# Presentation: 056439

## Effects of Renal Disease on Pharmacokinetics

**Juan J. L. Lertora, M.D., Ph.D.**
**Director **
**Clinical Pharmacology Program**
**Office of Clinical Research Training **
**and Medical Education**
**National Institutes of Health**
**Clinical Center**

## GOALS of Effects of Renal Disease on Pharmacokinetics Lecture

**   **
**Dose Adjustment in Patients with ****	****Renal Impairment**
**     ****Effect of Renal Disease on: **
**Renal Drug Elimination **
**            ****Hepatic Drug Metabolism **
**            ****Drug Distribution**
**            ****Drug Absorption**** **

## GOALS Of Effects of Renal Disease on PK Lecture 

***   ******DOSE ADJUSTMENT***** in Patients with Renal ****	****Impairment**
**    **
**	****Statement of the Problem**
**      ****	****How is renal function assessed?**
**      ****	****How is drug dose adjusted based on this ****	****assessment****?**

## PATHOPHYSIOLOGIC FACTORS NOT ACCOUNTED FOR IN DRUG DOSING*

*** Lesar TS, Briceland L, Stein DS. JAMA 1997;277:312-7.**

## Central Role of DRUG LABEL

**The *****DRUG LABEL***** is the primary source of drug prescribing information and is *****reviewed***** *****by the FDA***** as part of the drug approval process.**
**As such the drug label is *****a distillate***** *****of the***** *****entire drug development process.***
**    **

## INFORMATION CONTENT OF CURRENT DRUG LABELS*

| CORE INFORMATION
CATEGORY | Inclusion of Desirable Data Elements
MEAN (95% CI) |
| --- | --- |
| MECHANISM OF ACTION | 88%   (84% - 93%) |
| PHARMACODYNAMICS | 43%   (37% - 49%) |
| DRUG METABOLISM | 23%   (16% - 29%) |
| PHARMACOKINETICS | 42%   (35% - 49%) |
| DOSE ADJUSTMENT | 37%   (32% - 42%) |

*** Spyker DA, et al. Clin Pharmacol Ther 2000;67:196-200.**

## TIMING OF PK & PD STUDIES

## FDA GUIDANCE FOR INDUSTRY

***PHARMACOKINETICS IN PATIENTS WITH***** *****IMPAIRED RENAL FUNCTION***** – Study Design, Data Analysis, and Impact on Dosing and Labeling**

**AVAILABLE AT: http://www.fda.gov/cder/guidance/index.htm**

## GOALS of Renal Disease Effects Lecture

**   *****DOSE ADJUSTMENT***** in Patients with Renal ****	****Impairment**
**    ****-  Statement of the Problem**
**    ****-  How is renal function assessed?**
**    ****-  How is drug dose adjusted based on this ****	****assessment?**
**	**

## ELIMINATION by Different Routes

**MEASUREMENTS**       **RENAL**** ****  ****HEPATIC    DIALYSIS**
**Blood Flow    ****	****        ****  ****	****         ****+*****            +*              +**
**Afferent Concentration      ****+ ****             +                +**
**Efferent Concentration       ****0****                 0                   ****+**
**Eliminated Drug     ****           ****+****              ****0                   ****+ **
**	****	****	**
********not actually measured in routine PK studies***

## RENAL CLEARANCE EQUATION

**U  =  URINE CONCENTRATION**
**V  =  URINE VOLUME**
**P  =  PLASMA CONCENTRATION**

## CLEARANCE TECHNIQUES FOR ASSESSING RENAL FUNCTION

**   **_**GLOMERULAR FILTRATION**_**:**
**        ****Normal:          120 – 130 mL/min/1.73 m****2**
**            *****CLEARANCE MARKERS*****:****	**
**	****	****	****         ****Inulin**
**	****	****	****      ****Creatinine**
**	**** ****	****                 ****125****I-Iothalamate**
**    **_**RENAL BLOOD FLOW**_**:**
**          ****Normal:****	****	****♂  1,209 ± 256  ****mL/min/1.73 m****2**
**	****	****	****	****♀     ****982  ± 184 ****mL/min/1.73 m****2**
**	*****CLEARANCE MARKER*****:            **
**	****	****	****     ****Para-Aminohippuric Acid**

## GOALS of Renal Disease Effects Lecture

**   *****DOSE ADJUSTMENT***** in Patients with Renal ****	****Impairment**
**    **
**    ****-****  ****How is renal function assessed?**
**        ****(*****Usually estimated from the Cockcroft and Gault ******	******Equation if renal function is stable)***
**       **

