Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath®) in patients with chronic lymphocytic leukaemia and its link to treatment response

Aims: To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). Methods: Nonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. Results: Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where V_max (μg h^-1) was [1020 × (WBC count/10 × 10⁹ l^-1)^0.194], K_m was 338 μg l^-1, V₁ was 11.3 l, Q was 1.05 l h^-1 and V₂ was 41.5 l. Intersubject variability (ISV) in V_max, K_m, V₁ and V₂ was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for E _max, 306 μg l^-1 for EC₅₀, 1.56 × 10⁹ cells l^-1 h^-1 for K_in and 0.029 per h for K_out. The probability of achieving a complete or partial response was ≥50% when the maximal trough concentration exceeded 13.2 μg ml^-1 or when AUC_0-τ exceeded 484 μg h^-1 ml^-1. Conclusions: Alemtuzumab displayed time- and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.