Final L2 - PK in Renal disease

Question 1

Ideal marker of GFR

Answer 1

Standard measure of kidney function: GFR
Freely filtered, no clearance due to tubular secretion or reabsorption
Not metabolized by renal tissues
No effect on renal function

Question 2

Assessment of kidney function

Answer 2

Measured GFR is the gold standard
-Insulin, sinistrin, iohexol, iothalamate, and radiolabeled markers
-Cystatin C
Measured ClCr based on measured urinary clearance (urine collection)
Estimated ClCr or eGFr based on SeCr is widely used clinically

Question 3

CG

Answer 3

Estimates creatinine clearance, mL/min

Question 4

CKD-EPI

Answer 4

Estimates GFR, mL/min/1.72m^2

Question 5

Estimation of renal function

Answer 5

Use of eGFR is accepted as the most reliable means to determine eGFr and stage patients with CKD
-CKD-EPI equation methods
-eGFR widely reported in clinical practice

FDA guidance
-eGFR corrected to BSA and reported as mL/min for use in drug dosing
-CG ClCr with correction (IBW or AdjBW) in overweight and obese patients
-Will likely suggest eGFR in future and may even provide incentives to manufacturers

Question 6

Limitations in renal function

Answer 6

SeCr is generated from muscle mass and diet
-Amputees, body builders, vegan diet, etc. may be impacted
Tubular secretion of SeCr
-Overestimation of GFR, esp at low Clcr
-SeCR must be stable

Question 7

Bottom line for Estimation of Renal Function

Answer 7

One size fits all does not work
-Do not blindly use one estimate

Perform two estimates of renal function
-Units should correspond…ClCr gives mL/min; eGFR gives mL/min/1.73m2
-If estimates are different selection of dose should be targeted toward risk-benefit in individual patient

TDM and/or conservative dose if narrow therapeutic index drug

Aggressive for wide therapeutic index drug (esp when therapeutic failure justifies)

Actual measurement of Crcl (timed urine collection) may be necessary in certain clinical solutions

Question 8

Chronic Kidney disease

Answer 8

Characterized by kidney damage

Urine albumin-creatine ration >30mg/g

GFR <60mL/min for >3 months
Why so important to discuss
-Age-related reductions in renal function
-CKD medications
-Concomitant disorders

Question 9

CKD: ADME

Answer 9

Physiologic and biochemical changes associated with CKD may necessitate dose/regimen changes
Individualized dosing regimens will likely by necessary

Question 10

CKD: Pk changes absorption

Answer 10

No qualitative information to suggest any systemic changes
-D-xylose (marker of small intestinal absorption) absorption slowed
Potential impact of kidney disease
-Reduced absorption and gastric emptying due to diabetic gastropathy, uremic neuropathy, and uremic neuropathy
-Reduced bioavailability due to gut wall edema: furosemide
-Reduced due to drug interactions
Due to increased gastric pH
Formation of insoluble salts or chelates (e.g. FQ antibiotics + divalent cations)

Maybe reduced due to changes increased gastric pH (alter ionization and absorption of weakly basic drugs)