**	**

## STEADY STATE CONCENTRATION

_**Continuous Infusion**_**:**

_**Intermittent Dosing**_**:**

## ADDITIVITY OF CLEARANCES

**CL****R****  = RENAL CLEARANCE**
**CL****NR**** = NON-RENAL CLEARANCE**

## CL R VS. CL Cr IS LINEAR*

**IMPLIES NET TUBULAR SECRETION**

**CL ****R ****VS. CL ****Cr**** IS LINEAR***

*** From: Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.**

**CL****R**** = ****α**** CL****Cr**

## DETTLI Approach*

**NEED:    1. CL****E ****IN NORMAL SUBJECTS**
**               ****2. NORMAL % RENAL EXCRETION**

*** Dettli L. Med Clin North Am 1974;58:977-85**

## NOMOGRAM FOR CIMETIDINE DOSING*

***From: Atkinson AJ Jr, Craig RM. Therapy of peptic ulcer disease.**

## Key ASSUMPTIONS of Dettli Method

-   **CL****NR**** remains *****CONSTANT***** when renal**
**    ****function is impaired.**
**  ****CL****R**** declines in *****LINEAR FASHION***** with CL****CR**

## CIMETIDINE Case History

-   **A 67-year-old veteran had been ****functionally**** ****anephric****, requiring outpatient ****hemodialysis**** for several years.  He was hospitalized for revision of his arteriovenous shunt and postoperatively complained of symptoms of ****gastroesophageal reflux****.  This complaint prompted institution of ****cimetidine**** therapy in a dose of 300 mg every 6 hours. **

## CIMETIDINE Case History (cont.)

_***Rationale***__** for Prescribed Cimetidine Dose**_**:**
***At that time*****, 600 mg every 6 hours was the ****usual cimetidine dose**** for patients with normal renal function and the *****Physician’s***** *****Desk Reference***** recommended *****halving***** *****the***** *****cimetidine dose***** *****for patients “with***** *****creatinine clearance less than 30 cc/min”.***

## CIMETIDINE Case History (cont.)

**Three days later the patient was noted to be ****confused****.  The nephrology service entertained the diagnosis of *****dialysis dementia***** and informed the family that hemodialysis might be discontinued.  The teaching attending suggested that *****cimetidine be discontinued first*****.  Two days later the patient was ****alert**** and was discharged from the hospital to resume outpatient hemodialysis therapy.**

## LABELING FOR CIMETIDINE*

-   _***DOSAGE ADJUSTMENT***_
**    ****1/2 normal dose if CL****Cr**** < 30 mL/min**
**  **_**PHARMACOKINETICS**_
**    ****Following I.V. of I.M. administration in *****normal *****	*****subjects*****,**
**    ****~**** 75% of drug is recovered from the urine**** as ****	*****parent compound*****.**

*** Physician’s Desk Reference. 58****th**** edition, 2004.**** **

## NOMOGRAM FOR CIMETIDINE DOSING*

***From: Atkinson AJ Jr, Craig RM. Therapy of peptic ulcer disease.**

## DOSE ADJUSTMENT OPTIONS FOR PATIENTS WITH RENAL IMPAIRMENT

-   **MAINTAIN USUAL DOSING INTERVAL**** ****BUT**
**   *****REDUCE DOSE***** ****IN PROPORTION TO**** ↓CL****E**** **
**  ****MAINTAIN USUAL DOSE BUT**** *****INCREASE***
**   *****DOSING INTERVAL***** ****IN**** ****PROPORTION**** TO**** ↓CL****E**** **
**  *****ADJUST BOTH***** ****DOSE AND DOSING INTERVAL**

## ELIMINATION HALF-LIFE

## GOALS of Renal Disease Effects Lecture

**   ****EFFECT OF RENAL DISEASE ON RENAL**
**     ****DRUG ELIMINATION**
**    ****-  *****MECHANISMS***** ****OF RENAL DRUG ELIMINATION**** **
**    ****-  ****CONCEPT OF**** *****RESTRICTIVE ******VS.***
**        *****NONRESTRICTIVE***** ****ELIMINATION****  **

## MECHANISMS of Renal Drug Elimination

**	****Glomerular Filtration**
**	****Renal Tubular Secretion**
**	****Reabsorption by Non-Ionic Diffusion**
**	**
**	****Active Reabsorption**

