PK 10: Urinary PK

Question 1

When would you adjust dosing in patients with renal impairment (~GFR < 60 mL/min)?

Answer 1

when fe > 0.5

• for cases where there is limited/no information to guide dosing in renal impairment

exception 1: narrow therapeutic index drugs

• therapeutic concentrations are close or overlap with those that elicit toxic responses
• dosing adjustments may be considered for drugs with fe ≤ 0.5
• adjustment should be guided by biomarker/patient drug concentrations

exception 2: parent drug is metabolized into active (or toxic) metabolites that are renally cleared

Question 2

What are the 3 ways dosing in patients with renal impairment can be adjusted (for drugs that are administered chronically)?

Answer 2

• change dose
• change frequency
• change dose and frequency

Question 3

How can we defined fe using urinary excretion data?

Answer 3

• collect urine over several intervals following a single IV administration
• for each collection interval, compute the amount present in the urine (urine volume x urine concentration)
• compute cumulative amount excreted across intervals

Question 4

What does a plateau in a cumulative amount excreted in urine vs. time plot indicate?

Answer 4

indicates the study period was long enough to appropriately determine the total amount excreted in the urine (Ae0-∞)

(complete urinary drug collection)

Question 5

How are PK parameters (k and fe) derived from urinary excretion data?

Answer 5

using a similar approach to a 1-compartment IV bolus model

• k: –slope
• fe: ke/k
• intercept = rate0h = ke x A0
• applicability: urine collections following IV bolus dosing only
• assumption: systemic drug PK can be described using a 1-compartment mode

Question 6

How are systemic drug parameters (related to plasma) such as CL and V defined using urinary excretion data?

Answer 6

they cannot be defined using urinary excretion data alone

Question 7

Differentiate urinary excretion patterns for drugs that are predominantly excreted via (1) glomerular filtration, (2) active secretion, or (3) both.

Answer 7

predominant processes mediating urinary drug elimination can be identified by evaluating the relationship between urinary excretion rates and systemic drug concentrations

• CLR represents slope of the line between urinary drug excretion vs. plasma concentration data
• assessing linearity of the slope determines whether filtration vs. active secretion (or both) are responsible for renal drug elimination, and indicates whether renal drug excretion follows linear vs. non-linear PK
• filtration only: linear
• active secretion only: upside-down curve that plateaus
• filtration and active secretion: upside-down curve that continues

Question 8

What are some issues associated with obtaining urinary PK data?

Answer 8

• frequent collection intervals required
• accurate urine volumes needed
• requires a highly specific assay
• missed urinary collections
• incomplete voiding of bladder