATE CONCENTRATIONV = DIALYSATE VOLUMEt = DIALYSIS TIMEP = MEAN PLASMA CONCENTRATION
![Page 13: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/13.jpg)
PLASMA VS. BLOOD CLEARANCE
![Page 14: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/14.jpg)
GOALS OF DIALYSIS DISCUSSION
DISCUSSION OF DIALYSIS CLEARANCEMECHANISTIC - RENKIN APPROACHEMPIRICAL
FICK EQUATIONRECOVERY CLEARANCE
EFFECTS OF DIALYSIS ON PHARMACOKINETICS
HEMODYNAMIC CHANGES DURING DIALYSISUSE OF KINETIC METHODS FOR ANALYSISPATHOPHYSIOLOGIC CONSEQUENCES
![Page 15: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/15.jpg)
DATA SOURCES FOR PK ANALYSIS
![Page 16: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/16.jpg)
KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA*
* From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.
![Page 17: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/17.jpg)
KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA*
* From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.
![Page 18: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/18.jpg)
FICK CLEARANCE EQUATION
AQ
ClQV
ClAQAQV
QVQAClA
A
V-AQ Cl
![Page 19: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/19.jpg)
NAPA IN RBC IS DIALYZED
* QEFF = [ (1 - Hct) + (RBC/P) (HCT) ] QMEAS
![Page 20: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/20.jpg)
TWO PROBLEMS WITH FIXED-PARAMETER MODEL*
* From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.
1. DURING DIALYSIS [A] AND [V] DROP MORE THAN EXPECTED FROM DRUG RECOVERY2. AFTER DIALYSIS CONCENTRATION REBOUND IS LESS THAN EXPECTED
![Page 21: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/21.jpg)
KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA*
* From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.
ClS• G
![Page 22: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/22.jpg)
REDUCTION IN CLS DURING AND AFTER HEMODIALYSIS*
* From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.
![Page 23: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/23.jpg)
GOALS OF DIALYSIS DISCUSSION
DISCUSSION OF DIALYSIS CLEARANCEMECHANISTIC - RENKIN APPROACHEMPIRICAL
FICK EQUATIONRECOVERY CLEARANCE
EFFECTS OF DIALYSIS ON PHARMACOKINETICS
HEMODYNAMIC CHANGES DURING DIALYSISUSE OF KINETIC METHODS FOR ANALYSISPATHOPHYSIOLOGIC CONSEQUENCES
![Page 24: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/24.jpg)
MULTICOMPARTMENTAL MODEL OF INULIN AND UREA KINETICS*
* From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.
![Page 25: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/25.jpg)
UREA () AND INULIN () KINETICS DURING AND AFTER HEMODIALYSIS*
* From Bowsher DJ, et al. J Lab Clin Med 1985;105:489-97.
INULINUREA
UREA
INULIN
![Page 26: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/26.jpg)
RENKIN EQUATION*
)e(1QCl P/Q
* From Renkin EM. Am J Physiol 1953;183:125-36.
Q = capillary blood flow
P = capillary permeability coefficient-surface area product (sometimes denoted P•S).
![Page 27: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/27.jpg)
RELATIONSHIP BETWEEN BLOOD FLOW (Q) AND CLI *
* From Bowsher DJ, et al. J Lab Clin Med 1985;105:489-97.
![Page 28: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/28.jpg)
UREA AND INULIN KINETICS DURING AND AFTER HEMODIALYSIS
* ESTIMATED AS C.O. - Q S
![Page 29: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/29.jpg)
RENIN-ANGIOTENSIN SYSTEM ACTIVATION DURING AND AFTER HEMODIALYSIS*
* From Bowsher DJ, et al. J Lab Clin Med 1985;105:489-97.
![Page 30: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/30.jpg)
DIFFERENT MICROCIRCULATORY ACTIONS OF ANGIOTENSIN II AND AVP*
* From Atkinson AJ Jr: The Pharmacologist 1989;31:229-34.
![Page 31: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/31.jpg)
EFFECT OF AVP ON P S*
* From Atkinson AJ Jr: The Pharmacologist 1989;31:229-34.