## MECHANISMS OF RENAL ELIMINATION

**GLOMERULAR FILTRATION**
**  ****Affects all drugs and metabolites of ****appropriate molecular size****.**
** *****Influenced***** by ****protein binding**
**	****Drug Filtration Rate  =  GFR x f****u**** x [Drug]**
**	****(f****u ****= free fraction)**
**RENAL TUBULAR SECRETION**
**  *****Not influenced***** by protein binding**
**  ****May be affected by *****other drugs*****, etc.**
***    ******EXAMPLES:***
**     ****Active Drugs:****	****ACIDS**** – Penicillin**
**	****	****	****BASES**** – Procainamide**
**     ****Metabolites:  ****	****Glucuronides, Hippurates, etc. **

## RESTRICTIVE VS. NONRESTRICTIVE ELIMINATION

_**RESTRICTIVE**_**:**
**Clearance *****DEPENDS***** on Protein Binding.****   **
_**KIDNEY**_**:  Drug Filtration Rate = f****U****  ********  GFR **
_**LIVER**_**:     CL = f****U****  ********  Cl****int**
_**NONRESTRICTIVE**_**:**
**Clearance *****INDEPENDENT***** of Protein Binding**
_**KIDNEY**_**:  CL = Q  (renal blood flow) **

***EXAMPLE*****:****  ****PARA-AMINOHIPPURATE CLEARANCE**
**                       ****MEASURES RENAL BLOOD FLOW.**

## INTRINSIC CLEARANCE

***INTRINSIC CLEARANCE***** ****IS THE**** ****ELIMINATION CLEARANCE THAT**** *****WOULD***** *****BE OBSERVED***** IN THE**** *****ABSENCE OF ANY PROTEIN****** ******BINDING***** *****RESTRICTIONS*****.**

## RESTRICTIVE VS. NONRESTRICTIVE ELIMINATION

_**RESTRICTIVE**_**:**
**Clearance *****DEPENDS***** on Protein Binding**
_**KIDNEY**_**:  Drug Filtration Rate = f****U****  ********  GFR **
_**LIVER**_**:     CL = f****U****  ********  Cl****int**
_**NONRESTRICTIVE**_**:**
**Clearance *****INDEPENDENT***** of Protein Binding**
_**KIDNEY**_**: CL = Q  (renal blood flow)**
_**LIVER**_**:    CL = Q  (hepatic blood flow)**

## Renal REABSORPTION Mechanisms

**REABSORPTION BY NON-IONIC DIFFUSION**
**  ****Affects ****weak acids**** and ****weak bases****.**
**  ****Only important if excretion of *****free drug***** is major ****	****elimination pathway.**
***    ******EXAMPLES:***
**	****Weak Acids:****	****	****PHENOBARBITAL**
**	****Weak Bases:****	****	****QUINIDINE**
**ACTIVE REABSORPTION**
**   ****Affects ****ions****, not proved for other drugs. **
***    ******EXAMPLES:***
**	****Halides:****	****	**** FLUORIDE, BROMIDE**
**	****Alkaline Metals:         LITHIUM**

## RENAL EXCRETION OF DRUGS 

**   ****Regardless of mechanism, *****renal drug elimination*****     ****	*****declines in parallel with decreases in GFR*****.**
**   ****Therefore, ****CL****Cr**** ****can be used to assess impact of ****	****renal impairment on renal excretion of drugs.**

_**INTACT NEPHRON HYPOTHESIS**_**:  Provides a basis for dose adjustment when renal excretion of drug is impaired.**
** **

**WHAT ABOUT OTHER EXCRETION ROUTES?**

## GOALS of Renal Disease Effects Lecture

**   ****EFFECT OF RENAL DISEASE ON**** *****DRUG***
**     *****METABOLISM***
**	**

## PHASE I AND PHASE II METABOLIC REACTIONS 

***PHASE I AND PHASE II***** ****METABOLIC REACTIONS**** **

**PHASE II**
**GLUCURONIDE**
**CONJUGATION**

## Effect of Renal Disease on PHASE I DRUG METABOLISM

##      Effect of Renal Disease on PHASE I DRUG METABOLISM

_**HYDROLYSIS**_
**    ****Plasma esterase                 *****Slowed***
***        ******Example:  *****Procaine**
**    ****Plasma peptidase               *****Normal***
***        ******Example:  *****Angiotensin**
***    *****Tissue peptidase                *****Slowed***
***        ******Example:  *****Insulin**

