Renal Impairment (RI) studies
When is an RI study required?
- Fraction excreted unchanged in urine (fe) >30% (FDA). EMA has no fixed cutoff but recommends a study when RI is likely to significantly alter PK.
- Even drugs primarily cleared non-renally should consider a severe RI study – impaired renal function can alter absorption, protein binding, distribution, and hepatic/gut metabolism and transport.
- Almost all small molecules require RI studies.
- Biologics <69 kDa: generally required.
- mAbs (>69 kDa): generally not required.
Classification of renal function
GFR should be expressed as mL/min (absolute GFR). If a formula providing BSA-normalized GFR (mL/min/1.73 m2) has been used, recalculate to absolute GFR in mL/min in each individual. Preferably use exogenous markers (iohexol, inulin) or eGFR; avoid Cockcroft-Gault.
| RI severity | GFR (mL/min) |
|---|---|
| Normal | > 90 |
| Mild | 60–90 |
| Moderate | 30–60 |
| Severe (differs between FDA and EMA) | < 30, not requiring dialysis (EMA) |
| ESRD (differs between FDA and EMA) | < 15, requiring dialysis |
Study design
- Full design: All RI groups (normal, mild, moderate, severe, ESRD).
- Reduced design: Only normal, severe, and ESRD (skipping mild and moderate). If no PK difference between severe/ESRD and normal, no further study needed.
- Adaptive/staggered design: Start with one severity group + matched controls; extend based on results.
- 6–8 subjects in each RI group. This gives 80% power to detect ±40% change in exposure.
- Subjects are otherwise healthy (“HV”), apart from the RI.
- For safety reasons, the dose given to moderately/severely impaired groups may be lower.
TipPractical tips
- Measure unbound drug if the drug has high or nonlinear plasma protein binding – uremia alters protein binding.
- Include a PD marker when possible: if PK changes but PD does not, dose adjustment may be unnecessary.
- Measure active metabolites: they may accumulate in RI and drive the dose adjustment recommendation.