![Page 32: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/32.jpg)
CLINICAL CONSEQUENCES OF DIALYSIS-ASSOCIATED HEMODYNAMIC CHANGES
• PATHOGENEIC ROLE IN DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS
• IMPACT ON HEMODIALYSIS THERAPY OF DRUG TOXICITY
![Page 33: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/33.jpg)
PATHOGENESIS OF DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS
HEMODIALYSIS
PLASMA VOLUME CONTRACTION
UNMODULATED SYMPATHETIC ACTIVATION
PERIPHERAL VASOCONSTRICTION
DERECRUITMENT OF MUSCLE CAPILLARIES
IMPAIRED MUSCLE OXYGENATION
SKELETAL MUSCLE CRAMPS
X NaCl, MANNITOL
X PRAZOSINACE INHIBITOR +
![Page 34: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/34.jpg)
ACTIONS OF ANGIOTENSIN II & SYMPATHETIC NERVOUS SYSTEM
SYMPATHETIC NERVOUS SYSTEM
SYMPATHETIC NERVES
![Page 35: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/35.jpg)
ONLY SOME PATIENTS HAVE DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS*
* Sidhom OA, et al. Clin Pharmacol Ther 1994;56:445-51
![Page 36: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/36.jpg)
CLINICAL CONSEQUENCES OF DIALYSIS-ASSOCIATED HEMODYNAMIC CHANGES
• PATHOGENEIC ROLE IN DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS
• IMPACT ON HEMODIALYSIS THERAPY OF DRUG TOXICITY
![Page 37: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/37.jpg)
DIALYSIS CASE HISTORY
A 67 year-old woman became lethargic and confused and developed hypotension, renal insufficiency, junctional tachycardia and intraventricular conduction delay after ingesting an estimated 7gm of procainamide (PA). Plasma PA and NAPA concentrations were 57 μg/mL and 55 μg/mL, respectively.
![Page 38: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/38.jpg)
DIALYSIS CASE HISTORY (cont.)
Hemodialysis was performed for 4 hr. By the end of the second hour BP was maintained in the range of 110/80 mm Hg without vasopressor therapy. At the end of dialysis, the patient was alert and oriented although only 340 mg of PA and 470 mg of NAPA had been removed by this procedure.
![Page 39: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/39.jpg)
DIALYSIS CASE HISTORY (cont.)
Fifteen hours after dialysis, PA and NAPA levels were 9.2 μg/mL and 33 μg/mL, respectively. The patient had returned to normal sinus rhythm with QRS = 0.12 sec.
![Page 40: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/40.jpg)
KINETIC ANALYSIS OF HEMODIALYSIS FOR PROCAINAMIDE TOXICITY*
* From: Atkinson AJ Jr, et al. Clin Pharmacol Ther 1976;20:585-92.
![Page 41: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/41.jpg)
KINETIC ANALYSIS OF HEMODIALYSIS FOR PROCAINAMIDE TOXICITY*
50.4 L
GUT
60.4 L
340 mg 470 mg
68.3
12.6
45.854.2 16.1
DIALYSIS DIALYSIS
* From: Atkinson AJ Jr, et al. Clin Pharmacol Ther 1976;20:585-92.
PA NAPA
Clearances in mL/min
![Page 42: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/42.jpg)
WAS DIALYSIS EFFICACIOUS?
• DIALYSIS INCREASED DRUG CLEARANCE
PA – TWO FOLD
NAPA – 3.8 FOLD
• BUT 4 hr OF DIALYSIS REMOVED ONLY
340 mg PA470 mg NAPA
• HOWEVER, BLOOD LEVELS FELL SUBSTANTIALLY
PA: 25.7 µg/mL 15.5 µg/mL
NAPA: 47.0 µg/mL 35.5 µg/mL
AND PATIENT’S CONDITION STABILIZED
![Page 43: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/43.jpg)
PA & NAPA KINETICS IN TOXIC PATIENT
NORMAL PATIENT
PA NAPA PA NAPA
t1/2 (hr) 2.5 6.2 10.5 35.9
Vdβ (L/kg) 1.80 1.76 0.76 0.63
CLE (mL/min) 590 233 66.8 16.1
CLD (mL/min) 68.3 45.8
![Page 44: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/44.jpg)
ESTIMATION OF Vd
Question: Why did the patient appear to respond to hemodialysis when so little PA and NAPA were removed by this procedure?
![Page 45: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/45.jpg)
SEQUESTRATION OF DRUG IN SOMATIC TISSUES
83L
CLF
14L
CLS
7L
CLE
BIOPHASE
CLD
DIALYSIS
![Page 46: PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx](https://reader030.fdocuments.net/reader030/viewer/2022033106/56812bdb550346895d9048f6/html5/thumbnails/46.jpg)
EFFICACY OF EXTRACORPOREAL TREATMENT OF DRUG TOXICITY
• EFFICIENCY OF DRUG REMOVAL SOMETIMES SUFFICES TO AMELIORATE DRUG TOXICITY.
• ↓ INTERCOMPARTMENTAL CLEARANCE FROM SOMATIC TISSUES CAN CONTRIBUTE TO BENEFICIAL CLINICAL RESPONSE > EXTENT OF DRUG REMOVAL.