## 	Effect of Renal Disease on  PHASE II DRUG METABOLISM

**  **_**GLUCURONIDATION**_**              *****Normal***
**      *****Example:*****  Hydrocortisone**
**  **_**ACETYLATION**_**                     *****Slowed***
***      ******Example:  *****Procainamide**
**  **_**GLYCINE CONJUGATION**_**     *****Slowed***
***      ******Example:  p-*****Aminosalicylic acid**

##       Effect of Renal Disease on  PHASE II DRUG METABOLISM

**    ****O-****METHYLATION****                *****Normal***
***       ******Example:  *****Methyldopa**
**    ****SULFATE CONJUGATION****    *****Normal***
***       ******Example:  *****Acetaminophen**

## GOALS of Renal Disease Effects Lecture 

**        ****EFFECT OF RENAL DISEASE ON**** *****DRUG***
**        *****METABOLISM***
**      *****EXAMPLES:***
**	****	****PROCAINAMIDE - ****Acetylation**
**	****	****PHENYTOIN - ****Hydroxylation****	**

## PROCAINAMIDE ACETYLATION 

**NAT2: FAST VS. SLOW**

## Procainamide Kinetics in DIALYSIS PATIENTS*

*** From: Gibson TP. Kidney Int 1977;12:422-9.**

-    	        			       ***FUNCTIONALLY***** **
- 	       ***NORMALS*****      *****ANEPHRIC****** PATIENTS***
**	****   ****	****     ****Fast      Slow        Fast       Slow**
**T****1/2****   (hr)   ****	****       2.6****	**** 3.5****	****        12.2        17.0**
**CL****E****  (L/kg)****	****       809****	**** 600****	****        118    ****	****     94****	**
**  ****CL****R   ****(L/kg)****        426       357              0           0 **
**  ****CL****NR**** (L/kg)****       383****	**** 243 ****	****        118****	****     94**
**V****d(ss)****	****(L/kg)       1.95****	**** 1.93           1.41         1.93**

## Procainamide Dosing Nomogram(FAST ACETYLATORS)

## PHENYTOIN HYDROXYLATION BY P450

**   ****CYP2C9: Major, CYP2C19: Minor**

## Effect of Renal Disease onPHENYTOIN PROTEIN BINDING

## PHENYTOIN KINETICS IN DIALYSIS PATIENTS*

*** ****From: Odar-Cederlöf I, Borgå O: Eur J Clin Pharmacol 1974;7:31-7.**

-    	      	  **NORMALS     UREMIC PATIENTS**
**	****	****     ****(N = 4)****	**** ****	****         (N = 4)**
**% UNBOUND (f****u****)       12%****	****   ****	****	**** 26%**
**CL****H****	****	**** ****	****    2.46 L/hr****	****	****       7.63 L/hr**
**CL****int****	****	****	****    20.3 L/hr****	****	****       29.9 L/hr **

**CL****H**** = f****u****  ********  Cl****int ****,    So: Cl****int**** = CL****H****/f****u**

**NS**

## Effect of PROTEIN BINDING Changes on Phenytoin Plasma Concentration

**   **

**PHENYTOIN > 98% ELIMINATED BY HEPATIC METABOLISM, SO CL****E ****= CL****H**

## FREE AND TOTAL PHENYTOIN LEVELS(DOSE = 300 MG/DAY)

**CL****H     ****↑****  ****CL****INT**** =**

## THERAPEUTIC RANGE of Phenytoin Levels in Dialysis Patients 

***THERAPEUTIC RANGE***** of ****Phenytoin**** Levels in *****Dialysis Patients***** **

**           ****THERAPEUTIC RANGE FOR DIALYSIS PTS****:**
**          ****Based on “Total Levels”:     5 - 10 ********g/mL**
**          ****Based on “Free Levels”:      0.8 - 1.6 ********g/mL**

## PRIMARY DIFFICULTIES IN PHENYTOIN DOSE ADJUSTMENT

**  *****NONLINEAR***** ****Elimination Kinetics**
**  *****VARIATION ******IN****** BINDING***** ****to Plasma Proteins**** **

