2.3. Covariate analysis

Following structural model development, the influence of patient‐specific factors for variability in PK parameters were evaluated. Assessed covariates included body weight (BW), body surface area (BSA), fat free mass (FFM), age and renal function. These continuous covariates were evaluated using both a linear function and a power function. To implement body size descriptors on PK parameters, standard allometric scaling was applied, with p fixed at 0.75 (BW, FFM) or 1 (BSA) for clearances, and 1 for distribution volumes (BW, BSA, FFM).¹⁰

Renal function was evaluated as a covariate, since clofarabine is partly eliminated renally.¹ As creatinine levels were not measured daily, the most recent values of creatinine prior to infusion (maximum 10 days) were used. Subsequently, eGFR was calculated using the Cockcroft–Gault equation, which takes age into account.¹¹ eGFR for patients below the age of 17 years for women and 14 years for men was calculated using the Schwartz equation.¹² eGFR was capped to a maximum of 8.4 L/h/1.73 m² (140 mL/min/1.73 m²) and was assumed to increase to this level from birth until the age of 1.5 years, starting at 2.1 L/h/1.73 m² (35 mL/min/1.73 m²) (25% of maximum value). The absolute eGFR (in L/h) was standardized to 70 kg as shown in the equation. Relative renal function (RF) was normalized to a standard eGFR (eGFR _STD) of 6 L/h (100 mL/min):

where eGFR is the absolute estimated glomerular filtration rate in L/h, BW is body weight in kg and eGFR _STD is a standard eGFR (6 L/h was used in this model).

RF was included in the model, using a linear independent combination of renal and non‐renal CL parameters:

where CL _overall is the overall population value of parameter for clearance (CL). CL _non‐renal is non‐renal CL and CL _renal is renal CL.^{13, 14}

Because the dataset contained several infants, the effect of maturation on CL was implemented using the method described by Rhodin et al.¹⁵ They showed that maturation of renal clearance across the entire paediatric population was well described using postmenstrual age (PMA) with a sigmoidal Hill equation. The TM₅₀, the PMA at which clearance is 50% of the mature value, was estimated at 55.4 weeks and the Hill coefficient describing the slope of the sigmoidal curve at 3.33.¹⁵ For our population, exact PMA was not known, so the PMA was estimated using age in weeks plus mean gestational age (40 weeks):

The Hill coefficient and TM₅₀ were fixed to 3.92 and 54.2 weeks, respectively, according to published models.¹⁶