How is Carboplatin (carboplatin) dosing calculated in patients with varying degrees of impaired renal function (GFR)?

Carboplatin Dosing

Carboplatin should be dosed using the Calvert formula based on glomerular filtration rate (GFR) to achieve a target area under the curve (AUC), not by body surface area alone. 1, 2

The Calvert Formula

The standard dosing equation is: Total Dose (mg) = Target AUC (mg/mL·min) × [GFR (mL/min) + 25] 1, 3

• This formula calculates the total dose in mg, not mg/m², which is a critical distinction from traditional chemotherapy dosing 1, 2
• The formula was prospectively validated and accurately predicts carboplatin exposure across a wide range of renal function (GFR 33-136 mL/min) 3
• Carboplatin clearance is directly proportional to GFR because renal excretion is the major route of elimination 1, 4

Target AUC Selection

For previously treated patients: Target AUC of 4-6 mg/mL·min provides appropriate dosing, with AUC 5 mg/mL·min recommended as the standard target 3, 1

For previously untreated patients: Target AUC of 6-8 mg/mL·min is appropriate, with AUC 7 mg/mL·min recommended as the standard target 3

• Higher AUC values correlate with increased myelotoxicity: at AUC 4-5 mg/mL·min, 16% experience grade 3-4 thrombocytopenia versus 33% at AUC 6-7 mg/mL·min 1
• The target AUC must be adjusted for combination chemotherapy regimens, as the formula measures drug exposure, not toxicity 3

Critical GFR Caps and Adjustments

The GFR used in the Calvert formula should not exceed 125 mL/min 2

The maximum carboplatin dose should not exceed AUC (mg·min/mL) × 150 mL/min 2

• These caps prevent overdosing in patients with supranormal renal function 2
• For obese patients, dosing based on GFR (rather than capped BSA) is most reasonable because carboplatin clearance correlates with GFR, which correlates with BSA 2

Renal Impairment Dosing

For patients with baseline creatinine clearance below 60 mL/min who cannot use the Calvert formula, empiric BSA-based dosing with renal adjustment is an alternative 1:

• CrCl 41-59 mL/min: 250 mg/m² on day 1 1
• CrCl 16-40 mL/min: 200 mg/m² on day 1 1
• CrCl <15 mL/min: Insufficient data to recommend treatment 1

Patients with creatinine clearance below 60 mL/min are at increased risk of severe bone marrow suppression (approximately 25% incidence of severe leukopenia, neutropenia, or thrombocytopenia even with dose modifications) 1

Measuring GFR for Carboplatin Dosing

Direct measurement of GFR using radionuclide methods (⁵¹Cr-EDTA clearance) is the gold standard and should be used when precision is required due to carboplatin's narrow therapeutic index 3, 5

When direct measurement is unavailable:

• 24-hour urinary creatinine clearance is acceptable, though prone to collection errors 6
• Cockcroft-Gault equation shows the smallest bias (7.7 mL/min) and highest accuracy compared to measured GFR in oncology populations 5
• MDRD and CKD-EPI equations significantly overestimate GFR (bias 12.3 and 13.6 mL/min respectively), leading to carboplatin overdosing in 81-87% of patients 5

Critical pitfall: Using MDRD or CKD-EPI equations (which report GFR normalized to 1.73 m²) without back-calculating to absolute clearance will result in systematic dosing errors 6, 5

Geriatric Dosing Considerations

Formula dosing based on GFR estimates should always be used in elderly patients to provide predictable plasma carboplatin AUCs and minimize toxicity risk 1

• Elderly patients have age-related decline in renal function that may not be reflected in serum creatinine due to decreased muscle mass 7
• Never rely on serum creatinine alone to assess renal function in elderly patients when dosing carboplatin 7

Combination Therapy Example

For advanced ovarian cancer in combination with cyclophosphamide 1:

• Carboplatin: 300 mg/m² IV on day 1 every 4 weeks for 6 cycles (or use Calvert formula dosing)
• Cyclophosphamide: 600 mg/m² IV on day 1 every 4 weeks for 6 cycles
• Do not repeat courses until neutrophil count ≥2,000 and platelet count ≥100,000 1

Dose Adjustments for Toxicity

Based on nadir blood counts from the previous cycle 1:

• Platelets >100,000 AND neutrophils >2,000: Increase dose to 125% of prior dose
• Platelets 50,000-100,000 OR neutrophils 500-2,000: No adjustment
• Platelets <50,000 OR neutrophils <500: Reduce dose to 75% of prior dose

Do not escalate doses above 125% of the starting dose 1