## NONCANCER DRUGS CAUSING ADR’S*

***PHENYTOIN*****	****	****	****CARBAMAZEPINE**
**PREDNISONE****	****	****	****CODEINE**
**DIGOXIN****	****	****	****	****LITHIUM**
**AMIODARONE****	****	****	****THEOPHYLLINE**
**ASPIRIN****	****	****	****	****DESIPRAMINE**
**CO-TRIMOXAZOLE****	****	****DEXAMETHASONE**
**PENTAMIDINE****	****	****	****GENTAMICIN**

***   1988 NMH DATA (CLIN PHARMACOL THER 1996;60:363-7)**

## GOALS of Renal Disease Effects Lecture 

**  ****EFFECT OF RENAL DISEASE ON DRUG **
**    ****DISTRIBUTION**
**	****-   ****PLASMA PROTEIN BINDING**
**	****	*****EXAMPLE*****:  ****PHENYTOIN**
**	****-  TISSUE BINDING**
**	****	*****EXAMPLE*****:  ****DIGOXIN**

## Effect of Renal Disease onBINDING TO PLASMA PROTEINS*

***  ******BASIC ******OR****** NEUTRAL*****	****          ****NORMAL ****OR**
***  ******DRUGS*****:****	****	****	****          ****SLIGHTLY REDUCED**
*** ******ACIDIC DRUGS*****:****	****      ****	****REDUCED FOR MOST**

*** From: Reidenberg MM, Drayer DE: Clin Pharmacokinet**
**   ****1984;9(Suppl. 1):18-26.**

## Effect of Binding Changes on APPARENT DISTRIBUTION VOLUME*

*** Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.**

**Φ**** = TISSUE/PLASMA PARTITION RATIO**
**f****u**** = FRACTION NOT BOUND TO PLASMA**
**       ****PROTEINS**** **

**FOR PHENYTOIN: ****Φ**** = 10.4**

## PHENYTOIN DISTRIBUTION IN DIALYSIS PATIENTS*

*** ****From: Odar-Cederlöf I, Borgå O: Eur J Clin Pharmacol 1974;7:31-7.**

-    	      	  **NORMALS     UREMIC PATIENTS**
**% UNBOUND (f****u****)       12%****†****	****   ****	****	**** 26%**
**V****d(AREA)****	****              0.64 L/kg****	****                 1.40 L/kg**

** **

**† ****USUAL VALUE IN NORMAL SUBJECTS ~ 9%**

## GOALS OF RENAL DISEASE EFFECTS LECTURE 

**  ****EFFECT OF RENAL DISEASE ON DRUG **
**    ****DISTRIBUTION**
**	****-   PLASMA PROTEIN BINDING**
**	****	*****EXAMPLE*****:  ****PHENYTOIN**
**	****-  TISSUE BINDING**
**	****	*****EXAMPLE*****:  ****DIGOXIN**

## IMPAIRED RENAL FUNCTION REDUCES DIGOXIN DISTRIBUTION VOLUME*

*** Sheiner LB, et al. J Pharmacokinet Biopharm 1977;5:445-79.**

## EFFECT OF  RENAL DISEASE ON BIOAVAILABILITY

_***UNCHANGED***__** BIOAVAILABILITY**_**:**
***	******	******	******	*****CIMETIDINE**
**	****	****	****	****DIGOXIN**
_***DECREASED***__** BIOAVAILABILITY**_**:****	****	****	****	****	****	****	****D-XYLOSE**
**	****	****	****	****FUROSEMIDE**
_***INCREASED***__** BIOAVAILABILITY**_**:**
**	****	*****	******	*****PROPRANOLOL****	****	****	****	****	****	****DEXTROPROPOXYPHENE**

## CRITERIA FOR NORMAL ABSORPTIONOF 25 GRAM D-XYLOSE DOSE

**5-hr URINE RECOVERY****	****       > 4 g**
**[SERUM] 1 hr AFTER DOSE       ******** 0.2 mg/mL**
**% DOSE ABSORBED****	****	****       > 42%**
**k****a****	****	****	****	****	****          ****> 0.37 hr****-1**

## KINETIC MODEL USED TO ANALYZE D-XYLOSE ABSORPTION*

*** From Worwag EM, et al. Clin Pharmacol Ther 1987;41:351-7.**

## CALCULATION OF BIOAVAILABILITY FROM FIRST-ORDER ABSORPTION MODEL

## EFFECT OF  RENAL DISEASE ON D-XYLOSE ABSORPTION*

**PATIENT ****	****      k****a****	****	****      k****o****	****	**** % DOSE**
**GROUP****	****    (hr ****-1****)****	****    (hr ****-1****)****	****ABSORBED****	**
**NORMALS****	****1.03 ± 0.33****	****0.49 ± 0.35****	****69.4 ± 13.6****	**
**MODERATE****	****0.64 ± 0.28****	****0.19 ± 0.15****	****77.4 ± 14.8****	**
**DIALYSIS****	****0.56 ± 0.42****	****0.67 ± 0.61****	****48.6 ± 13.3**

*** From: Worwag EM et al. Clin Pharmacol Ther 1987;41:351-7.**

## FUROSEMIDE 

## FUROSEMIDE ABSORPTION WITH ADVANCED RENAL IMPAIRMENT*

*** From Huang CM, et al. Clin Pharmacol Ther 1974;16:659-66.**

## RELATIONSHIP BETWEEN FUROSEMIDE ka AND F*

*** From Huang CM, et al. Clin Pharmacol Ther 1974;16:659-66.**

## FACTORS AFFECTING RATE ANDEXTENT OF  DRUG ABSORPTION

## BIOPHARMACEUTIC CLASSIFICATION OF FUROSEMIDE* 

*** ****From: Lenneräs. J Pharm Pharmacol 1997;49:627-38.**

## BIOPHARMACEUTIC DRUG CLASSIFICATIONOF FUROSEMIDE * 

**CLASS IV:**
**   ****LOW SOLUBILITY-LOW PERMEABILITY**
**  *****in vitro***** – *****in vivo***** correlation poor**
**  ****good bioavailability not expected**

*** ****From: Lenneräs, et al. Pharm Res 1995;12:S396 **

## TORSEMIDE vs. FUROSEMIDE in Congestive Heart Failure 

***    From: Vargo D, et al. Clin Pharmacol Ther 1995;57:601-9.**

|  | TORSEMIDE | FUROSEMIDE |
| --- | --- | --- |
|  Bioavailability in CHF * |  |  |
|                    F | 89.0 ± 8.9% | 71.8 ± 29.8% |
|                  TMAX | 1.1 ± 0.9 hr | 2.4 ± 2.5 hr |

## TORSEMIDE vs. FUROSEMIDE in Congestive Heart Failure

***    From: Vargo D, et al. Clin Pharmacol Ther 1995;57:601-9.**
****  From: Murray MD, et al. Am J Med 2001;111:513-20.**

|  | TORSEMIDE | FUROSEMIDE |
| --- | --- | --- |
| Bioavailability in CHF * |  |  |
|                  F | 89.0 ± 8.9% | 71.8 ± 29.8% |
|                TMAX | 1.1 ± 0.9 hr | 2.4 ± 2.5 hr |
| 1-Year CHF Therapy** |  |  |
|    CHF Readmit   p<0.01 | 17% | 32% |
|    Dose ↑             p<0.01 | 27% | 45% |
|    Dose ↓             p=0.06 | 32% | 22% |

## CURRENT REGULATORY PARADOX

**   *****Detailed guidances***** for studying kinetics of drug**
**         ****elimination in patients with impaired renal ****	****and hepatic function.**
**   *****Assumption***** that bioavailability studies in     ****	*****normal subjects *****reflect drug absorption in ****	****patients.**** **
**     **

## FDA GUIDANCE FOR INDUSTRY

***PHARMACOKINETICS IN PATIENTS WITH***** *****IMPAIRED RENAL FUNCTION***** – Study Design, Data Analysis, and Impact on Dosing and Labeling**

**AVAILABLE AT: http://www.fda.gov/cder/guidance/index.htm**

## BASIC “FULL” STUDY DESIGN

## 3-COMPARTMENT MAMMILLARY MODEL OF NAPA PK*

*** Strong JM, et al. J Pharmacokinet Biopharm 1973;3: 223-5**

##  NAPA PLASMA LEVELS IN A FUNCTIONALLY ANEPHRIC PATIENT*

*** From Stec, et al.  Clin Pharmacol Ther 1979;26:618-28****.**

## NAPA ELIMINATION HALF LIFE IN FUNCTIONALLY ANEPHRIC PATIENTS

**HEALTHY SUBJECTS****:****	****           ****	****                6.2 hr**
***PREDICTED***** ****for DIALYSIS PATIENTS****:       42.8 hr ***
***MEASURED***** ****in DIALYSIS PATIENTS****:         41.9 hr ***

***  See Study Problem at end of Chapter 5.**

## NOMOGRAM FOR NAPA DOSING